Publications

Double emulsions (DEs) are hierarchical nested-droplet systems that can compartmentalize hydrophilic and lipophilic compounds within two coupled liquid-liquid interfaces. Their performance is governed by interfacial composition, transport across the intermediate phase, osmotic coupling, and baseline instability pathways. Consequently, a structural change observed after exposure to a chemical, biochemical, or physical cue does not, by itself, demonstrate deliberately designed stimuli-responsiveness. This review critically examines double-emulsion systems in which a responsive motif, a phase transition, or a switchable interfacial component is intentionally incorporated to produce a measurable structural, interfacial, or transport response under a defined stimulus. Particular attention is given to water-in-oil-in-water and oil-inwater-in-oil architectures. Baseline instability mechanisms and preparation routes are first discussed as determinants of droplet architecture, barrier properties, and response reproducibility. Representative systems are then assessed according to the applied stimulus, the location of the responsive element, the immediate physicochemical mechanism, the resulting structural or transport response, and the evidence required to distinguish designed triggering from non-specific destabilization. The review further distinguishes liquid DEs intended to remain compartmentalized during use from DEtemplated carriers, for which the double emulsion serves primarily as a fabrication intermediate. Across the available evidence, robust stimuli-responsive behavior requires the simultaneous control of baseline stability, osmotic balance, interfacial mechanics, barrier-phase transport, and stimulus exposure conditions. Future progress will depend on standardized characterization methods, quantitative stimulus-response assays, and formulation strategies compatible with reproducible manufacturing and application-relevant constraints.

Osteoarthritis (OA) remains a major cause of disability worldwide; however, current non-surgical treatments offer transient symptom relief without altering disease course. This leaves a therapeutic gap for patients with early-to-moderate disease who are not candidates for surgery but continue to experience pain and functional limitation. Intra-articular interventions such as nonsteroidal anti-inflammatory drugs, hyaluronic acid, and platelet-rich plasma may ease symptoms, but do not modify disease progression. By contrast, cell therapy products hold promise as regenerative approaches that may both alleviate pain and influence disease trajectory. Cell therapy products for knee OA exert multimodal effects through paracrine and immunomodulatory mechanisms, including modulation of synovial inflammation, attenuation of senescence-associated pathways, and support of extracellular matrix production. Despite encouraging preclinical and clinical signals, only a few cell therapy products have been approved globally, and most remain in development. However, substantial translational challenges remain, including variability in cell source and potency, limited persistence in joint environment, small clinical trial sizes, and regulatory and manufacturing hurdles. To achieve broader adoption, it will be essential to demonstrate superiority to minimally manipulated orthobiologics, clarify redosing strategies, and generate robust long-term evidence. This Review discusses recent clinical trial data, mechanistic insights, regulatory considerations, and operational challenges shaping the evolving role of cell therapy products for OA as nextgeneration candidates to bridge the gap between pharmacological and surgical interventions. In addition, this Review is written to support regulatory agencies as well as academics and clinicians involved in the development and evaluation of cell therapy products.

Objective This systematic review aimed to evaluate the diagnostic accuracy of D-dimer testing for splanchnic vein thrombosis (SVT), a clinical setting where its role remains uncertain due to confounders such as hepatic dysfunction and inflammation. Methods This review was registered on the Open Science Framework (https://osf.io/4pnr5) and conducted in accordance with PRISMA-DTA guidelines. PubMed and EMBASE were searched from inception through January 3, 2026. Studies evaluating D-dimer diagnostic accuracy for SVT, with imaging as the reference standard, were included. Methodological quality was assessed using QUADAS-2 and PROBAST. Data were synthesized narratively due to clinical and methodological heterogeneity. Results Twenty-five studies comprising 9,052 patients were included. Among the 14 studies with originally reported diagnostic metrics, sensitivity ranged from 54.5% to 95.3%, specificity from 33.0% to 96.0% and the area under the curve (AUC) from 0.615 to 0.982. Diagnostic performance varied notably by clinical context, with post-splenectomy AUC of 0.615–0.89, and cirrhosis AUC of 0.678–0.982. In cirrhotic patients, accuracy declined with worsening hepatic function (AUC of 0.809–0.963 in Child-Pugh class A versus 0.691–0.698 in class C). Optimal cut-off values varied widely (300–13,255 ng/mL), reflecting population and assay diversity. Multimarker models combining D-dimer with P-selectin or von Willebrand factor outperformed D-dimer alone (AUC of 0.807–0.975). Conclusions D-dimer demonstrates variable diagnostic accuracy for SVT, with performance markedly influenced by hepatic function and clinical setting. Current evidence does not support its use as a universal standalone rule-out test across the full spectrum of clinical settings, despite a high negative predictive value in selected low-risk populations. Multimarker approaches show promise but require prospective validation in well-designed studies.

Point mutations in p53 favour tumour aggressivity, particularly in gastric cancer (GC), and offer a target for small molecule-based anticancer treatments. This study focused on the p53-Y220C mutation, which causes p53 misfolding due to thermal instability associated with the creation of a pocket that may accommodate small molecules. This mutation also creates an additional free cysteine thiol group that may react with Michael acceptors. Using an integrated in silico and in vitro approach, four compounds (AG1, AG2, AG3, and RK349) were screened for potential reactivation of p53-Y220C in GC cells. AG3, a compound with zinc chelation and Michael acceptor properties, was found to induce p53 target gene expression via p53-dependent and -independent pathways. AG3 limited reactive oxygen species production, reducing toxicity to healthy cells. Furthermore, AG3 induced p53-dependent cytotoxicity and enhanced chemotherapy response. This study presents a novel compound with p53-Y220C reactivation potential, highlighting its promise for further development.

Anterior cruciate ligament reconstruction relies on interference screw fixation, yet insufficient graft osseointegration remains a critical clinical challenge. This study aimed to develop and characterize a 3D-printed polymeric-hydroxyapatite composite interference screw with an osteoinductive surface to enhance localized osteogenic responses. Screws were designed, modeled, and fabricated using fused deposition modeling 3D printing with a polycaprolactone-poly(lactic-co-glycolic acid)-hydroxyapatite composite. Physico-chemical characterization was performed using scanning electron microscopy. Biocompatibility was assessed through mesenchymal stem cell metabolic activity assays and morphological analysis. Osteogenic gene expression was quantified by RT-qPCR following culture in osteogenic differentiation medium. In vivo osseointegration was evaluated histologically at five and nine weeks following implantation in the proximal tibial epiphysis of a rat model. 3D printing successfully produced screws with consistent geometry and surface characteristics. The composite material supported robust mesenchymal stem cell proliferation without cytotoxicity or morphological abnormalities. Histological examination revealed progressive bone formation with no adverse tissue reactions, including the absence of cyst formation, osteolysis, or excessive fibrosis. RT-qPCR revealed upregulation of osteogenic markers in those enhanced screws. These results indicate that the 3D-printed polymeric-hydroxyapatite composite screws are biocompatible and capable of stimulating localized osteogenic activity, supporting their potential as a biological foundation for future evaluation in anterior cruciate ligament reconstruction applications.

Respiratory viruses, such as influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remain major global health threats, and the emergence of drug-resistant variants underscores the urgent need for host-tar geted antiviral strategies. Prohibitins (PHBs), mitochondrial scaffold proteins involved in diverse cellular processes, are host factors exploited by multiple viruses. Here, we investigated the antiviral potential of two PHB-binding triazine melanogenin derivatives, Mel56 and Mel6, against IAV and SARS-CoV-2. Mel56, but not Mel6, exhibited potent anti-IAV activity. In particular, Mel56 increased cell survival, suppressed viral nucleo protein expression, and reduced viral gene transcription in IAV-infected Madin-Darby canine kidney (MDCK) cells and A549 human lung carcinoma cells. PHB2 knockdown enhanced the inhibitory effect of Mel56, supporting the involvement of PHBs in its antiviral mechanism. Transcriptomic profiling revealed that Mel56 downregulates virus-induced immune response genes while upregulating antioxidant response-rela ted genes, including nuclear factor erythroid 2-related factor 2 (NRF2) target genes. NRF2 activation by Mel56 was confirmed using a reporter assay. Consistent with these findings, Mel56 impaired mitochondrial ATP synthesis and electron transport in isolated rat liver mitochondria and attenuated mitochondrial membrane potential and promo ted mitochondrial reactive oxygen species production in live MDCK cells. Importantly, Mel56 exhibited potent anti-SARS-CoV-2 activity in human induced pluripotent stem cell-derived lung organoids. Mel56 did not upregulate NRF2 target genes in SARS-CoV-2infected organoids. These findings identify Mel56 as a PHB-binding compound with broad-spectrum antiviral activity and support the development of PHB-targeting ligands as a novel host-directed therapeutic strategy against respiratory viral infections. IMPORTANCE This study identifies Mel56 as a novel host-directed antiviral compound that targets prohibitins and suppresses both influenza A virus and severe acute respiratory syndrome coronavirus 2. Mel56 exhibits broad-spectrum antiviral activity in conventional cell culture models as well as in physiologically relevant human lung organoids. Mechanistically, Mel56 upregulates antioxidant response-related genes, activates nuclear factor erythroid 2-related factor 2, impairs mitochondrial function, and enhances mitochondrial reactive oxygen species production. Notably, its effects differ depending on the cellular context, underscoring the complexity of host signal ing pathways during viral infection. These findings highlight prohibitins as promising therapeutic targets and provide proof of concept for the development of host-directed strategies to combat respiratory viruses and mitigate the emergence of drug resistance.

WNT10A mutations, a major genetic determinant of dental agenesis and ectodermal dysplasia, exert profound effects on craniofacial development. Although classified as rare disorders, these mutations account for more than half of oligodontia cases, reflecting their critical role. The associated phenotypes span a broad clinical spectrum, ranging from isolated tooth agenesis to complex multisystem disorders, including hypodontia, enamel and root defects, palmoplantar keratoderma, alopecia, nail dystrophy, skin xerosis, hypohidrosis, eyelid cysts, and skin cancer, skeletal abnormalities and impaired bone homeostasis, underscoring their systemic impact. This review synthesizes current biological and clinical knowledge by linking phenotypes of WNT10A mutations to disruptions in Wnt/β-catenin signaling and its interactions with BMP, SMAD, RANK/RANKL/OPG, VEGF, and other regulatory pathways. Altered pathway activity affects key processes in tooth morphogenesis, osteogenesis, cellular proliferation, and tissue maintenance, offering mechanistic explanations for the heterogeneity and severity of patient presentations. A clearer understanding of these pathways is essential for improving diagnosis and management of WNT10A-associated oligodontia, particularly in treatment planning for growth-dependent interventions, regenerative strategies, and implant rehabilitation. Despite significant progress, critical gaps remain in defining the molecular basis of variable expressivity and genotype–phenotype relationships. Elucidating these mechanisms will be pivotal for advancing precision approaches in dental and craniofacial care.

Abstract This ENETS guidance paper, developed by a multidisciplinary working group, provides up‐to‐date and practical advice on the diagnosis and management of lung and thymic carcinoids, based on recent developments and study results. These recommendations aim to provide practical recommendations for the diagnosis, treatment and follow‐up of these tumours, and pave the road for more standardised care for our patients expecting improved outcomes. This paper is structured on a question‐answer format in order to address common dilemmas encountered in clinical practice, including controversial issues and areas of uncertainty, based on the best available evidence and expert opinion when good quality evidence is not available. Each recommendation will provide a level of evidence and grade of recommendation as per the GRADE system (adapted from the Infectious Disease Society of United States Public Health Service grading system).

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Among the myriad consequences of climate change, global warming and extreme weather events are particularly critical due to their well-documented impact on neurological and psychological well-being. However, the severity of these impacts varies significantly by geography. This article assesses the potential adverse effects of climate change on "brain health" through a risk management framework. The analysis begins by evaluating existing governance and risk-assessment procedures, followed by an examination of human adaptive capacities and natural risks. The latter draws upon climatological data-specifically regarding global warming and the "tropicalization" of the Euro-Mediterranean region-as well as anthropological insights. Building on this foundation, we propose strategies for effective risk control, including adaptation, mitigation, and preparedness. Success depends on the mobilization of public health researchers and professionals to drive organizational change and implement preventative measures to address extreme events. Consequently, the article advocates for specific decisions regarding communication, education, and early-warning systems to enhance rescue efficiency and prevent disasters. The discussion concludes with a focus on mitigation strategies specifically tailored to the Euro-Mediterranean region to address the challenges of climate tropicalization.

Introduction The practice of Continuing Dental Education (CDE) serves as a fundamental requirement for lifelong learning but there is limited knowledge about how dental students handle CDE during their final educational period. This study examined how final-year French dental students perceive CDE through their expectations, motivation and their decision-making methods. Methods In 2024 and 2025, an online questionnaire was distributed to final year students from all French dental faculties. The survey contained 45 questions categorized into three sections that assessed: (1) self-evaluation of participants’ knowledge across all dental fields, (2) participants’ objectives regarding future clinical practice and (3) awareness of existing CDE. Results One hundred and seventy one students responded to the survey which represented a response rate of 13.5%. Only 36.2% of the respondents were fully satisfied with undergraduate training, and the disciplines most often perceived as insufficient (implantology, oral surgery, fixed prosthodontics) were also those most desired for CDE or specialization. Students demonstrated trust in university-based programs while selecting diploma-granting courses but only 10.5% of them had selected a specific educational path. Students primarily used the Internet for information retrieval, but they prefer in-person interactive and clinical training courses over digital courses. Conclusion For French dental students, CDE is seen both as lifelong learning and a way to fill training gaps, highlighting the need for clearer guidance and practice-oriented, evidence-based courses.

Background and purpose. Anthracycline‐induced cardiotoxicity, particularly from doxorubicin, remains a major limitation in cancer therapy, contributing to heart failure and long‐term morbidity. Prokineticin receptor‐1 (PKR 1 ), involved in cardiomyocyte survival and anti‐fibrotic signalling, represents a promising therapeutic target. This study evaluated the cardioprotective potential of IS39, a novel non‐peptide PKR 1 agonist, in models of doxorubicin‐induced cardiac injury. Experimental approach. In silico ADME–toxicity profiling, scaffold optimisation and molecular docking were used to refine non‐peptide PKR 1 agonists, replacing the dehydroamide moiety of first‐generation compounds with a D‐aminoacyl group to enhance metabolic stability. The lead compound IS39 was evaluated in vitro in primary cardiomyocytes and in vivo in a murine model of doxorubicin‐induced cardiotoxicity. Parallel studies assessed potential interference with doxorubicin antitumour activity in breast cancer cell lines and 3D tumour spheroids. Endpoints included cardiomyocyte viability, oxidative stress, fibrotic markers, cardiac function, histopathology and systemic tolerability. Key results. IS39 selectively activated PKR 1 , reduced reactive oxygen species, suppressed profibrotic gene expression and protected cardiomyocytes from doxorubicin‐induced cytotoxicity in vitro. These effects were abolished by PKR 1 knockdown or antagonism, confirming on‐target activity, and IS39 did not impair doxorubicin antitumour efficacy. In vivo, IS39 preserved left ventricular ejection fraction, attenuated myocardial fibrosis and apoptosis, and improved cardiac morphology. However, systemic IS39 administration exacerbated doxorubicin‐associated weight loss and did not improve overall survival. Conclusions and implications. IS39 confers cardioprotection via PKR1‐mediated antioxidant and antifibrotic mechanisms. Despite systemic tolerability limitations, these findings support PKR1 as a therapeutic target and justify development of tissue‐selective PKR1 agonists for cardio‐oncology applications.

Background Timely reperfusion is a key quality-of-care target in ST-segment–elevation myocardial infarction (STEMI). When primary percutaneous coronary intervention (PPCI) cannot be delivered within 120 minutes from first medical contact (FMC), guidelines recommend fibrinolysis as early as possible within 12 hours of symptom onset in eligible patients. We quantified missed opportunities for fibrinolysis in a nationwide STEMI network. Methods We analysed consecutive STEMI patients enrolled ≤24 hours from symptom onset in the France-PCI registry (2014–2022). FMC was approximated by the first diagnostic ECG. Initial reperfusion was classified as timely PPCI (FMC-to-device ≤120 min), delayed PPCI (&gt;120 min), or fibrinolysis. Among delayed PPCI, eligibility for fibrinolysis required no oral anticoagulant, no prior stroke, and no documented contraindication. We evaluated temporal trends, regional variation, and outcomes. Results Among 19,472 patients, 12,633 (64.9%) underwent timely PPCI, 5,895 (30.3%) delayed PPCI, and 944 (4.8%) fibrinolysis. Timely PPCI increased over time, whereas fibrinolysis declined. Among delayed PPCI, 3,279/5,895 (55.6%) presented within the prespecified early-presenter window (symptom-to-ECG ≤3 h) and met our strict fibrinolysis-eligibility criteria, yet underwent delayed PPCI; this proportion remained stable across years, with marked regional heterogeneity. Fibrinolysis use was favoured by mobile intensive care units, helicopter transport, and longer distance to PPCI centres, whereas older age was associated with delayed PPCI without fibrinolysis. Conclusions In this national STEMI network, more than half of delayed PPCI in eligible early presenters represented a persistent missed-fibrinolysis gap. Routine audit of delayed PCI and missed fibrinolysis as system-level quality metrics should guide time-based pre-hospital triage and align reperfusion with guideline-recommended targets.

Anthracyclines, key chemotherapy agents, pose cardiotoxicity risks. In a 3-year study of 89 breast cancer patients treated with doxorubicin or epirubicin, more than 50% showed reduced left ventricular ejection fraction and progressive ventricular dilation. Although troponin-I flagged acute damage, it failed to predict long-term remodeling. Using a human methylome atlas, researchers identified 33 heart-specific methylated CpG sites and validated methylated PIH1D1 (mPIH1D1) as a novel biomarker. Elevated mPIH1D1 levels strongly correlated with ventricular dilation but not left ventricular ejection fraction decline, indicating its sensitivity to early cardiac remodeling. mPIH1D1 may complement troponin-I in risk assessment and cardiotoxicity management for patients undergoing anthracycline-based chemotherapy.

<div><p>Purpose: Sepsis-induced disseminated intravascular coagulation (DIC) is characterized by impaired fibrinolysis, partly due to neutrophil elastase-mediated plasminogen degradation. We aimed to evaluate whether plasminogen supplementation could restore fibrinolytic capacity in patients with sepsis-induced coagulopathy and in a murine model of septic DIC.</p><p>Methods: 60 patients with sepsis-induced coagulopathy were randomized to receive 12 mL/kg of placebo (NaCl 0.9%) or OctaplasLG ® , a pathogen-inactivated pooled human plasma containing 2 µM plasminogen. Pre-and post-infusion levels of functional plasminogen, plasmin generation, and fibrinolysis markers (plasmin-antiplasmin complexes, plasminogen activator inhibitor-1, and tissue-type plasminogen activator) were measured. In parallel, in a sepsis-induced DIC model, transgenic TM pro/pro mice received either purified plasminogen or placebo. Functional plasminogen levels and plasmin generation were assessed via enzymatic assays.</p></div> <div>Results:<p>In patients, baseline plasminogen and plasmin generation were significantly lower than in healthy controls. OctaplasLG ® significantly increased functional plasminogen (+ 46 nM [-96; 118] vs. -84 [-180; 27] nM, p &lt; 0.05) and improved plasmin generation (0.12 [-0.25; 1.27] vs. -0.36 [-1.58; 0.12] fmol, p &lt; 0.05). No changes were observed in plasmin-antiplasmin, plasminogen activator inhibitor-1, or tissue-type plasminogen activator levels. A non-significant trend toward reduced mortality was noted in patients receiving OctaplasLG ® (42.3% vs. 60.0%).</p><p>Septic DIC-mice also exhibited reduced functional plasminogen (100 [66-126] vs. 295 [268-343] nM) and impaired plasmin generation (1.8 [1.4-2.1] vs. 3.0 [2.8-3.3] fmol, p &lt; 0.05), which were restored after plasminogen supplementation (plasminogen: 346 [287; 360] nM; plasmin generation: 4.1 [3.7; 5.5] fmol).</p></div> <div>Conclusion:<p>Plasminogen supplementation restores fibrinolytic capacity, supporting its therapeutic potential in sepsis-induced DIC.</p></div>

<div><p>Purpose: Sepsis-induced disseminated intravascular coagulation (DIC) is characterized by impaired fibrinolysis, partly due to neutrophil elastase-mediated plasminogen degradation. We aimed to evaluate whether plasminogen supplementation could restore fibrinolytic capacity in patients with sepsis-induced coagulopathy and in a murine model of septic DIC.</p><p>Methods: 60 patients with sepsis-induced coagulopathy were randomized to receive 12 mL/kg of placebo (NaCl 0.9%) or OctaplasLG ® , a pathogen-inactivated pooled human plasma containing 2 µM plasminogen. Pre-and post-infusion levels of functional plasminogen, plasmin generation, and fibrinolysis markers (plasmin-antiplasmin complexes, plasminogen activator inhibitor-1, and tissue-type plasminogen activator) were measured. In parallel, in a sepsis-induced DIC model, transgenic TM pro/pro mice received either purified plasminogen or placebo. Functional plasminogen levels and plasmin generation were assessed via enzymatic assays.</p></div> <div>Results:<p>In patients, baseline plasminogen and plasmin generation were significantly lower than in healthy controls. OctaplasLG ® significantly increased functional plasminogen (+ 46 nM [-96; 118] vs. -84 [-180; 27] nM, p &lt; 0.05) and improved plasmin generation (0.12 [-0.25; 1.27] vs. -0.36 [-1.58; 0.12] fmol, p &lt; 0.05). No changes were observed in plasmin-antiplasmin, plasminogen activator inhibitor-1, or tissue-type plasminogen activator levels. A non-significant trend toward reduced mortality was noted in patients receiving OctaplasLG ® (42.3% vs. 60.0%).</p><p>Septic DIC-mice also exhibited reduced functional plasminogen (100 [66-126] vs. 295 [268-343] nM) and impaired plasmin generation (1.8 [1.4-2.1] vs. 3.0 [2.8-3.3] fmol, p &lt; 0.05), which were restored after plasminogen supplementation (plasminogen: 346 [287; 360] nM; plasmin generation: 4.1 [3.7; 5.5] fmol).</p></div> <div>Conclusion:<p>Plasminogen supplementation restores fibrinolytic capacity, supporting its therapeutic potential in sepsis-induced DIC.</p></div>

During the heart development, epicardial-to-mesenchymal transition (EMT) drives the production of progenitor cell populations that contribute to heart formation; however, the molecular control of EMT and its paracrine effects on cardiomyocytes remain poorly elucidated. Here, we defined a novel PKR1–miR-124–SNAI2 signaling axis that orchestrates EMT and coordinates myocardial maturation. Conditional deletion of the prokineticin receptor (PKR1) in mice Tcf21+ epicardial cells caused embryonic lethality and congenital heart disease-like anomalies, including ventricular rupture, arrhythmia, myocardial fibrosis, and impaired contractility. Transcriptomic profiling revealed marked upregulation of miR-124, concurrent with deregulation of EMT genes and signatures of immature cardiomyocytes. Mechanistically, miR-124 directly targets the 3′ untranslated region of SNAI2, suppressing this key EMT regulator, resulting in failed EMT, apoptosis, and fibrosis in the epicardium. Functional rescue through miR-124 inhibition or PKR1 reintroduction restores SNAI2 expression, revives EMT, enhances cell survival, and promotes proper cardiomyocyte maturation. Paracrine effects were substantiated by conditioned media and ex vivo assays, demonstrating that epicardial-derived miR-124 suppressed cardiomyocyte contractility and cardiac maturity gene expression—thereby functionally linking epicardial disruption to myocardial immaturity. These findings establish miR-124 as a critical mediator of epicardial–myocardial communication with PKR1 as its upstream regulator. By integrating epicardial plasticity, myocardial maturation, and ECM homeostasis, our work reveals that targeting the PKR1–miR-124–SNAI2 pathway offers a novel mechanistic framework and potential therapeutic target for preventing or treating congenital heart disease.

BACKGROUND: The optimal time interval between the two surgical stages of a delayed coloanal anastomosis has never been investigated. OBJECTIVE: Assess the influence of time interval on anastomotic leakage occurrence DESIGN: Retrospective cohort study. SETTINGS: Multicentric study (30 colorectal centers). PATIENTS: All patients who underwent delayed coloanal anastomosis (2010-2021). MAIN OUTCOME MEASURES: anastomotic leakage in relation to the time interval between the two surgical stages. RESULTS: A total of 506 patients (female: 42%, median age: 62.1 years) underwent delayed colo-anal anastomosis, 63% immediately after a low anterior resection (primary delayed coloanal anastomosis) and 37% after failure of primary pelvic surgery as a salvage procedure (salvage delayed coloanal anastomosis). The main reasons for salvage delayed coloanal anastomosis were chronic pelvic sepsis (42%) and rectovaginal fistula (38%). The mean time interval between two stages was 8.6 ± 3.8 days, ranging from 1 to 22 days. In the entire cohort, the incidence of anastomotic leakage was 18% (89/506, 95 CI [14%, 21%]) and time interval did not affect the occurrence of anastomotic leakage ( p = 0.529). In sub-group analysis, anastomotic leakage risk was not associated with time interval among primary delayed coloanal anastomosis patients ( p = 0.579) whereas it was for salvage delayed coloanal anastomosis patients ( p = 0.013). In salvage delayed coloanal anastomosis patients, multivariate analysis showed that a longer time interval (adjusted OR=0.89, 95 CI [0.81-0.98], p = 0.035) and surgery in centers performing ≥4 delayed coloanal anastomosis per year (adjusted OR = 0.07, 95 CI [0.01-0.36], p = 0.011) were significantly linked to a lower risk of anastomotic leakage. Each additional day between the two salvage delayed coloanal anastomosis procedures was estimated to reduce the risk of anastomotic leakage by 11%. LIMITATIONS: The retrospective design. CONCLUSIONS: In the context of primary delayed coloanal anastomosis, increasing the time interval between the two stages of delayed coloanal anastomosis does not influence the risk of anastomotic leakage. For salvage delayed coloanal anastomosis, extending the time interval significantly reduces the risk of anastomotic leakage.

Aims Health‐related quality of life (HRQoL) assessment is increasingly integrated into type 1 diabetes (T1D) monitoring to promote a holistic approach. To investigate HRQoL in adults with T1D and to assess the impact of the severity of complications on HRQoL. Materials and Methods This is a cross‐sectional analysis of baseline characteristics of adults living with T1D included in Société Francophone du Diabète – Cohorte Diabète de Type 1 (SFDT1), a French longitudinal cohort study. HRQoL was assessed using generic (EuroQol 5‐Dimensions 5‐Level questionnaire [EQ‐5D‐5L]) and diabetes‐specific (Audit of Diabetes‐Dependent Quality of Life) instruments. The severity of diabetes complications was measured using an adapted Diabetes Complication Score Index (DCSI) ranging from 0 to 14. We used multiple imputations to deal with missing data. Results We included 1892 adults, 48% women, with a median (interquartile range [IQR]) age of 38 (28; 51) years. The mean overall EQ‐5D‐5L HRQoL score was 71.1 ± 17.7 (maximum 100), with the following number of participants negatively impacted for each domain: 271 (14%) for mobility, 94 (5%) for self‐care, 378 (19%) for usual activities, 853 (45%) for pain/discomfort and 983 (52%) for anxiety/depression. The median (IQR) DCSI was 1 (0; 2). In multivariable models, a one‐step increase in DCSI was associated with a 1.5% decrease in overall EQ‐5D‐5L HRQoL. DCSI was also inversely associated with all domains of the generic scale except anxiety/depression and 17 domains of the diabetes‐specific scale. Conclusions We observed an inverse association between the severity of complications and overall HRQoL and most of its dimensions. Our results highlight the need to reinforce the prevention of complications to improve the overall well‐being of people with T1D.

No abstract available

Abstract This narrative review written by experts aims to provide a comprehensive synthesis of current knowledge and guidelines on lung carcinoids, emphasizing the multidimensional approach required for effective diagnosis and management. The manuscript will: i) Define and classify lung carcinoids in accordance with the latest WHO classification system, and emphasize the importance of molecular markers for precise subtyping; ii) Analyze epidemiological trends, discuss prevalence, incidence, and mortality rates, alongside key risk factors including genetic predispositions (MEN1) and precursor lesions such as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH); iii) Investigate the etiology and carcinogenesis of lung carcinoids, including insights into the molecular hallmarks and pathways that underlie tumor development and progression; iv) Detail clinical presentations, distinguishing pulmonary symptoms from secretory syndromes (carcinoid syndrome and Cushing’s syndrome), supported by visual aids to elucidate symptom prevalence and implications; v) Present an integrated diagnostic approach, encompassing state-of-the-art imaging modalities (CT, MRI, 68Ga-SSA-PET-CT) and advanced molecular pathology techniques; vi) Outline evidence-based treatment strategies, addressing early-stage interventions, systemic therapies, locoregional therapies, and emerging modalities such as immunotherapy and agnostic approaches; vii) Explore the role of multidisciplinary management, highlighting the critical importance of tumor boards dedicated to lung carcinoids and provide a checklist of key items for comprehensive case discussion and decision-making; viii) Conclude with future perspectives, identifying gaps in current knowledge and suggest directions for research to enhance diagnosis, treatment, and overall patient quality of life.

The last specific international European recommendations regarding the management of cardiogenic shock (CS) regardless of the etiology were issued over 10years ago. We present herein recommendations for the management of CS in adults, developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system by an expert group of from the French Intensive Care Society [Société de réanimation de langue française (SRLF)] and the French Society of Cardiology [Société française de cardiologie (SFC)], with the participation of the French Society of Anesthesia and Intensive Care [Société française d'anesthésie et de réanimation (SFAR)], and the French Society of Thoracic and Cardiovascular Surgery [Société française de chirurgie thoracique et cardio-vasculaire (SFCTCV)]. The recommendations covered six fields of application: CS teams and expert centers, symptomatic medical management, etiological management, organ support, temporary circulatory support and de-escalation and early post-CS management. Twenty-three \"Patient Intervention Comparator Outcome\" (PICO) questions were identified, leading to 41 recommendations regarding management of CS in adult patients. Seven recommendations were scored with high level of evidence (Grade 1), 11 with moderate level of evidence (Grade 2) and 17 with low level of evidence (Expert opinion). In 6 cases, the experts were not able to give an answer. All of the recommendations obtained strong agreement from the expert committee. The experts highlight the fact that optimal management of CS requires organization including a structured, multidisciplinary shock team and regional referral network, applying standardized protocols for diagnosis and staging. Early etiological treatment-such as culprit-lesion revascularization or urgent valve intervention-is central to improve outcomes. Hemodynamic support should prioritize norepinephrine as first-line vasopressor and privilege selective inotrope use. Temporary mechanical circulatory support (Impella, VA-ECMO) should be reserved for carefully selected patients following discussion by the expert team.

Background: Community-acquired bacterial infections (CABIs) remain a leading cause of pediatric morbidity and mortality. This study aimed to provide a contemporary description of pediatric CABIs requiring admission to pediatric intensive care units (PICUs) in France. Methods: The CAPRICE study is a prospective, multicenter cohort including all children with suspected CABIs who were admitted to 28 French PICUs from January to December 2024. Demographic, clinical, microbiologic, and outcome data were prospectively collected. The primary outcome was mortality at day 28 and secondary outcomes included sequelae at day 28, PICU length of stay, and total hospital stay. Independent predictors of mortality were identified by multivariable logistic regression. Results: Among 897 children, the median age was 1.9 years (IQR 0.2-8.8); 55% were male, and 30% had a chronic condition. The leading infections were lower respiratory tract infection (43%), meningitis (20%), and ear-nose-throat infections (13%). Septic shock occurred in 17% of cases. A pathogen was identified in 89% of cases: Bordetella pertussis (22%) and Mycoplasma pneumoniae (15%) were predominant, followed by Streptococcus pneumoniae (13%), and Staphylococcus aureus (11%). In all, 34% patients had viral co-infection and 70% required organ support. Overall mortality was 7%, increasing to 19% with septic shock. Independent predictors of death included multiple organ failure, meningitis, and B. pertussis infection. Sequelae occurred in 15% of survivors. Conclusions: Severe CABIs in French PICUs in 2024 were mainly caused by B. pertussis and M. pneumoniae, followed by S. pneumoniae and S. aureus. Mortality and morbidity of these infections remain substantial.

Aurora kinase A/AURKA is a serine/threonine kinase frequently overexpressed in cancer. Recent discoveries pointed to subcellular pools of AURKA, including at mitochondria. There, AURKA induces organelle clearance by mitophagy together with the autophagy mediator LC3, and its receptor PHB2.Here, we show that the natural product capsaicin modifies the AURKA/PHB2 interaction. We synthesize 16 capsaicin analogs, and Förster's Resonance Energy Transfer/Fluorescence Lifetime Imaging Microscopy (FRET/FLIM) in breast cancer cells reveals that compounds 12 and 13 increase the AURKA/PHB2 interaction. Molecular docking shows that they bind to the inhibitory pocket of PHB2 and to the AURKA active site. We demonstrate that compound 13 specifically inhibits mitophagy while leaving AURKA activation unaltered at centrosomes. Our results demonstrate that compound 13 is a PHB ligand acting on the AURKA/PHB2 interaction. Thanks to its specificity, it may lead to the development of anticancer drugs targeting the mitochondrial functions of AURKA.

<div><p>The last specific international European recommendations regarding the management of cardiogenic shock (CS) regardless of the etiology were issued over 10 years ago. We present herein recommendations for the management of CS in adults, developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system by an expert group of from the French Intensive Care Society [Societéde Reánimation de Langue Française (SRLF)] and the French Society of Cardiology [SocietéFrançaise de Cardiologie (SFC)], with the participation of the French Society of Anesthesia and Intensive Care [SocieteF rançaise d'Anestheśie et de Reánimation (SFAR)], and the French Society of Thoracic and Cardiovascular Surgery [SocietéFrançaise de Chirurgie Thoracique et Cardio-Vasculaire (SFCTCV)].</p><p>The recommendations covered six fields of application: CS teams and expert centers, symptomatic medical management, etiological management, organ support, temporary circulatory support and de-escalation and early post-CS management. Twenty-three "Patient Intervention Comparator Outcome" (PICO) questions were identified, leading to 41 recommendations regarding management of CS in adult patients. Seven recommendations were scored with high level of evidence (Grade 1), 11 with moderate level of evidence (Grade 2) and 17 with low level of evidence (Expert opinion). In 6 cases, the experts were not able to give an answer. All of the recommendations obtained strong agreement from the expert committee.</p><p>The experts highlight the fact that optimal management of CS requires organization including a structured, multidisciplinary shock team and regional referral network, applying standardized protocols for diagnosis and staging. Early etiological treatment-such as culprit-lesion revascularization or urgent valve intervention-is central to improve outcomes. Hemodynamic support should prioritize norepinephrine as first-line vasopressor and privilege selective inotrope use. Temporary mechanical circulatory support (Impella, VA-ECMO) should be reserved for carefully selected patients following discussion by the expert team.</p></div>

The p53 protein plays an important role in preventing cancer and is critical in inducing an antiproliferative response. Unfortunately, the p53 pathway is compromised in almost all cancers, and mutations to p53 lead to loss of function due to protein unfolding, compromised Zn2+ binding, aggregation and amyloid formation. Herein, two new multidentate N,O donor ligands LI-A and LH-A were tested to potentially restore Zn2+ binding to mutant p53, while also inhibiting protein aggregation. The design of these ligands centered on combining an iminodiacetate (IDA) metal binding moiety which was previously determined to exhibit favourable Zn2+ binding affinity and Cu2+/Zn2+ selectivity ratio, with a benzothiazole unit that has been demonstrated to limit mutant p53 protein aggregation. The new ligands were shown to exhibit Zn2+ Kd values in the low nM range based on a fluorophore competition assay, while also inhibiting mutant p53 aggregation via a Thioflavin-T (ThT) assay. In cell-based assays and NCI-60 screening, neither of the new ligands displayed significant cytotoxicity. A reactive oxygen species (ROS) assay showed that neither of the new ligands increased intracellular ROS, however, the previously studied LI compound did show an increase in ROS, providing further information on the mechanism of action of this class of compounds. The current results highlight that the dipicolylamine (DPA) unit is important for anticancer activity, and that phenolate substitution has an important role in dictating the mechanism of cytotoxicity.

While the hydrolase activity of soluble epoxide hydrolase (sEH) reduces vascular calcification, it is not known whether the phosphatase activity of sEH (sEH-P) is also involved. Pharmacological and genetic inhibition of sEH-P reduced the increased calcium deposition in rat aortic rings cultured under high-phosphate conditions. This was associated with decreased mRNA expression of the osteochondrogenic markers Msx2 and Sox9 . Deendothelialization of the aortic rings abolished this anticalcifying effect, while the calcification of human aortic smooth muscle cells was unaffected by sEH-P inhibition, suggesting a predominant role of the endothelium. Endothelial NO release did not appear to contribute, but an increased level of the calcification inhibitor pyrophosphate anions (PPi) was observed in the culture supernatant of aortic rings when sEH-P was inhibited. In vitro experiments demonstrated that PPi is a substrate of sEH-P, and that inhibiting sEH-P prevented the high-phosphate induced decrease of PPi in human aortic endothelial cells. Furthermore, the aortic calcification related to chronic kidney disease induced by subtotal nephrectomy was reduced in sEH-P-deficient rats compared to wild-type rats. This was associated with an improvement in flow-induced isolated mesenteric artery dilatation and a reduction of cardiac hypertrophy and fibrosis. Vascular calcification is regulated by sEH-P through the metabolism of endothelial PPi. The prevention of vascular calcification, together with the reduction in vascular dysfunction and cardiac remodeling, suggests that inhibiting sEH-P may help to prevent the cardiovascular complications associated with chronic kidney disease.

Lipid nanoparticles (LNPs) are emerging as nonviral vectors for gene therapy; yet, their strong liver tropism and lack of tissue specificity remain limiting. Here, we developed, through rational design, a skeletal muscle-targeted delivery platform by functionalizing LNPs with MyomP1, an extracellular conserved peptide derived from the muscle-specific fusogenic protein Myomerger. MyomP1-LNPs were engineered to encapsulate plasmid DNA or mRNA. In vitro, MyomP1 conjugation significantly increased transduction efficiency in murine and human myoblasts and myotubes. In vivo, MyomP1-LNPs significantly enhanced muscle transduction when delivering DNA cargo, strongly reduced liver accumulation following intramuscular and intravenous mRNA delivery, and attenuated local immune activation. This work demonstrates a ligand-guided strategy to overcome organ-specific barriers in nonviral gene transfer, with improved safety and specificity. It suggests that MyomP1-engineered LNPs hold strong potential to improve therapeutic outcomes for patients with rare muscle diseases, offering a promising alternative to traditional viral gene therapy platforms.

Selected diffuse malignant peritoneal mesothelioma (DMPM) patients may be radically treated with complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Two thirds of them recur with the possibility of iterative CRS-HIPEC and/or systemic chemotherapy. The postoperative follow-up management is based on scarce data. The recurrence profile was explored in a large national database to challenge the standard follow-up protocol.

Implantable scaffolds are increasingly recognized as transformative tools in regenerative medicine, offering the potential to prevent or mitigate tissue degeneration. Osteoarthritis is a widespread degenerative joint disease that often progresses from early focal lesions to severe joint damage, creating substantial clinical and socioeconomic burdens. Preventive strategies for early-stage lesions remain limited. This study reports the design and development of a functional polymeric scaffold intended to support early tissue regeneration and potentially prevent lesion progression. The scaffold consists of an electrospun poly (ε-caprolactone) nanofibrous membrane enriched with glycosaminoglycans, including hyaluronic acid and chondroitin sulfate, to mimic essential features of the cartilage extracellular matrix and provide a supportive microenvironment. Complete structural, physicochemical, and mechanical characterization was performed to assess the scaffold architecture, stability, hydration properties, and suitability for tissue environments. In vitro investigations were conducted to evaluate cytocompatibility and the interaction of the scaffold with relevant cell types. The scaffold is designed as a potential future preventive strategy to support cartilage integrity and limit disease progression. This approach represents a promising strategy to preserve joint integrity and function, addressing a critical unmet clinical need and enabling translation toward clinical application.

Photodynamic therapy (PDT) is a promising strategy for head and neck squamous cell carcinoma (HNSCC), but the immune consequences of tumor cell death remain incompletely understood. We compared two ruthenium(II) polypyridine photosensitizers (PSs) in HNSCC models and found that both were potently phototoxic (nanomolar IC 50 s), triggered diverse cell death pathways (including autophagy and ferroptosis), and promoted hallmark danger signals of immunogenic cell death (ICD). Strikingly, only one PS induced apoptosis and strong endoplasmic reticulum (ER) stress, yet paradoxically led to immune tolerance in vivo. Conversely, the PS that did not induce apoptotic cell death with milder stress responses resulted in a better antitumor immunity in vivo. These unexpected findings challenge the prevailing view that PDT-triggered apoptosis and ER stress are essential for ICD. Our study underscores the complexity of PDT-induced cell death balance and immunogenic signals and highlights the need to redefine ICD-inducing criteria for the rational design of next-generation PSs.

The dental pulp is a dynamic connective tissue essential for tooth vitality, sensory function, immune defense, and reparative dentinogenesis. Conventional endodontic procedures, while effective in eradicating infection, often result in a non-functional, devitalized tooth, highlighting the need for biologically based regenerative approaches. The emergence of three-dimensional (3D) culture systems has transformed pulp biology and endodontic research by providing physiologically relevant microenvironments that better reproduce the dentino-pulp interface, vascular and neural networks, and immune interactions. This review synthesizes current advances in 3D dental pulp modeling, from scaffold-based and hydrogel systems to spheroids, organoids, bioprinted constructs, and microfluidic "toothon-a-chip" platforms. Each system's composition, biological relevance, and translational potential are critically examined with respect to odontogenic differentiation, angiogenesis, neurogenesis, and inflammatory response. Applications in disease modeling, biomaterial screening, and regenerative endodontics are highlighted, showing how these models bridge fundamental biology and therapeutic innovation. Finally, we discuss key challenges including vascularization, innervation, standardization, and clinical translation, and propose integrative strategies combining bioprinting, stem-cell engineering, and organ-on-chip technologies to achieve functional pulp regeneration. Overall, 3D pulp models represent a paradigm shift from reductionist cultures to bioinstructive, patient-relevant platforms that accelerate the development of next-generation endodontic therapies.

This study examined the acute effects of polyphenol (PP)-rich fruit juice supplementation on the exercise capacity of healthy humans. Thirty-five healthy, sedentary volunteers participated in this randomized, controlled, crossover study. They performed a 6 min walk test two hours after consuming 200 mL of a PP-rich fruit juice (fruit juice) or a PP-poor control juice (apple), separated by a one-week washout. In addition to monitoring the heart rate during exercise, we determined the reactive hyperemia index (RHI), an indicator of vascular dilatation that contributes to exercise capacity. The distance walked during the 6 min test tended to be greater after the consumption of the PP-rich juice, compared to the PP-poor juice (588 ± 15 vs. 561 ± 14 m, respectively). The increase in heart rate was similar in both situations. The RHI increases were similar after both juices’ intake at 1 h, but after 2 h, the RHI increase was significant only after the PP-rich juice intake (from 6.78 ± 0.46 to 8.47 ± 0.47, p &lt; 0.001). In conclusion, acute consumption of PP-rich juice increases vessel dilatation and tends to improve exercise capacity. These data support further studies to determine whether greater consumption of PP-rich fruit juices could improve exercise capacity in healthy subjects.

Pancreatic islet transplantation is a promising treatment strategy for type 1 diabetes patients; however, there are still major challenges to overcome, including vascularization. Despite a substantial need to understand the islet graft decline observed in patients 5–10 years post transplantation, clinical translation remains challenging, probably because of species-specific features and the lack of in vitro vascularized models. Here, we report results of a human assembloid composed of self-organizing 3D blood vessel organoids (BVOs) with human pancreatic islets. We demonstrate that co-culture of islets and BVOs ex vivo leads to an auto-organized assembloid (by light-sheet fluorescence microscopy) and improves insulin secretion over time (functionality assays) on 5 independent human islet donors (from 3 different hospital facilities). Taken together, this study could accelerate our understanding of type 1 diabetes and facilitate therapeutic development for type 1 diabetes patients.

Endometriosis is a chronic gynaecological disease affecting 1 in 10 reproductive-age women. It is defined as the presence of endometrium-like tissue outside the uterus. Beyond this placid anatomical definition, endometriosis is a complex, hormonal, inflammatory, and systemic condition that poses significant familial, psychological, and economic burden. The interaction between the cardiovascular system and endometriosis has become a field of interest as the underlying mutual mechanisms become better understood. On the basis of accumulating fundamental and clinical evidence, it is likely that there exists a close relationship between endometriosis and the cardiovascular system. Therefore, investigating the endometriosis-cardiovascular interaction is highly clinically significant. In this review, we highlight our current understanding of the pathophysiology of endometriosis with systemic hormonal, pro-inflammatory, pro-angiogenic, immunologic, and genetic processes beyond the peritoneal microenvironment. Additionally, we provide current clinical evidence about how endometriosis interacts with cardiovascular risk factors and cardiovascular disease (CVD). To date, only small associations between endometriosis and CVD have been reported in observational studies, inherently limited by the potential influence of unmeasured confounding. Cardiovascular disease in women with endometriosis remains understudied, under-recognized, and underdiagnosed. More detailed study of the cardiovascular-endometriosis interaction is needed to fully understand its clinical relevance, underlying pathophysiology, possible means of early diagnosis and prevention.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) (also termed thrombosis with thrombocytopenia syndrome or vaccineinduced thrombotic thrombocytopenia or vaccine-induced immune thrombocytopenia) is characterized by (i) venous or arterial thrombosis; (ii) mild-to-severe thrombocytopenia; (iii) positive antiplatelet factor 4 (PF4)–polyanion antibodies or anti-PF4–heparin antibodies detected by the HIT (heparin-induced thrombocytopenia) ELISA; (iv) occurring 5–30 days after ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Johnson &amp; Johnson/Janssen) vaccination. VITT’s incidence is 1 per 100 000 vaccinated people irrespective of age and up to 1 in 50 000 for people &lt;50 years of age with the AstraZeneca COVID-19 vaccine. The exact mechanism by which adenovirusvectored COVID-19 vaccines trigger this syndrome is still unclear, as for the increased risk for acute cerebral sinus venous thrombosis and splanchnic vein thrombosis as compared to other locations of venous thrombotic events. VITT is associated with the detection of anti-PF4 antibodies, unrelated to previous use of heparin therapy. PF4 antibodies are thought to activate platelets via the platelet FccRIIA receptors leading to further platelet activation that causes thrombosis and thrombocytopenia.

Lipid nanoemulsions (NEs) are promising green nanocarriers for diagnostic and therapeutic applications, but their functionalization with biomolecules, such as antibodies, remains a challenge due to liquid nature of their core. Here, we developed an original plug-and-play strategy to graft an antibody (trastuzumab) at the surface of NEs, using components generally recognized as safe (GRAS). We synthesized a reactive 4nitrophenyl carbonate of cholesterol (NPC-Chol) and a Biotin-PEG 3000 -Lysine linker, which can react within one-pot formulation to form an amphiphilic carbamate Biotin-PEG 3000 -Cholesterol. The cholesterol ensures anchorage of the linker, which effectively exposes biotin moiety at the surface of NEs for further antibody grafting using a biotin-neutravidin coupling. The reaction between the Biotin-PEG 3000 -Lysine linker and NPC-Chol was confirmed by 1 H-NMR and absorption spectroscopy. The obtained biotinylated 50-nm NEs loaded with a near-infrared dye were successfully targeted to neutravidin-coated glass surfaces and imaged at the single-droplet level. The biotinylated NEs bearing the trastuzumab antibody targeted specifically HER2-amplified breast cancer models HCC-1954 and SKBR3, in contrast to control MDA-MB-231 (HER2-low) cells. Altogether, our study proposes an efficient methodology for grafting antibodies to the surface of NEs, which offers new opportunities of application of these green nanocarriers in biomedicine.

Background and purpose: Despite advances in immunotherapy, doxorubicin (Dox) chemotherapy is still the irreplaceable first-line therapy for solid tumours such as breast cancer. However, chemotherapy resistance is the major limiting factor, requiring the use of high doses of Dox to achieve the anti-tumour actions, often leading to severe side effects. Unravelling the mechanisms behind chemoresistance and identifying potential biomarkers for mitigating this resistance could enhance current treatment strategies and improve patient outcomes. Experimental approach: We developed human 3D breast cancer spheroids (HBCSs) as a model that closely mimics in vivo tumour structure and microenvironment. Given that hypoxia and elevated levels of the angiogenic cytokine, prokineticin-2 (PK2), are associated with chemoresistance to antiangiogenic therapy, we explored the effect of a hypoxia-inducible factor (HIF-1α) inhibitor on viability defect in HBCSs and the levels of PK2 in the conditioned medium following Dox treatment. We also assessed levels of HIF-1α, active caspase-3, TUNEL and reactive oxygen species (ROS), and CD73 enzymatic activity in HBCSs. Key results: Results showed that HIF-1α inhibitor increased viability defect in the Dox-resistant HBCSs. Interestingly, at higher Dox concentrations, chemoresistance was mitigated independently of HIF-1α and promoted apoptosis and ROS accumulation, which were correlated with PK2 release. Conclusions and implications: Our findings provide the first evidence that PK2 may serve as a predictive pharmacodynamic marker, offering a potential strategy to overcome drug resistance in targeted cancer therapy.

Background : Chronic lung allograft dysfunction (CLAD) is the main cause of death following lung transplantation (LT). Its pathophysiology and risk factors remain poorly understood. Donor or recipient genetic characteristics could be involved. MUC5B promoter rs35705950 polymorphism is one of the major genetic factors associated with pulmonary fibrosis. We aimed to correlate the MUC5B genotype of recipients and donors with LT outcomes. Methods : Recipient and donor blood samples from the Cohort in Lung Transplantation biobank were used. MUC5B status was determined by quantitative PCR using probes for rs35705950 polymorphism. CLAD occurrence and phenotype were blindly adjudicated. Results : 210 recipient–donor pairs were analysed. At 5 years, 68 patients (32.4%) had CLAD. The MUC5B rs35705950 polymorphism, whether in the donor or the recipient, was not associated with CLAD at 5 years (OR 1.07 (95% CI 0.53–2.11), p=0.8, and OR 0.79 (95% CI 0.37–1.60), p=0.5, respectively), CLAD-free survival or CLAD phenotype. The prevalence of the recipients’ T allele differed among underlying respiratory diseases (20.0% in interstitial lung disease, 8.4% in emphysema, 13.4% in cystic fibrosis and 5.6% for others, p=0.03). Risk of antibody-mediated rejection (AMR) was independent of the donor MUC5B polymorphism genotype, whereas the presence of the T allele in the recipient was associated with a reduced occurrence of AMR (OR 0.26 (95% CI 0.08–0.69), p=0.015). Conclusion : MUC5B rs35705950 polymorphism in the donor or the recipient does not affect LT outcomes. The significant association between the recipients’ polymorphism and reduced AMR occurrence has yet to be confirmed.

<div><p>Background: Recent guidelines have proposed dichotomizing acute heart failure and cardiogenic shock phenotypes based on signs/symptoms of hypoperfusion/congestion. Aim: We aimed to assess the prognostic significance of congestion and its early evolution during the first 24 hours in a nationwide cardiogenic shock cohort. Methods: FRENSHOCK was a prospective registry including 772 patients with cardiogenic shock from 49 centres. Patients were classified as cold and wet or cold and dry according to congestive signs. Death at 30 days was analysed according to baseline phenotype.</p><p>Results: Among 593 patients with cardiogenic shock included, 70.7% were male; the median age was 67.0 (58.0-77.0) years, and 521 patients (87.9%) presented with congestion. Congestive patients had higher rates of previous cardiac disease (60.5% vs. 43.1%; P &lt; 0.01) and chronic kidney disease (24.2% vs. 12.5%; P = 0.04). No differences were found regarding Society for Cardiovascular Angiography and Interventions class distribution and lactate concentrations. Congestion was associated with an increased 30-day all-cause death rate (hazard ratio: 1.99, 95% confidence interval: 1.05-3.78; P = 0.04), particularly among patients with persistent congestion beyond 24 hours (hazard ratio: 2.29, 95% confidence interval: 1.20-4.36; P = 0.01). Conversely, patients with resolved congestion at 24 hours had similar outcomes to non-congestive patients (hazard ratio: 0.76, confidence interval: 0.31-1.88; P = 0.56). The negative impact of congestion was confirmed in multivariable Cox regression analysis. Conclusions: Congestion and its persistence beyond 24 hours of management are frequent in patients with cardiogenic shock, and are significantly associated with an increased 30-day all-cause death rate, which may reflect either a direct harmful effect of congestion or difficulties in achieving decongestion in sicker patients. Further studies are warranted to clarify optimal decongestion strategies in patients with cardiogenic shock.</p></div>

Extracellular vesicles (EVs) represent a cytokine-independent pathway though which skeletal muscle (SkM) cells influence the fate of neighbouring cells, thereby regulating SkM metabolic homeostasis and regeneration. Although SkM-EVs are increasingly being explored as a therapeutic strategy to enhance muscle regeneration or to induce the myogenic differentiation of induced pluripotent stem cells (iPSCs), the mechanisms governing their release from muscle cells remain poorly described. Moreover, because muscle regeneration involves a tightly regulated inflammatory response it also important to determine how inflammation alters SkM-EV cargo and function in order to design more effective EV-based therapies. To address this knowledge gap, we isolated and characterized the large and small EVs (lEVs, sEVs) released from SkM cells under basal conditions and in response to TNF-α, a well-established inflammatory mediator elevated in both acute muscle injury and chronic inflammatory conditions such as type 2 diabetes. We then evaluated the regenerative roles of these EV subtypes in vivo using a mouse model of cardiotoxin-induced muscle injury, with a specific focus on their bioactive sphingolipid content. Using transmission, scanning or cryo-electron microscopy, lipidomic profiling and an adenoviral construct to express labelled CD63 in myotubes, we demonstrated that SkM cells release both sEVs and lEVs primarily from the plasma membrane. Notably, sEVs were generated from specialized membrane folds enriched in the EV markers ALIX (ALG-2 interacting protein X) and TSG101, as well as lipid raft-associated lipids. During regeneration, sEVs promoted M1 macrophage polarization and migration and muscle stem cell (MuSC) differentiation, thereby accelerating muscle repair. In contrast, lEVs inhibited and promoted MuSC proliferation and impaired the transition from the pro-inflammatory to the anti-inflammatory response, an essential step for promoting MuSC differentiation. Treatment of isolated muscle fibres with SkM-EVs revealed that the distinct effects of sEVs and lEVs on MuSC behaviour and macrophage phenotype could be largely explained by differences in their lipid composition, particularly the ratio of sphingosine-1-phosphate (S1P) subspecies. However, TNF-α exposure altered these ratios in sEVs and impaired their regenerative functions on MuSC and their effect on macrophage migration and polarization. These results demonstrate for the first time the importance of the sphingolipid content of EVs released by skeletal muscle in their regenerative function within muscle tissue, largely explained by their role as carriers of different subspecies of sphingosine-1-phosphate. This suggests that modulating the sphingolipid composition of EVs could be a viable strategy to enhance the regenerative potential of muscle tissue in addition to therapeutic interventions.

Sjögren's disease (SjD) and systemic lupus erythematosus (SLE) share genetic risk at the DDX6-CXCR5 locus (11q23.3). Identifying and functionally characterising shared SNPs spanning this locus can provide new insights into common genetic mechanisms of autoimmunity.

ABSTRACT Objectives The aim of this study was to evaluate the effect of M101 gel in bone and peri‐implantitis healing and its safety of use. Materials and Methods M101 gel and solution (1 g/L) were evaluated in four different models: (i) human osteoblast culture; (ii) mouse calvarial defect; (iii) extraction model in dogs; (iv) peri‐implantitis model in dogs. M101 cytocompatibility was evaluated in osteoblasts, and expression of ALP, Runx2, and BMP‐2 was determined. Calvarial defect was induced in mice by bone drilling, and healing was evaluated after 5 weeks. In dogs, peri‐implantitis was treated by non‐surgical and surgical approaches with or without M101 gel application. Analyses were performed after 2 months. Socket healing was evaluated by micro‐CT after tooth extraction. Local and systemic responses were evaluated after gel administration and intravenous injection. Results The cytocompatibility of M101 was confirmed in osteoblasts, and ALP, Runx2, and BMP‐2 gene expression was increased after exposure ( p &lt; 0.05). In mice, calvarial bone defect healing was 1.6 folds more in the M101 gel treated group than in the untreated group ( p &lt; 0.001). In the extraction model, the local M101 gel application and systemic M101 administration did not induce an immunological response. In the peri‐implantitis dog model, M101 gel as an adjuvant to non‐surgical treatment led to improved PiPD reduction ( p &lt; 0.05) when compared to non‐surgical treatment without M101 gel. No difference was observed when used as an adjunct to surgical treatment. Conclusion M101 may be a safe and interesting candidate as an adjuvant to improve bone healing and non‐surgical treatment in peri‐implantitis.

Objectives This split‐mouth multicentre randomized controlled trial (RCT) aimed to compare the clinical and radiographic success rates of zirconia crowns (ZCs) and stainless steel crowns (SSCs) on primary molars. Secondary objectives were to compare the study groups in terms of retention and preferences of both parents and children. Methods In 105 children, 210 teeth were randomized to receive either ZC or SSC. The primary outcome success rate was defined by the absence of major failure, such as signs of irreversible pulpitis or infectious complications, over a 2‐year follow‐up period. Secondary outcomes included retention rate and participant preference. Data were analyzed with Poisson regression, paired t ‐tests, and ANCOVA, with the significance level set at 5%. Results Success rates were comparable between the ZC and SSC groups (Rate Ratio [RR] = 0.99, 95% confidence interval [CI]:0.96–1.01, p = 0.350). Retention rate was lower for ZCs compared to SSCs (RR = 0.95, 95% CI:0.92–0.98, p = 0.001). Approximately two‐thirds of parents preferred ZCs, while children did not show a clear preference for either type of crown. Conclusions The success rate between ZC and SSC was similar over 2 years, but ZC showed lower retention. Unlike children, parents tended to prefer ZC.

Demonstrating the efficacy of new treatments in any condition may be a challenging endeavor, and is particularly the case in sepsis. In the early 21st century, recombinant activated protein C showed a survival benefit in severe sepsis; however, subsequent studies could not replicate these results, leading to the discontinuation of this agent. Several potential reasons have been proposed for the unfavorable results of trials, including choosing an inappropriate outcome target. Concerning anticoagulant therapies, some studies have targeted sepsis with disseminated intravascular coagulation (DIC) and demonstrated clinical benefits, while other studies have focused on severe sepsis or septic shock independent of whether patients had DIC. The timing for treatment initiation, dosage, and duration of anticoagulant agents could be significant factors contributing to the limitations faced in these trials. Moreover, relying solely on 28-day mortality as the primary endpoint for sepsis trials may not be appropriate, as it can be influenced by various factors beyond anticoagulant therapies, and discernment in a shorter period might be more pertinent. Success in clinical trials is more likely if these issues are addressed and improvements are made. Recent clinical trials concentrating on anticoagulants are increasingly targeting sepsis or septic shock with coagulopathy, and adopting composite endpoints, including DIC resolution, is anticipated to overcome some of these challenges.

Introduction: The main objective : To assess the efficacy of Intact fish skin graft (IFSG) for the closure of University of Texas (UT) Grade 2 and 3 Diabetic foot ulcers (DFUs) versus local standard of care (SOC). Methods: In the French subgroup of a multinational randomized trial, 180 (179 in primary endpoint analysis) patients with UT grade 2 and 3 DFUs (8 centers) were randomized to receive IFSG or SOC, that adhered to the International Working Group on the Diabetic Foot (IWGDF) guidelines. Primary endpoint was complete epithelialization at 16 weeks. Secondary endpoints were healing curve, percentage of wounds healed to 80 % or more in an average of 16 weeks, percentage healed at 20 weeks. Results: The primary endpoint was 41.6 % closure rate in IFSG group versus 22.2 % in SOC group (P = 0.0053). In the intent to treat analysis (ITT), there was a statistically significant difference (P &lt; 0.05) in mean relative wound area between the IFSG and SOC arms at weeks 6.The proportion of patients with complete epithelialization at 20 weeks was 2.11 times higher in the IFSG group than in the SOC group. For those patients that healed a median of 7 graft applications was required. Conclusions: In France, the addition of IFSG to the care plan of patients with deep diabetic foot wounds improved the closure rate by 41.6 % in IFSG group versus 22.2 % in SOC

Background Millions of households have cats or dogs as pets, and infections due to bites or scratches are increasing, with the most common pathogens being Pasteurella spp., Bartonella spp., Capnocytophaga spp, and Francisella tularensis. The objective of this study was to describe patients admitted to the intensive care unit (ICU) for infection transmitted by cats or dogs, as well as their outcomes. Methods The retrospective multicentre observational cohort study PETSEPSIS included consecutive adults admitted to 46 ICUs in France between 2009 and 2019 for sepsis due to cat or dog bites and/or caused by any of the four above-listed bacteria. We described their features and outcomes and performed univariate and multivariate analyses to identify factors associated with death. Results We included 174 patients with a median age of 64 [50–74] years; 58.1% were male. The median SAPS II score was 42 [28–58]. Mechanical ventilation was required in 51.2% of patients, for a median duration of 7 [4–13] days. Vasopressor support was used in 53.5%, renal replacement therapy in 19%, and limb amputation in 3.6% of the patients. The median ICU length of stay was 7 [4–16] days. Hospital mortality was 24.1%. The clinical presentation and severity of sepsis were similar across bacteria, although patients with Pasteurella spp. were older and had more comorbidities. Contact with cats were more often reported for Pasteurella spp. and Bartonella spp. infections and contact with dogs for Capnocytophaga spp. infections. Risk factors for hospital mortality present on ICU admission were older age, smoking, preexisting liver disease, high serum creatinine, and anaemia. Neither the type of micro-organism nor the initial antimicrobial treatment was associated with mortality. Conclusions This large multicentre study shows that infections transmitted by cats and dogs are infrequent reasons for ICU admission but are associated with substantial morbidity and mortality. Mortality was associated with older age and comorbidities but not with the type of microorganism or initial antibiotic treatment.

Since its emergence in 2019, the study of biomarkers in COVID-19 has focused on predicting the course of this potentially fatal disease. The eosinophil/lymphocyte ratio (ELR) appears to be a new indicator of systemic inflammation, morbidity, and mortality in inflammatory, allergic and cancer. The aim of our study was to determine the prognostic value of ELR and its early variation in predicting in-hospital mortality and severity in emergency department (ED) patients with SARS-CoV-2 Infection. Between March 1st and April 30th, 2020, we conducted a multicenter, retrospective study in six major hospitals in northeastern France. The cohort included patients with a confirmed diagnosis of SARS-CoV-2 infection (moderate to severe disease) hospitalized after admission to the ED. A total of 1035 patients were included in this study. ELR at H24 (OR: 0.0054, 95% CI: (0.0001-0.2523), p = 0.008) was associated with severity of infection. The only biochemical factor significantly associated with mortality was ΔELR at H24, i.e., the difference between ELR values at H24 and at admission (OR: 0.0305, 95% CI: (0.0026-0.3626), p = 0.006) in univariate analysis. The best ELR threshold for predicting severity of infection was found with the ELR at H24 with a result of 0.0007 (sensitivity 63.8%; specificity 61%), and for predicting mortality, ΔELR H24 found significant values with a threshold of -0.013 (sensitivity 77.4%; specificity 8.48%). In conclusion, ELR at H24 after ED admission may be a potentially useful biomarker for early prediction of severity of SARS-CoV-2 infection, but its isolated use remains limited for mortality prediction.

Purpose: Decision-making for management of immunosuppressive drugs in solid organ transplant patients admitted to the ICU remains controversial. This study aimed to evaluate the impact of a temporary suspension strategy (interruption of immunosuppressive drugs &gt; 24h) on day-90 mortality and ICU-acquired infections. Methods: This multicenter observational retrospective study conducted in solid organ transplant patients admitted to nine ICUs used a Bayesian approach with priors based on a belief elicitation process conducted among a panel of experts. Results: Among 591 enrolled patients, suspension strategy was used in 34% of them, during a median period of 5 days [IQR: 3-10]. This approach was more common in patients admitted for sepsis (38%) or COVID-19 (49%) than for non-septic causes (24%) (p &lt; 0.001). Overall, day-90 mortality reached 30%, and Bayesian analysis revealed substantial uncertainty with an OR at 1.13 (95% Credible Interval (CrI): 0.74-1.70), and a 15% probability of a beneficial effect. In the subgroup of patients with sepsis, OR was at 0.90 (95% CrI: 0.55-1.55), with a 50% probability of a beneficial effect. ICU-acquired infections occurred in 26% of patients. The suspension strategy indicated a potential benefit, both in the entire cohort, with a 73% probability of a beneficial effect [OR: 0.74 (95% CrI: 0.49-1.15)], and in the subgroup of sepsis patients with a 78% probability of beneficial effect [OR 0.70 (95% CrI, 0.42-1.16)]. Conclusion: Temporary suspension of immunosuppressive drugs may reduce the risk of ICU-acquired infections, with a true uncertainty on day-90 mortality. Prospective studies are warranted to confirm these results.

<div>Periodontitis is an inflammatory disease caused<p>by bacterial infection. Recent studies have identified extracellular vesicles (EVs) as potential mediators of inflammation. This study aimed to evaluate the pro-inflammatory properties and miRNA content of EVs secreted in response to Porphyromonas gingivalis infection. Oral epithelial cells (ECs) were infected with P. gingivalis (MOI 100) for 24 h. EVs from infected (P.g.-ECs-EVs) and uninfected cells (ECs-EVs) were isolated, characterized, and tested on naive ECs. Cellular activity, inflammatory markers (TNF-α, IL-1β), and miRNA content of the secreted EVs were evaluated. Bioinformatic analysis was subsequently performed to identify potential targets of differentially expressed miRNAs. P. gingivalis infection increased EV production by 10 2 -fold. P.g.-ECs-EVs exhibited distinct properties compared to ECs-EVs, including higher metabolic activity and elevated TNF-α and IL-1β expression and secretion levels in exposed ECs. Several inflammation-related miRNAs were highly upregulated in P.g.-ECs-EVs (11-to 142-fold; p &lt; 0.001). P. gingivalis promotes the secretion of pro-inflammatory EVs by ECs, suggesting their role as key mediators in P. gingivalisinduced inflammation and periodontal tissue destruction.</p></div>

The risk of developing symptomatic knee osteoarthritis (KOA) during a lifetime, i.e., pain, aching, or stiffness in a joint associated with radiographic KOA, was estimated in 2008 to be around 40% in men and 47% in women. The clinical and scientific communities lack an efficient diagnostic method to effectively monitor, evaluate, and predict the evolution of KOA before and during the therapeutic protocol. In this review, we summarize the main methods that are used or seem promising for the diagnosis of osteoarthritis, with a specific focus on non- or low-invasive methods. As standard diagnostic tools, arthroscopy, magnetic resonance imaging (MRI), and X-ray radiography provide spatial and direct visualization of the joint. However, discrepancies between findings and patient feelings often occur, indicating a lack of correlation between current imaging methods and clinical symptoms. Alternative strategies are in development, including the analysis of biochemical markers or acoustic emission recordings. These methods have undergone deep development and propose, with non- or minimally invasive procedures, to obtain data on tissue condition. However, they present some drawbacks, such as possible interference or the lack of direct visualization of the tissue. Other original methods show strong potential in the field of KOA monitoring, such as electrical bioimpedance or near-infrared spectrometry. These methods could permit us to obtain cheap, portable, and non-invasive data on joint tissue health, while they still need strong implementation to be validated. Also, the use of Artificial Intelligence (AI) in the diagnosis seems essential to effectively develop and validate predictive models for KOA evolution, provided that a large and robust database is available. This would offer a powerful tool for researchers and clinicians to improve therapeutic strategies while permitting an anticipated adaptation of the clinical protocols, moving toward reliable and personalized medicine.

Background: The KCNH1 gene (OMIM #603,305) encodes a voltage-gated potassium channel primarily found in the central nervous system. Recent discoveries have linked pathogenic variations in this gene to Temple-Baraitser syndrome (TMBTS, OMIM #611,816) and Zimmermann-Laband syndrome (ZLS, OMIM #135,500). A common manifestation of these syndromes is gingival fibromatosis, which may partially or completely cover tooth crowns, leading in some cases to functional and aesthetic problems, as well as delayed tooth eruption. Case presentation: A four-year-old boy and his parents first consulted for delayed primary molars eruption. Shortly after birth, he was diagnosed with a developmental encephalopathy caused by a de novo pathogenic variant in KCNH1. Treatment: The first step of oral treatment consisted of myofunctional and speech/language therapy to stimulate biting and chewing. It also helped with the rehabilitation of proper tongue function. This was followed by a gingivoplasty to expose the submerged teeth. We propose a clinical approach to optimize disease management. This aims to minimize complications associated with this rare disorder. Conclusion: This case illustrates the need for appropriate and early gingivoplasty to prevent teeth impaction and restore dental function. Additionally, it explores potential complications and provides grounds for a comprehensive protocol for managing gingival fibromatosis for patients with KCNH1 variant.

Epicardial adipose tissue (EAT), a unique fat depot surrounding the heart, plays a multifaceted role in glucose and lipid metabolism, thermogenesis, and the secretion of bioactive molecules that influence cardiac structure and function. Its proximity to the myocardium allows it to contribute directly to CVDs, including coronary artery disease, arrhythmias, and heart failure. In particular, excessive EAT has emerged as a significant factor in heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure, especially in individuals with obesity and diabetes. Traditional metrics like body mass index (BMI) fail to capture the complexities of visceral fat, as patients with similar BMIs can exhibit varying CVD risks. EAT accumulation induces mechanical stress and fosters a pro-inflammatory and fibrotic environment, driving cardiac remodeling and dysfunction. Pharmacological modulation of EAT has shown promise in delivering cardiometabolic benefits. Recent advancements in diabetes therapies, such as SGLT2 inhibitors and GLP-1 receptor agonists, and antilipidemic drugs have demonstrated their potential in reducing pro-inflammatory cytokine production and improving glucose regulation, which directly influences EAT. These discoveries suggest that EAT could be a significant therapeutic target, though further investigation is necessary to elucidate its role in HFpEF and other CVDs. Recent advances have identified the prokineticin/PKR1 signaling pathway as pivotal in EAT development and remodeling. This pathway regulates epicardial progenitor cells (EPDCs), promoting angiogenesis while reducing EAT accumulation and metabolic stress on the heart, particularly under high-calorie conditions. Prokineticin, acting through its receptor PKR1, limits visceral adipose tissue growth, enhances insulin sensitivity, and offers cardioprotection by reducing oxidative stress and activating cellular survival pathways. In this review, we provide a comprehensive analysis of EAT's role in CVDs, explore novel therapeutic strategies targeting EAT, and highlight the potential of prokineticin signaling as a promising treatment for HFpEF, obesity, and diabetes.

Comment les compétences psychosociales (CSP) peuvent-elles offrir un cadre pertinent pour intégrer l’empathie dans les processus pédagogiques et évaluatifs des études de santé ? Les CSP sont définies par l’Organisation mondiale de la santé et Santé publique France comme un ensemble cohérent et interrelié de capacités psychologiques. Elles permettent à une personne de maintenir un état de bien-être psychique et d’adopter des comportements adaptés et positifs. En nous appuyant sur les dispositifs évaluatifs déjà en place dans les études de santé, nous proposons des pistes pour inscrire durablement l’empathie, à la fois dans les référentiels de compétences et dans les modalités d’évaluation tout au long des cursus en santé.

Aims Patients living with highly unstable type 1 diabetes (T1D) are eligible for beta-cell replacement (βCR) therapy (islet or pancreas transplantation). This study aimed to evaluate glycemic control in patients treated with automated insulin delivery (AID) following failed βCR therapy, defined as secondary graft failure or marginal function. Material and Methods A national, multicenter, retrospective study was conducted with 23 patients who had βCR failure treated with AID for at least three months. The primary outcome was the proportion of patients achieving recommended glucose targets (time in 70–180mg/dl range [TIR] &gt; 70 %, time below range [TBR] &lt; 4 % and HbA1c &lt; 7 %). Secondary outcomes included TIR, glycemia risk index (GRI), HbA1c, coefficient of variation (CV), body weight, insulin doses, severe hypoglycemia and AID discontinuation. Results The proportion of patients achieving recommended glucose targets under AID increased from 5.0 % to 57.1 % after 12 months. TIR increased from 54.2 ± 18.0 % to 75.5 ± 9.6 % after 12-month AID, while GRI decreased from 45.8 ± 22.2 % to 25.6 ± 10.3 %. HbA1c levels decreased from 7.5 ± 0.9 % to 7.0 ± 1.1 % after 12-month AID. CV, body weight and insulin doses did not change. All patients were free from severe hypoglycemia under AID, including those who had experienced severe hypoglycemia after βCR failure. No patient discontinued the AID. Conclusions This study highlights the effectiveness of AID in achieving glucose control targets and preventing severe hypoglycemia in patients with T1D following βCR failure. AID may serve as a valuable therapeutic option to improve glucose control when graft function declines.

Patients with a history of periodontitis often require bone augmentation prior to implant placement; however, the mid-term outcomes of implants in augmented sites are not well documented. The aim of this retrospective study was to evaluate the mid-term survival and peri-implant health of implants placed in xenograft-augmented sites in patients with a history of periodontitis. Records of 34 patients (mean age: 65.3 ± 12 years; 64.7% Stage III, 29.4% Stage IV periodontitis) treated at the University of Strasbourg between 2015 and 2023 were analyzed, including 62 implants placed in xenograft-augmented sites. The mean follow-up was 5.74 ± 2.3 years. No implant failures occurred, yielding a 100% survival rate. The mean probing depth was 2.98 mm, and bleeding on probing averaged 25.5%. Marginal bone loss averaged 0.86 mm (distal) and 0.87 mm (mesial), corresponding to an annual bone loss of 0.18 mm; the most frequent bone loss pattern was vertical (71%). No peri-implantitis was observed; 54.8% of implants presented peri-implant mucositis, and 45.2% were classified as healthy. Within the limitations of this study, implants placed in xenograft-augmented sites in periodontally compromised patients demonstrated excellent mid-term survival and peri-implant tissue stability.

Basic and translational research in lung cancer is a rapidly evolving field with a transformational impact on early detection, diagnosis, therapeutic development, and personalization of care. Recent advances have greatly increased our understanding of the molecular genomics, proteomics, pathogenesis, and cellular biology of this deadly malignancy. The International Association for the Study of Lung Cancer (IASLC) recently formed a Basic and Translational Science (BaTS) Committee to further enhance the scientific leadership of IASLC in thoracic cancer research. This review by members of the committee highlights the breadth of current research in NSCLC, with a focus on molecular risk factors and processes in tumorigenesis, heterogeneity, phenotypic plasticity, metabolic reprogramming, immunobiology, the immune microenvironment, and microbiome. This review also identifies future research areas that may lead to further improvement in survival outcomes and curative therapies especially for patients with advanced NSCLC.

Purpose: The loss of interdental papilla (IDP) is a significant esthetic concern often associated with black triangles (BT). BT are potential consequences of periodontitis, orthodontic treatment, and anatomical variations due to their influence on the critical distance from the contact point to the bone crest. Various treatment options, both invasive and non-invasive, have been proposed to address this issue. Recently, the injection of hyaluronic acid (HA) has emerged as a promising minimally invasive alternative. This systematic review aims to evaluate the effectiveness of HA injections for IDP reconstruction in esthetic zones in humans. Materials and methods: A comprehensive literature search was conducted using Cochrane library, PubMed/MEDLINE, and Embase databases with keywords like 'interdental papilla,' 'hyaluronic acid,' and 'human'. Change in BT mean height (mm) was considered as the primary outcome while percentage of change in BT area was considered as the secondary outcome. Results: 177 articles were screened, and 15 eligible studies were included, focusing on the therapeutic effects of HA injections on interdental papilla dimensions in humans. Clinical trials have demonstrated varying degrees of success and patient satisfaction with HA injections for IDP reconstruction over a period of 4 weeks to 25 months. Several studies showed significant improvements related to BT height and width, although complete papilla fill remains unpredictable. Higher success rates were observed in the maxilla compared to the mandible, and patients with thicker gingival phenotype showed better outcomes. The initial size of the defect, the number of HA applications and the analysis method significantly influenced the results. Conclusion: HA injections look promising for IDP reconstruction. However, the need for multiple injections and long-term efficacy remains to be fully understood. Further research is necessary to standardise treatment protocols and evaluate long-term outcomes and patient satisfaction comprehensively.

No abstract available

Onco-hematological (OH) patients face significant cardiovascular risks due to malignancy and drug toxicity. Data are limited on the characteristics and outcomes of OH patients with cardiogenic shock (CS) in intensive care units (ICUs).

Background: The forced expiratory volume in one second (FEV1) is the standard measure used to monitor the lung function after lung transplantation. However, little is known about the FEV1 trajectories post transplantation, and their associations with clinical outcomes. Methods: Adult patients who received a bilateral lung transplant between January 1, 2010 and January 1, 2021 were included from 15 centers in France, Belgium, Austria and the US. Three French centers formed the development cohort and the remaining centers formed the external validation cohorts. All centers performed routine spirometry measurements commencing shortly after lung transplantation and continuing at regular intervals of maximum three months afterwards. Recipient, donor and transplant characteristics were collected. Latent class mixed models were used to identify FEV1 trajectories. The number of FEV1 trajectories was defined according to the Akaike Information Criterion, Bayesian Information Criterion, the discrimination, the entropy and the interpretability of the model. Findings: A total of 2305 patients were included with 59 034 FEV1 measurements collected. The median follow-up post-transplantation was 4.3 years (IQR 2.3-6.2). In the development cohort (n=605), the best latent class mixed model identified seven clinically meaningful FEV1 trajectories. Trajectory #1 (25.6%) was characterized by patients with moderate and stable lung function (3-year patient survival = 79.9%); trajectory #2 (24.0%) and #3 (27.3%) were characterized by patients with moderate/high and stable lung function (3-year patient survival = 96.6% and 95.7% respectively); trajectory #4 (3.8%) was characterized by patients with increasing lung function (3-year patient survival = 69.6%); trajectory #5 (11.7%) was characterized by patients with a slow decline (3-year patient survival = 90.1%); and trajectory #6 (3.0%) and #7 (4.6%) were characterized by patients with accelerated decline (3-year patient survival = 33.3% and 59.5% respectively). Patients belonging to trajectories were associated with gender (p=0.020) and underlying disease (p=0.004). Similar FEV1 trajectories and patient outcomes were identified in the external validation cohorts on the basis of independent analyses. The trajectories were also confirmed in a series of subpopulations. Last, FEV1 value and slope at 1 year post transplant were strongly associated with FEV1 trajectories, in both the development cohort and the external validation cohorts. Interpretation: We identified and validated FEV1 trajectories that capture different clinical scenarios associated with post-transplant recipient outcomes. Our results may provide the basis for a trajectory-based risk assessment of lung transplant recipients. Funding: "Vaincre la mucoviscidose" grant, the association Grégory Lemarchal, ANR grant, PHRC grant, the FP7 collaborative project, IRSRPL grant, the Fondation du Souffle and PLUTO DITCAP grant from Vaincre la Mucoviscidose and Association Grégory Lemarchal.

Objective To provide updated guidelines for the management of acute pain in adult patients in emergency settings. Design A consensus committee of 31 experts from the French Society for Emergency Medicine (Société française de médecine d’urgence, SFMU), including 10 pain specialists (with national/international publications), was convened. A formal conflict-of-interest (COI) policy was developed at the beginning of the process and enforced throughout. The entire guideline construction process was conducted independently of any industrial funding (i.e., pharmaceutical, medical devices). The authors were required to follow the rules of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence. Methods The aim of this expert panel was to evaluate the medical treatment of acute pain in emergency care settings both inside and outside of hospitals. The experts explored questions within three domains: 1) indication for analgesic treatment following pain assessment and the organization of the health care teams; 2) pharmacological and non-pharmacological management; and 3) continuation of analgesic treatment following discharge from the emergency department or during hospital admission. Each question was formulated according to the PICO (Patients Intervention Comparison Outcome) model, and corresponding evidence profiles were produced. Based on these clinical questions, an extensive bibliographical search over the last 20 years was carried out using predefined keywords in accordance with PRISMA recommendations. Data quality was analyzed using the GRADE method. Recommendations were then formulated using the GRADE method and voted on by all the experts according to the GRADE Grid method. Results The experts’ synthesis work and the application of the GRADE® method resulted in 35 recommendations and 1 diagram. After 2 rounds of voting and several amendments, strong consensus was reached for all the recommendations. Among the formalized recommendations, 5 have high levels of evidence (GRADE 1) and 13 have low levels of evidence (GRADE 2). For 17 recommendations, the GRADE method could not be applied, resulting in expert opinions. For 4 questions, no recommendation could be made due to a lack of available data. Conclusions: There was strong expert consensus on 35 recommendations to improve the management of acute pain in adult patients in emergency settings.

Objectives: In recent years, targeted therapy and immunotherapy have been demonstrated to improve survival in non-operable, non-small cell lung cancer (NSCLC) patients. The results of salvage lung resection in patients with initially unresectable advanced NSCLC after immune checkpoint inhibitor (ICI) or Target Therapy (TT) treatment remain unclear. This study aimed to define the outcomes of patients undergoing salvage surgery in a multi-center real-life setting. Methods: An international multicenter retrospective cohort study was conducted. Patients included in the study were judged inoperable, according to a multidisciplinary tumor board decision, before being submitted to ICI or TKI treatment. The rate of complications, the overall survival (OS), and progression-free survival (PFS) were compared. Crude and Multivariable-adjusted analysis were conducted. Results: Nighty-eight patients affected by NSCLC were included in the study. Most patients were female (N = 50-51 %), and the median age at surgery was 62 years. While ICI was performed in 29 patients (30 %), TT was done in 45 (46 %), and ICI plus chemotherapy in 24 (24 %). The inoperability was determined by metastatic disease in 43 cases (44 %), N2-N3 advanced disease in 18 (18 %), local invasiveness in 10 (10 %), a combination of local invasiveness and N-status in 26 (27 %), and other reasons in 1 case (1 %). Overall, the complication rate was 30 %, the mortality rate was 1 %, and the median LOS was 6 days. No residual lung disease (ypT0) was observed in 30 patients (31 %). The 5-year OS was 74 %, while the 5-year PFS was 44 %. Performing sublobar resections was an independent adverse prognostic factor in the multivariable analysis for survival (P &lt; 0.01), while the pathological complete response (pCR) was an independent prognostic predictor of improved survival (P = 0.025). On multivariable analysis performing a sublobar resection (P &lt; 0.01), an increasing ypT stage (P &lt; 0.01), and postoperative therapy (P &lt; 0.01) were independent prognostic predictors, correlating with impaired disease progression. Conclusions: Patients selected for Salvage Surgery after ICI or TT have reasonable post-operative and long-term outcomes. In this context, Salvage Surgery could be proposed in selected patients after a careful multidisciplinary evaluation.

Aims Understanding and integrating patients' preferences into clinical practice can enhance personalized care, improve patient's adherence to treatment, and lead to better therapeutic outcomes. The aim of this scoping review was to map the existing literature investigating patients' preferences in periodontal and implant therapy while identifying key areas for future research and development. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines, an electronic search was conducted in four databases (PubMed, Google Scholar, Cochrane Library, and ScienceDirect) in July 2024 to identify studies evaluating patients' preferences for periodontal and implant therapy. Results The literature search yielded 384 studies, of which eight articles met the inclusion criteria. These studies were conducted between 2003 and 2019 in Brazil, China, Austria, Italy, Germany, Canada, USA, Chile, France, Spain, and Portugal. A total of 1642 patients were included. Preferences were assessed using various quantitative and mixed methodologies. Results indicate a strong preference for treatments aimed at preserving teeth, favoring conservative approaches. When teeth cannot be restored, most patients prefer an implant-supported fixed partial denture to avoid damaging adjacent teeth with a conventional tooth-supported fixed partial denture. In this context, treatment predictability is ranked as the most important factor. While no sociodemographic factors appeared to be associated with preferences in periodontal treatments, several predictors were identified for dental implant therapy. Younger patients, women, individuals with higher education levels, and those with high perceived dental health showed a higher willingness to pay for dental implants. Conclusion The literature on patients' preferences in periodontal and implant therapies is scarce. Several trends are identified but further longitudinal studies are needed to explore patients' preferences over time and the role of sociodemographic and cultural segmentation criteria.

Rationale : Bronchiolitis obliterans syndrome (BOS) limits long-term survival after lung transplantation (LuTx) and may be triggered by infections. As immunoglobulin (Ig)A is crucial to ensure adequate mucosal immunity, we explored whether IgA-related mucosal immunity is impaired in BOS. Methods : Sixty LuTx recipients from the COLT cohort were retrospectively included. All participants were in stable condition within the first year post-transplant. At 3.5 years post-LuTx, 30 remained stable and 30 had developed BOS. Bronchoalveolar lavage fluid (BALF) and sera collected pre-transplant and at 6 (M6) and 12 months (M12) post-transplant were assessed for monomeric IgA, secretory (S)-IgA, secretory component (SC) and cytokine profiling. Second, bronchiolar polymeric Ig receptor (pIgR) expression and subepithelial IgA-producing B-cell numbers were compared across graft tissue samples from 54 LuTx recipients classified as stable, pre-BOS, BOS or end-stage BOS. Results : S-IgA levels in BALF decreased between M6 and M12 (p=0.0001) and were reduced in BOS patients at M12 (p=0.0018). Patients with lower S-IgA levels had higher infection rates. BOS patients exhibited elevated SC levels in serum (p&lt;0.01). Both reduced S-IgA in BALF and increased SC in serum were associated with higher risk of BOS. Lastly, a reduction in bronchiolar pIgR expression was observed in BOS patients (p=0.0001), that paralleled BOS severity. Conclusions : This study demonstrates an early impairment of mucosal IgA immunity in LuTx patients, which was linked to the later development of BOS, suggesting that IgA-related markers may serve as early predictors of BOS onset.

IntroductionLateral opening wedge distal femoral varus osteotomy (LOWDFO) is indicated for early isolated lateral compartment osteoarthritis in young patients with genu valgum due to an isolated distal femoral metaphyseal deformity. A medial hinge fracture is considered a poor prognostic factor for radio-clinical outcomes, hence its prevention is crucial. The protective role of a temporary pin has been demonstrated in the literature. The primary objective of this study was to evaluate the influence of the antero-posterior position of this pin on hinge protection.HypothesisThe main hypothesis was that a centrally positioned pin offers the best resistance to breakage compared to anterior and posterior positions.Materials and methodsThe experimental model was a 3D model of a distal femur, fabricated and printed from the pre-operative CT scan of a patient who underwent a LOWDFO. ABS polymer was chosen for printing these models due to its fracture characteristics similar to bone. Fifteen specimens were printed. Three different cutting guides were also printed, each corresponding to one of the three pin protection positions, the use of these cutting guides ensure the reproducibility of pin positioning. Three pin positions were defined: 25% anterior and 75% posterior junction (anterior group) on a horizontal plane of the distal femur, 50%-50% junction (central group), and 75% anterior and 25% posterior junction (posterior group). The tests were conducted on a single-column traction-compression machine 3345® (Instron™, Norwood, MA, USA). The protocol involved opening the osteotomy until breakage, defined by the appearance of the first fissure at the hinge. The primary outcome measure was the maximum force at breakage, and secondary outcomes were displacement before breakage and stiffness.ResultsThe "Central group" showed, in absolute terms (mean of 130.9 N), the greatest breaking force. This difference was statistically significant (SS) only compared to the "Anterior group" (mean of 85.09 N). The "Central group" also demonstrated the highest stiffness (mean of 15.70 N/mm) with a SS difference compared to the other two groups (9.06 N/mm for the anterior group and 11.98 N/mm for the posterior group).DiscussionThese results confirm the working hypothesis: a centrally positioned pin provides increased protection of the medial hinge during a LOWDFO. Although this in vitro study can only approximate actual in vivo conditions, it provides valuable insights into the optimal position of the pin for hinge protection. However clinical studies are needed.

The purpose of this study was to compare the length of stay (LOS) and costs of diagnostic workup by Ultra Low Dose (ULD) chest computed tomography and radiography for patients treated for a community-acquired pneumonia (CAP) in the emergency department (ED). Methods: We conducted a real-life retrospective study of patients treated for a CAP in two ED between March 1, 2019 and February 29, 2020. We estimated length of stay (LOS) as the difference between ED discharge and entry times, total hospital costs at 60 days including ED, initial admissions and readmissions. Patients with initial radiography were compared with patients with initial ULD CT using inverse probability weighing of the propensity score calculated from demographic variables, vital parameters and clinical presentation. We calculated the incremental cost effectiveness ratio as the difference between costs and the difference between LOS. Variability of the results was assessed using non-parametric bootstrapping. Results: We included 1609 consecutive patients, 1476 patients with radiography and 133 patients with ULD CT. The average costs were respectively €4317 [3483; 5067] and €4223 [4034; 4612] with 11.9 [10.1; 13.2] and 11.7 [11.5; 12.2] hours of LOS in the ED for chest radiography and ULD chest CT respectively, resulting in lower costs of € -94 [-870; 819] and a decreased LOS of 12 [-108; 76.9] minutes in favor of ULD chest CT. Conclusions: In this real-life study, the management of CAP in ED by ULD chest CT compared with chest radiography resulted in lower costs without increasing LOS.

Background: Maxillary canine impaction is the second most common dental eruption anomaly, affecting approximately 0.2-3% of individuals, with a higher incidence in females. This condition often results in complications such as the misalignment of adjacent teeth, root resorption, and the development of cystic lesions. In some cases, abstention is recommended for impacted canine is kept with the lacteal tooth held on the dental arch. But in the longer term an implant therapy is nevertheless indicated. Case presentation: A 42-year-old man presented with persistent swelling and pain in the maxillary region associated with a transcanine implant placed one year ago by his dental practitioner. Imaging assessment showed the implant's apex inserted into the impacted canine which presented a crown and root resorption and was associated to a radiolucency around. In order to preserve implant and reduce morbidity related to a full extraction of the tooth, a coronectomy was performed allowing inflammatory surrounding tissues curettage. Discussion: This case shows an infectious complication of a transcanine implant and demonstrates an approach for managing these complications while preserving this implant. The coronectomy is a less invasive technique that reduces potential surgical complications and supports healing. A 2-year follow-up revealed complete bone reossification reinforcing the effectiveness of this method in similar clinical scenarios. Conclusion: This case suggests that coronectomy may be a viable option for managing impacted canines in proximity to implants when complete extraction poses a high risk of complications. However, given the limited number of reported cases and the absence of long-term data, this approach should be considered with caution. Further studies are necessary to better define the indications, long-term outcomes, and potential risks of this technique.

Aims Cardiogenic shock (CS) is a heterogeneous syndrome in which recent guidelines have proposed clinical phenotyping based on the presence of hypoperfusion and/or congestion signs and symptoms. However, the impact of this clinical phenotype on outcomes remains poorly characterized. Methods and results FRENSHOCK is a prospective registry including 772 CS patients from 49 centres. Patients were categorized into multiple phenotypic groups based on three clinically assessed bedside criteria at admission: congestion, hypotension and skin mottling. The primary endpoint was 30‐day all‐cause mortality. Among 475 CS patients included, 69.7% were male, with a median age of 67.0 (59.0–78.0) years. Most patients presented with SCAI stage C (37.1%) or D (51.2%). At admission, 424 patients (89.3%) presented with congestion (50.7% on both sides, 39.2% left‐sided, 10.1% right‐sided), 343 (72.2%) with hypotension and 180 (37.9%) with mottling. At 30 days, 113 patients (23.8%) had died, spanning from 8.8% for patients with isolated hypotension (without congestion/mottling) to 26.5% for patients with hypotension and congestion, and 32.3% for patients with hypotension, congestion and mottling. The corresponding ORs for 30‐day all‐cause mortality remained significant even after adjustment for potential confounders, with 1.19 [(1.02–1.39), P = 0.03] for hypotension and congestion and 1.26 [(1.08–1.48), P &lt; 0.01] for hypotension, congestion and mottling. Conclusions A simple clinical bedside evaluation of the CS phenotype based on hypotension, congestion and mottling allows for quick and costless stratification of 30‐day mortality risk and can be used to guide the level of monitoring intensity and/or patient management.

Background : There are limited data on optimal management of chronic lung allograft dysfunction (CLAD). We aimed to describe the variability of diagnostic and therapeutic practices in Europe. Methods : A structured questionnaire was sent to 71 centres in 24 countries. Questions were related to contemporary clinical practices for workup, monitoring and treatment of CLAD. The number of lung transplant procedures and patients in follow-up were collected. Results : 44 centres (62%) responded from 20 countries, representing 74% of European activity. The prevalence of CLAD was estimated at 9.1 cases per million population (25th and 75th percentiles of 4.4, 15.7). Preferred initial workup for probable CLAD consisted of chest computed tomography (CT) (inspiratory 91% and expiratory 74%), donor-specific antibody (DSA) measurement (86%), bronchoalveolar lavage (BAL) (85%) and transbronchial biopsy (81%). For monitoring of definite CLAD, inspiratory CT (67%), DSA (61%) and BAL (43%) were preferred. Body plethysmography was unavailable for 16% of cases. Prophylaxis was based on preventing infections (cytomegalovirus 99%, inhaled antibiotics 70% and antifungals 65%), tacrolimus-based immunosuppression (96%), azithromycin (72%) and universal proton pump inhibitor treatment (84%). First-line treatment of CLAD was based on azithromycin (82%) and steroid augmentation (74%). Photopheresis was used in 26% of cases. Conclusion : Current European practice CLAD detection is based on spirometry, inspiratory CT and DSA, with limited access to plethysmography and expiratory CT. Prophylactic treatment is based on azithromycin, tacrolimus-based immunosuppression and treatment of risk factors. No single treatment strategy is universally used, highlighting the need for an effective treatment of CLAD. The preferred first-line strategy is azithromycin and steroid augmentation.

<div><p>In recent years, photodynamic therapy (PDT) has emerged as a promising alternative to classical chemotherapy for treating cancer. PDT is based on a nontoxic prodrug called photosensitizer (PS) activated by light at the desired location. Upon irradiation, the PS reacts with the oxygen present in the tumor, producing cytotoxic reactive oxygen species (ROS). Compounds with highly conjugated π-bond systems, such as porphyrins and chlorins, have proven to be excellent light scavengers, and introducing a metal atom in their structure improved the generation of ROS. In this work, a series of tetrapyrrole-ruthenium(II) complexes derived from protoporphyrin IX and the commercial drug verteporfin were designed as photosensitizers for PDT. The complexes were almost nontoxic on human gastric cancer cells under dark conditions, revealing remarkable cytotoxicity upon irradiation with light. The ruthenium atom in the central cavity of the chlorin ligand allowed combined mechanisms in photodynamic therapy, as both singlet oxygen and superoxide radicals were detected. Additionally, one complex produced large amounts of singlet oxygen under hypoxic conditions. Biological assays demonstrated that the ruthenium derivatives caused cell death through a caspase 3 mediated apoptotic pathway and via CHOP, an endoplasmic reticulum stress-inducible transcription factor involved in apoptosis and growth arrest.</p></div>

OBJECTIVE This study aimed to evaluate the impact of islet transplantation (IT) on diabetes complications, death, and cancer incidence. RESEARCH DESIGN AND METHODS This retrospective, multicenter, cohort study included patients from three IT clinical trials (intervention group) and from the French health insurance claims database Système National des Données de Santé (SNDS) (control group). Two cohorts of IT recipients were analyzed: IT recipients after kidney transplantation (IAK) and IT recipients alone (ITA). They were matched with patients living with type 1 diabetes (T1D) from the SNDS using a propensity score. The primary outcome was a composite criterion including death, dialysis, amputation, nonfatal stroke, nonfatal myocardial infarction, and transient ischemic attack. The secondary outcome was cancer. Hazard ratio (HRs) and P values were obtained using Cox proportional hazards analysis and log-rank test, respectively. RESULTS The study included 61 ITA recipients matched to 610 T1D control patients and 45 IAK recipients matched to 45 T1D control patients over a median follow-up period >10 years. Compared with T1D control patients, ITA and IAK recipients had a lower composite outcome risk (HR 0.39 [95% CI 0.21–0.71; P = 0.002] and 0.52 [0.30–0.88; P = 0.014], respectively) that seemed driven by reduced mortality (0.22 [0.09–0.54]; P < 0.001) for ITA and reduced dialysis (0.19 [0.07–0.50]; P < 0.001) for IAK. Both groups showed no significant changes in cancer risk. CONCLUSIONS This study suggests long-term benefits of IT on diabetes-related outcomes. Furthermore, despite the use of immunosuppressive drugs following IT, we observed no significant increase in the risk of cancer. Altogether, these findings highlight a favorable risk-benefit ratio of IT in treating patients with unstable T1D.

Background and objective Given the conflicting evidence currently available in the literature, our aim was to assess the prognostic and predictive values of the deficient mismatch repair (dMMR) phenotype in a large cohort of upper tract urothelial carcinoma (UTUC) patients. Methods Based on our national network, we performed a retrospective multicenter study including 281 UTUC patients treated with radical nephroureterectomy between 2000 and 2015 at ten French hospitals. The dMMR phenotype as well as PD-L1 and PD-1 expression were determined using immunohistochemistry analyses based on 2-mm-core tissue microarrays. Multivariable Cox regression models were fitted to assess the impact of the dMMR phenotype on recurrence-free (RFS), cancer-specific (CSS), and overall (OS) survival using interaction terms to test the heterogeneity of the treatment effect of adjuvant chemotherapy (AC). Multivariable logistic regression models were also fitted to assess the impact of the dMMR phenotype on PD-L1 and PD-1 expression. Key findings and limitations Overall, 76 (27.0%) patients had a dMMR phenotype, which was an independent predictor of prolonged RFS (hazard ratio [HR] = 0.41; 95% confidence interval [CI] = [0.21–0.83]; p = 0.01), CSS (HR = 0.38; 95% CI = [0.18–0.83]; p = 0.02), and OS (HR = 0.44; 95% CI = [0.22–0.89]; p = 0.02), with a significant interaction with the use of AC in multivariable Cox regression models (all pinteraction < 0.05). Subgroup analyses showed that the use of AC was significantly associated with prolonged RFS (HR = 0.14; 95% CI = [0.06–0.30]; p < 0.001), CSS (HR = 0.10; 95% CI = [0.03–0.29]; p < 0.001), and OS (HR = 0.23; 95% CI = [0.10–0.54]; p = 0.001) in non-dMMR patients only, without any significant benefit in dMMR patients (all p > 0.05). In multivariable logistic regression analyses, the dMMR phenotype was significantly associated with inverse PD-L1 (OR = 0.20; 95% CI = [0.10–0.80]; p = 0.001) and PD-1 (OR = 0.36; 95% CI = [0.16–0.79]; p = 0.01) expression. Conclusions and clinical implications We observed that the dMMR phenotype was associated with favorable pathological characteristics and prognosis in UTUC patients, despite conferring decreased sensitivity to AC and lower PD-L1 or PD-1 expression.

<div><p>Purpose Cardiogenic shock (CS) remains a critical condition with high mortality rates despite advances in treatment. This study aims to comprehensively evaluate both macrocirculatory and tissue perfusion variables over the initial 24 h post-admission to determine their impact on patient prognosis and identify potential hemodynamic thresholds for optimal outcomes. Secondary aims were to explore the correlation between macrocirculatory and tissue perfusion variables.</p><p>Design This is a post hoc analysis of data from two prospective studies, OptimaCC (NCT01367743) and MicroShock (NCT03436641), involving only patients with CS. Both studies applied regular assessment of hemodynamic variables at specific time points (admission, 6, 12, and 24 h) to ensure consistency in data collection, enrolling 118 patients between September 2011 and July 2021, with similar inclusion criteria and care processes.</p></div> <div>Results<p>The median age of the cohort was 69 years, 59% being male. The primary outcome, 30-day mortality, occurred in 37% of patients. Average macrocirculation variables over the first 24 h of CS such as mean arterial pressure (MAP), cardiac output (CO), cardiac index (CI), and cardiac power index (CPI) were significantly lower in patients meeting the primary outcome. Accordingly, average tissue perfusion variables (ΔPCO 2 and ΔPCO 2 /C(a-v)O 2 ) over the first 24 h of CS were also consistently impaired in patients meeting the primary outcome. The optimal clinically relevant thresholds of the first 24 h time course for poor outcomes, closely approximating the optimal values identified in the analysis, were: mean SAP &lt; 95 mmHg, MAP &lt; 70 mmHg, CO &lt; 3.5 L/min, CI ≤ 1.8 L/min/m 2 , CPI &lt; 0.27 W/m 2 , ScvO 2 &lt; 70%, ΔPCO 2 ≥ 9 mmHg, and ΔPCO 2 /C(a-v)O 2 ≥ 1.5 mmHg/mL.</p></div> <div>Conclusions<p>This study is the first to identify critical hemodynamic thresholds, encompassing both macrocirculatory and tissue perfusion variables, within the initial 24 h of CS that are associated with adverse outcomes. The identified thresholds suggest specific hemodynamic targets that may guide resuscitation strategies.</p></div>

Background: Patient characteristics, technology and clinical practice surrounding primary prevention implantable cardioverter defibrillators have evolved continuously over time. Aim: To explore the temporal changes in patient characteristics, pharmacological therapy and device types among implantable cardioverter defibrillator recipients implanted for the primary prevention of sudden cardiac death over the last two decades in France. Methods: Characteristics of participants and type of device from the retrospective DAI-PP Pilot Study (2002-2012) were compared with those from the ongoing prospective DAI-PP Consortium (2018 onwards). Results: This study included 9588 participants overall (DAI-PP Pilot Study, n=5539; DAI-PP Consortium, n=4049). Compared with the DAI-PP Pilot Study, the DAI-PP Consortium subjects were older at implantation (62.5 vs 65.2 years; P=0.001) and had a higher proportion of women (15.1% vs 20.6%; P&lt;0.001), a similar proportion of ischaemic heart disease (60.2% vs 60.2%; P=0.98), a higher left ventricular ejection fraction (27±7% vs 30±8%; P&lt;0.001) and more patients with narrow QRS complexes (30.5% vs 46.0%; P&lt;0.001). The proportion of patients treated with heart failure drugs increased significantly (70.1% vs 83.1%; P&lt;0.001), whereas the use of amiodarone became much less frequent (22.7% vs 14.7%; P&lt;0.001). Finally, the proportions of cardiac resynchronization therapy defibrillators (53.8% vs 46.4%; P&lt;0.001) and dual-chamber defibrillators (23.3% vs 17.3%; P&lt;0.001) decreased, whereas subcutaneous implantable cardioverter defibrillators now account for a sizeable proportion of implants (14.6%). Conclusions: Over a 20-year period, the primary prevention implantable cardioverter defibrillator population has evolved significantly, with an older age and a higher proportion of women. The type of device has changed, with fewer cardiac resynchronization therapy defibrillators and more subcutaneous implantable cardioverter defibrillators.

Background: Cardiogenic shock (CS) in patients with left ventricular hypertrophy (LVH) due to hypertrophic cardiomyopathy (HCM) or hypertensive heart disease, is underreported in the literature. This study aimed to delineate the characteristics, management strategies and outcomes of patients experiencing CS with preexisting LVH and HCM.Methods: FRENSHOCK is a prospective multicenter registry including 772 unselected CS patients from 49 centers. Baseline characteristics, management and 1-year outcomes were analyzed according to the occurrence on preexisting LVH.Results: Within 772 CS patients included, CS occur on a preexisting LVH in 34 patients (4.4%, 1.4% with HCM). Clinical characteristics, medical history, and usual medications, as well as hemodynamic parameters upon inclusion, did not differ between patients with or without LVH. The LVEF in CS patients with LVH was 27.3 ± 14.5% indicating a non-obstructive cause of CS. In-hospital management according to LVH and non-LVH groups indicated no differences between the groups. The 1-month and 1-year mortality did not differ between CS patients with and without LVH (respectively 26.5% vs 26%, (adjusted HR [95% CI]: 0.87 [0.44-1.72]) and 55.9% vs 44.7%, (adjusted HR [95% CI]:0.88 [0.54-1.42]). Subgroup analyses comparing HCM (n =11) and hypertensive LVH (n=23) revealed similar clinical characteristics, in-hospital management, and one-year rehospitalization rates for these patients.Conclusion: In a large and unselected CS population, the prevalence of LVH patients is low (4.4%) with less than half having HCM (1.4%). The presentation, management, and outcomes of CS are similar to the broader CS population in our series. However, HCM-CS represents a distinct clinical entity necessitating tailored management approaches.

Introduction and aims: EMONO (equimolar oxygen-nitrous oxide mixture) is widely used in dentistry to achieve sedation for dental care. In addition, pure nonmedical nitrous oxide (N2O) has become a very popular psychoactive substance among health students. Thus, for dental students, the perception of a same substance, N2O, which can either be used as medicine in the form of EMONO in their daily practice, or consumed illegally for recreational purposes in the form of pure nonmedical N2O, is of concern. This study aims to estimate the prevalence of N2O (EMONO and pure nonmedical N2O) use among French dental students.<p>Methods: A cross-sectional multicentre study was carried out in six French dental schools. A self-administered questionnaire was offered to 2nd to 6th-year odontology students about their position with regard to N2O and its potential use.</p> <div>Results:<p>The prevalence of N2O use among the 1124 responding students was 50.4%, with heterogeneity according to dental school. 84% of the students who used N2O did so at least once for recreational purpose, while 16% used it only in the context of care and/or training.</p><p>Students with recreational N2O use were more likely to use other substances than students with care/training use. Nearly three-quarters of the students sought and experienced euphoria and laughter.</p></div> <div>Conclusion:<p>Nearly half the students in our study reported having used N2O recreationally, most of them regularly, a much higher prevalence than among nonhealthcare students.</p></div>

Aim Alteration of bowel function after delayed coloanal anastomosis (DCAA) might be a limitation to its utilization. Our aim was to assess the long‐term bowel function of DCAA in a large multicentric cohort. Method All patients who underwent DCAA interventions at 29 GRECCAR‐affiliated hospitals between 2010 and 2021 were retrospectively included. Low anterior resection syndrome (LARS) score or confection of a stoma due to poor bowel function was assessed in eligible patients. Good bowel function was defined by the preservation of bowel continuity with no LARS or a minor LARS. Results Among the 385 eligible patients to assess long‐term bowel continuity, 63% ( n = 243) responded to the questionnaire or had a definitive stoma because of poor bowel function. After a median follow‐up of 32 months, good bowel function was reported by 60% ( n = 146) of patients (with no LARS 36% and minor LARS 24%), whereas 40% of patients ( n = 146) had a poor bowel function including major LARS (36%) and definitive stoma due to poor bowel function (4%). No variables tested were predictive of a poor bowel function after DCAA, including a history of pelvic radiotherapy ( P = 0.722), salvage DCAA after failure of a previous anastomosis ( P = 0.755), presence of a diverting stoma ( P = 0.556), occurrence of an anastomotic leakage ( P = 0.416) and time interval from the DCAA to the bowel function assessment ( P = 0.350). Conclusions No LARS or minor LARS was reached for 60% of patients after DCAA. Less than 5% of patients received a definitive stoma due to a poor bowel function.

Objectif Cette étude vise à présenter et analyser les résultats de la cohorte française dans une enquête de l’European Board of Ophthalmology (EBO) sur la formation à la chirurgie de la cataracte en Europe, mettant en lumière les particularités de la formation française. Matériels et méthodes Un questionnaire électronique de 23 questions a été envoyé aux internes candidats à l’examen de l’EBO de 2018 à 2022. Les réponses des participants français ont été spécifiquement collectées et analysées. Résultats Sur 122 ophtalmologistes français répondants, l’âge moyen était de 31,0±2,8 ans avec une répartition égale entre hommes et femmes. Les séances de formation pré-patient les plus fréquentes étaient sur simulateurs de réalité virtuelle (8,6±8,2 séances). Les répondants français déclaraient un nombre moyen plus élevé de chirurgies partielles (124,1±94,8) et complètes (96,4±93,1), avec une confiance accrue (échelle de 0 à 10) dans l’exécution de chirurgies simples (7,3±2,4) et complexes (5,51±2,6), ainsi que dans la gestion de ruptures capsulaires postérieures (7,2±2,5) ou réalisation de sutures cornéennes (3,9±2,7) par rapport à la moyenne des participants européens. Discussion Dans le paysage européen, la formation française en chirurgie de la cataracte s’inscrit dans un modèle de « chirurgie pour tous », sans disparité de genre. Des variations régionales marquent cependant le paysage français, contrastant avec d’autres nations européennes comme l’Espagne ou l’Allemagne. Conclusion Pour une harmonisation des formations en chirurgie de la cataracte en Europe, il est conseillé d’établir des recommandations et stratégies éducatives, y compris la standardisation des formations pré-patients pour assurer la validation des compétences chirurgicales.

Background: Conflicting data exist regarding sex-specific outcomes after cardiac arrest. This study investigates sex disparities in the provision of critical care and outcomes of in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) patients. Methods: Analysis of adult cardiac arrest patients admitted to certified Swiss intensive care units (ICUs) (01/200812/2022) using the nationwide prospective ICU registry. The primary outcome was ICU mortality, with secondary outcomes including ICU admission probability and advanced treatment provision. Results: Among 41,733 individuals (34.9% women), 21,692 patients (30.6% women) were admitted to ICUs (16,571 OHCA patients/5121 IHCA patients). Women were less likely to be admitted to the ICU than men (incidence rate ratio 0.82 [95% CI 0.80–0.85] and had a higher ICU mortality (41.8% vs 36.2%; p &lt; 0.001). Mortality differences were more pronounced in OHCA patients (unadjusted HR: 1.35 [95% CI 1.28–1.43]; adjusted HR: 1.19 [95% CI 1.12–1.25]). In IHCA patients, mortality differences were less pronounced (unadjusted HR: 1.14 [95% CI 1.04–1.25]) and vanished after adjustment for confounders: adjusted HR: 1.03 [95% CI 0.94–1.13]). Women after cardiac arrest were older, more severely ill, and received fewer interventions before (44.7% vs 54.0%; p &lt; 0.001) and during ICU stay. A subgroup analysis of 11,202 patients revealed that treatment limitations were more frequent in women (46.7% vs 38.7%; p &lt; 0.001). However, these limitations were associated with an increased risk of death in both sexes. Conclusions: This study highlights sex disparities in short-term mortality and ICU resource allocation among cardiac arrest patients, with women potentially facing disadvantages, in particular after OHCA. The limitations of ICU registry data, particularly the lack of detailed cardiac arrest-specific and comorbidity information, restrict definitive conclusions. Future research should prioritize prospective studies with more granular data to better understand and address these disparities.

Aim: Pancreatic βcells are susceptible to inflammation, leading to decreased insulin production/secretion and cell death. Previously, we have identified a novel triceps-derived myokine, DECORIN, which plays a pivotal role in skeletal muscleto-pancreas interorgan communication. However, whether DECORIN can directly impact βcell function and susceptibility to inflammation remains unexplored. <div>Methods:<p>The effect of DECORIN was assessed in sorted human and rat βcell and human islets from healthy and type 2 diabetes (T2D) donors. We assessed glucose-stimulated insulin secretion (GSIS) and cytokine-mediated cell death.</p><p>We then challenged sorted βcells and human islets with inflammatory cytokines commonly associated with diabetes, such as tumor necrosis factor-α (TNF-α) alone or in combination with interleukin1-β (IL1-β) and interferon-γ (cytomix).</p><p>Results: DECORIN enhanced cell spreading and the localization of phosphorylated FAK at adhesions, promoting GSIS under basal conditions. It also increased insulin granule docking adhesion length and countered the inhibitory effects of TNF-α on adhesion and actin remodeling at the βcell surface, resulting in preserved GSIS. DECORIN protected from cell death in sorted βcells and islets challenged with TNF-α alone or TNF-α + cytomix. Interestingly, DECORIN increased both insulin content and secretion in human islets from T2D individuals. Additionally, DECORIN treatment reversed the impaired gene expression caused by T2D and enhanced the expression of genes essential for islet function and metabolism.</p></div> <div>Conclusion:<p>Collectively, we have shown that DECORIN had a beneficial effect on human islets, protecting them from inflammation-induced cell death. In T2D islets, DECORIN restores islet function and reverses the expression of T2Dassociated genes. Based on our data, we propose that DECORIN is a promising therapeutic target for diabetes-associated inflammation and diabetes itself.</p></div>

To mimic the structural aspects of staurosporine, a potent but unspecific kinase inhibitor, several coordination compounds based on two readily available diimine ligands containing hydrogen bonding donor/acceptor sites (NH-CO fragment) have been designed and synthesized. These complexes are constructed around Ru(II) and Pt(II) metal centers. A total of 9 compounds, named Ru(1)-(5) and Pt(1)-(4), were obtained through straightforward synthetic approaches. The cytotoxicity of the compounds was evaluated on AGS gastric cancer cells (GC) through standard MTT assays. All ruthenium and platinum complexes with low toxicity, i.e.Ru(3), Ru(5), Pt(3) and Pt(4), were docked in the ATP binding pocket of two protein kinases (S6K1 and MST2). The docking scores highlighted a preferred affinity of Ru(5) for the MST2 binding pocket, whereas the platinum compounds are predicted to bind stronger to the S6K1 binding site. Inhibitory activity of the metal complexes on the MST2 and S6K1 signaling pathways was evaluated by analyzing via western blot experiments the phosphorylation state of YAP, a downstream component of the Hippo pathway and the protein expression of S6 and its phosphorylated analogue p-S6. A clear difference of behavior between the Pt(II) and the Ru(II) complexes depending on the type of kinase was observed.

Background: Mitochondria generate the adenosine triphosphate (ATP) necessary for eukaryotic cells, serving as their primary energy suppliers, and contribute to host defense by producing reactive oxygen species. In many critical illnesses, including sepsis, major trauma, and heatstroke, the vicious cycle between activated coagulation and inflammation results in tissue hypoxia-induced mitochondrial dysfunction, and impaired mitochondrial function contributes to thromboinflammation and cell death. Methods: A computer-based online search was performed using the PubMed and Web of Science databases for published articles concerning sepsis, trauma, critical illnesses, cell death, mitochondria, inflammation, coagulopathy, and organ dysfunction. Results: Mitochondrial outer membrane permeabilization triggers apoptosis by releasing cytochrome c and activating caspases. Apoptosis is a non-inflammatory programmed cell death but requires sufficient ATP supply. Therefore, conversion to inflammatory necrosis may occur due to a lack of ATP in critical illness. Severely damaged mitochondria release excess reactive oxygen species and injurious mitochondrial DNA, inducing cell death. Besides non-programmed necrosis, mitochondrial damage can trigger programmed inflammatory cell death, including necroptosis, pyroptosis, and ferroptosis. Additionally, a unique form of DNA-ejecting cell death, known as etosis, occurs in monocytes and granulocytes following external stimuli and mitochondrial damage. The type of cell death chosen remains uncertain but is known to depend on the cell type, the nature of the injury, and the degree of damage. Conclusions: Mitochondria damage is the major contributor to the cell death mechanism that leads to organ damage in critical illnesses. Regulating and restoring mitochondrial function holds promise for developing new therapeutic approaches for mitigating critical diseases.

The incidence of heat-related illnesses and heatstroke continues to rise amidst global warming. Hyperthermia triggers inflammation, coagulation, and progressive multiorgan dysfunction, and, at levels above 40 °C, can even lead to cell death. Blood cells, particularly granulocytes and platelets, are highly sensitive to heat, which promotes proinflammatory and procoagulant changes. Key factors in heatstroke pathophysiology involve mitochondrial thermal damage and excessive oxidative stress, which drive apoptosis and necrosis. While the kinetics of cellular damage from heat have been extensively studied, the mechanisms driving heat-induced organ damage and death are not yet fully understood. Converse to hyperthermia, hypothermia is generally protective, as seen in therapeutic hypothermia. However, accidental hypothermia presents another environmental threat due to arrhythmias, cardiac arrest, and coagulopathy. From a cellular physiology perspective, hypothermia generally supports mitochondrial homeostasis and enhances cell preservation, aiding whole-body recovery following resuscitation. This review summarizes recent findings on temperature-related cellular damage and preservation and suggests future research directions for understanding the tempo-physiologic axis.

Prostate cancer is one of the most common diseases among men worldwide and continues to pose a serious threat to health. This review shows the history and the new developments in the management of prostate cancer, with an emphasis on a range of therapeutic approaches, such as hormone therapy, radiation therapy, surgery, and innovative targeted therapeutics. The evolution of these treatments is examined in light of clinical outcomes, patient quality of life, and emerging resistance mechanisms, such as the recently shown vitamin D-based strategies. New developments that have the potential to increase survival rates and reduce side effects are also discussed, including PARP inhibitors (PARPis), immunotherapy, and tailored medication. Additionally, the use of biomarkers and sophisticated imaging methods in therapeutic decision-making is explored, with a focus on how these tools might improve patient care. The absolute necessity for a multidisciplinary approach for improving treatment strategies is becoming more and more apparent as our understanding of the biology of prostate cancer deepens. This approach ensures that patients receive customized medicines that fit their unique profiles. Future avenues of investigation will focus on resolving issues dealing with treatment efficacy and resistance to improve treatment results, ultimately leading to disease cure for prostate cancer patients.

Background Lung transplantation (LT) is a highly dynamic segment of solid organ transplantation in which gender plays a central role . Our objective was to investigate the causes of outcome differences between women and men all along the LT pathway. Methods We used data from the COhort in Lung Transplantation (COLT) study (12 participating LT centers). Analyses were performed in three phases: baseline clinical characteristics, peri-transplantation period, and post-transplantation follow-up. Results Overall, 1710 participants (802 women and 908 men) were included in this study. Women were less likely than men to undergo transplantation (91.6% versus 95.6%, p=0.001) and waited longer before transplantation (115 versus 73 days, p&lt;0.001). Female gender and pre-transplant class I anti-HLA antibodies were identified as independent factors associated with longer waiting time duration. Female LT recipients commonly received lungs from height- and sex-matched donors, despite higher female waiting-list mortality and a higher proportion of male donors. Importantly, women with oversized lung transplantation (defined by predicted TLC ratio and weight mismatch) did not have worse survival. The overall post-transplant survival of female recipients was significantly higher than that of male recipients (65.6% versus 57.3%, p&lt;0.001), although the prevalence of specific major LT outcomes did not differ according to gender. Conclusion Women waited longer and were less likely to undergo transplant. Women transplanted with an oversized lung did not have worse survival after transplantation, suggesting that size matching criteria based on pTLC ratio and weight mismatch may be less stringent in this context.

Integrating genomic medicine into healthcare systems is a health policy challenge that requires continuously transferring scientific advances into clinics and ensuring equal access for patients. France was one of the first countries to integrate genome sequencing into clinical practice at a nationwide level, with the ambition to provide more accurate diagnostics and personalized treatments. Since 2016, the French government has invested €239M in the 2025 French Genomic Medicine Initiative (PFMG2025) which has so far focused on patients with rare diseases (RD), cancer genetic predisposition (CGP) and cancers. PFMG2025 has addressed numerous challenges to set up an operational organizational framework. As of December the 31st 2023, 12,737 results were returned to prescribers for RD/CGP patients (median delivery time: 202 days, diagnostic yield: 30.6%) and 3109 for cancer patients (median delivery time: 45 days). PFMG2025's future priorities encompass ensuring economic sustainability, strengthening links with research, empowering patients and practitioners, and fostering collaborations with European partners.<p>Funding As of December the 31st 2023, €239M have been invested by the French government.</p>

The main limitation to long-term lung transplant (LT) survival is chronic lung allograft dysfunction (CLAD), which leads to irreversible lung damage and significant mortality. Individual factors can impact CLAD, but no large genetic investigation has been conducted to date. We established the multicentric Genetic COhort in Lung Transplantation (GenCOLT) biobank from a rich and homogeneous sub-part of COLT cohort. GenCOLT collected DNA, high-quality GWAS (genome-wide association study) genotyping and robust HLA data for donors and recipients to supplement COLT clinical data. GenCOLT closely mirrors the global COLT cohort without significant variations in variables like demographics, initial disease and survival rates ( P &gt; 0.05). The GenCOLT donors were 45 years-old on average, 44% women, and primarily died of stroke (54%). The recipients were 48 years-old at transplantation on average, 45% women, and the main underlying disease was chronic obstructive pulmonary disease (45%). The mean follow-up time was 67 months and survival at 5 years was 57.3% for the CLAD subgroup and 97.4% for the non-CLAD subgroup. After stringent quality controls, GenCOLT gathered more than 7.3 million SNP and HLA genotypes for 387 LT pairs, including 91% pairs composed of donor and recipient of European ancestry. Overall, GenCOLT is an accurate snapshot of LT clinical practice in France and Belgium between 2009 and 2018. It currently represents one of the largest genetic biobanks dedicated to LT with data available simultaneously for donors and recipients. This unique cohort will empower to run comprehensive GWAS investigations of CLAD and other LT outcomes.

BACKGROUND: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is common in intensive care units (ICUs), yet optimal amikacin dosing in this context remains poorly understood. METHODS: We conducted a prospective observational study across 18 French hospitals from April 2020 to January 2022. Adult ICU patients (aged \textgreater 18 years) receiving their first amikacin dose while on RRT were included. Data on demographics, RRT modalities, amikacin dosing, and therapeutic drug monitoring were collected. Using a pharmacokinetic modeling approach, we evaluated various amikacin regimens and simulated target attainment probabilities across different minimum inhibitory concentrations (MICs). RESULTS: A total of 111 patients were included, with approximately two-thirds receiving continuous RRT. The median amikacin dose was 27 (25-30) mg/kg. Amikacin peak (Cmax) and trough concentrations were monitored in 53 (47.8%) and 76 (68.5%) patients, respectively. Continuous RRT and a history of chronic kidney disease reduced dialytic clearance. For a MIC ≤ 4 mg/L, a 15 mg/kg amikacin dose achieved Cmax/MIC and AUC/MIC targets in ≥ 90% of patients on intermittent dialysis, while 20 mg/kg was required for those on continuous dialysis. For a MIC = 8 mg/L, a 30 mg/kg dose was necessary to achieve Cmax/MIC ≥ 8. CONCLUSIONS: Our findings highlight suboptimal adherence to amikacin monitoring guidelines in ICU patients on RRT. Using pharmacokinetic modeling, we identified amikacin dosing recommendations ranging from 15 to 35 mg/kg to optimize efficacy and minimize risks, depending on MIC and dialysis modality.

Introduction: Sotorasib has shown efficacy in a phase 3 trial compared to docetaxel among previously treated non-small cell lung cancer (NSCLC) patients with a KRAS G12C mutation. However, its real-world effectiveness and tolerance, especially post-immunotherapy, remain debated. Methods: This French retrospective multicentre study analysed NSCLC patients receiving at least one dose of sotorasib as part of early access program The main objective was to assess real-world progression-free survival (rwPFS), and secondary objectives included assessment of overall survival (rwOS) and sotorasib-related hepatotoxicity. Results: 458 patients from 76 centres were analysed, with a median age 65.8. Among them, 43.4 % were female, 28.3 % had performance status ≥ 2, 95.4 % were active/former smokers, and 38.0 % had brain metastases with 55.2 % in progression at sotorasib initiation. PD-L1 expression was &lt; 1 %, ≥ 1-49 %, ≥ 50 %, and unknown in 35.1 %, 34.1 %, 23.4 %, and 7.4 % of patients, respectively. Most patients had received prior treatments (96.7 %), including immunotherapy (54.9 %). Median (95 % confidence interval [CI]) rwPFS and rwOS were 3.5 (3.1-4.2) and 8.3 (7.5-9.3) months, with a median (95 % CI) follow-up of 15.8 (13.9-17.3) and 16.4 (15.5-17.3) months, respectively. The real-world objective response rate (rwORR) was 33.2 % and disease control rate (rwDCR) was 63.2 %. In patients with brain metastases, cerebral rwORR and rwDCR were 20.1 % and 66.9 %, respectively. Grade 3-4 adverse events related to hepatotoxicity occurred in 5.2 % of patients. Sotorasib was discontinued for toxicity in 16.5 % of patients. Conclusion: This study gave insights into effectiveness and safety of sotorasib in a real-world setting, in advanced or metastatic KRAS G12C-mutated non-squamous NSCLC.

Background In the context of tumor lysis syndrome (TLS), the optimal timing and criteria for initiating kidney replacement therapy (KRT) remain unclear. This study aims to assess the effect of initiating KRT at various phosphatemia thresholds on Major Adverse Kidney Events at day 30 (MAKE30). Methods and results We retrospectively emulated a pragmatic clinical trial comparing the effect of KRT initiation at various phosphatemia thresholds versus a conventional approach during TLS on MAKE30. All consecutive patients admitted to the ICU at Saint-Louis University hospital in Paris and Angers University hospital between January 2007 and June 2020, presenting with laboratory TLS were included. The design criteria of a clinical trial were mimicked by using the cloning, censoring and weighting method. The primary outcome was the MAKE30 composite outcome, considering only KRT requirement between day 7 and day 30 for the dialysis criteria. We evaluated multiple phosphatemia thresholds to guide KRT initiation, ranging from 6.20 mg.dL-1 to 9.30 mg.dL-1. Among the initial population of 220 patients, 192 were included in the emulated trial (median age 60 years old, with non-Hodgkin Lymphoma and Acute Leukemia being the most frequent hematological malignancies). TLS-related AKI occurred in 140 patients, and 75 patients met the criteria for MAKE30. Regardless of the phosphate threshold considered, KRT initiation based on phosphate level was not associated with a significant difference in the MAKE30 rate. KRT requirement during the first 7 days (Odd Ratio [OR] 4.01 [1.65–4.86], p = 0.003) and non-renal SOFA (OR 1.39 per 1 point increment [1.25–1.57], p &lt; 0.001) were identified as factors associated with MAKE30 (multivariable analysis). Conclusion Our results do not support the strategy of KRT initiation based on a sole critical phosphatemia level in TLS patients.

Renal collecting duct carcinoma is a rare and aggressive cancer with poor prognosis. This retrospective study analyzed 29 patients from the UroCCR database. Median cancer-specific survival was 21 months, with frequent early recurrences. Localized disease and smaller tumors were linked to better outcomes, highlighting the important need for improved management and innovative therapeutic approaches. Objectives: To describe characteristics and survival outcomes of patients with renal collecting duct carcinoma (RCDC). Methods: We retrospectively analyzed data from patients treated for RCDC and included in the UroCCR database between 2007 and 2023. All tumors had a centralized pathological review by a CARARE network pathologist. Oncologic outcomes for cancer-specific survival (CSS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Results: A total of 29 patients with RCDC were included. The prevalence of RCDC in the UroCCR database was 0.18% (29/16133). The median age was 63 years (45-81). At diagnosis, 20 (69%) patients were symptomatic and 9 (31%) had a metastatic disease. Partial and radical nephrectomy were performed in respectively 8 (29.6%) and 19 (70.4%) cases. The median CSS were 21 months (95% CI 9.6-32) and median PFS was 7 months (95% CI 3.6-10.3). In the nonmetastatic group, the median CSS was 22 months (95% CI: 6.2-37), and median PFS was 12 months (95% CI: 0-39). Two years estimated PFS and CSS rates were respectively 29.7% and 38%. A localized disease ( P = .012) and a tumor size inferior to 4 cm ( P = .045) were associated with better oncological outcomes. Conclusion: RCDC is a rare cancer with poor prognosis, and no treatment has demonstrated a significant improvement in survival. Recurrences are frequent and early. Management is heterogeneous and ineffective. These outcomes reinforce the need to better understand this tumor and evaluate alternative treatments. Clinical Genitourinary Cancer, Vol. 23, No.xxx, 102305 (c) 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Background: Circulating extracellular vesicles (EVs) have shown promising results as noninvasive biomarkers for predicting disease outcomes in solid organ transplantation. Because in situ graft cell expression of the tolerogenic molecule HLA-G is associated with acceptance after lung transplantation (LTx), we hypothesized that plasma EV-bound HLA-G (HLA-G EV ) levels could predict chronic lung allograft dysfunction (CLAD) development. Methods: We analyzed 78 LTx recipients from the Cohort-for-Lung-Transplantation cohort, all in a stable (STA) state within the first year post-LTx. At 3 y, 41 patients remained STA, and 37 had CLAD (bronchiolitis obliterans syndrome, BOS, [n = 32] or restrictive allograft syndrome [n = 5]). HLA-G EV plasma levels were measured at month 6 (M6) and M12 in 78 patients. CLAD occurrence and graft failure at 3 y post-LTx were assessed according to early HLA-G EV plasma levels. Results: In patients with subsequent BOS, (1) HLA-G EV levels at M12 were significantly lower than those in STA patients ( P = 0.013) and (2) also significantly lower than their previous levels at M6 ( P = 0.04).A lower incidence of CLAD and BOS and higher graft survival at 3 y were observed in patients with high HLA-G EV plasma levels at M12 (high versus low HLA-G EVs patients [cutoff 21.3 ng/mL]: freedom from CLAD, P = 0.002; freedom from BOS, P &lt; 0.001; and graft survival, P = 0.04, [log-rank]). Furthermore, in multivariate analyses, low HLA-G EV levels at M12 were independently associated with a subsequent risk of CLAD, BOS, and graft failure at 3 y ( P = 0.015, P = 0.036, and P = 0.026, respectively [Cox models]). Conclusions: This exploratory study suggests the potential of EV-bound HLA-G plasma levels as a liquid biopsy in predicting CLAD/BOS onset and subsequent graft failure. Trial registration: ClinicalTrials.gov NCT00980967.

Immunocompromised patients were excluded most of the time from trials testing corticosteroids in COVID-19. This study aimed to assess the associations between early corticosteroid use and (1) mortality at day 60, and (2) the occurrence of nosocomial infections in immunocompromised patients with severe COVID-19 admitted to the ICU. It was a multicentre retrospective study, achieved in French ICUs of the Outcomerea™ network and medical ICUs of 4 other hospitals in France. This study included immunocompromised patients admitted to an ICU between January 1, 2020, and August 31, 2022, for severe COVID-19, with an ICU stay of more than 2 days. Patients were classified as receiving early corticosteroid therapy if they were given steroids within the first 5 days following ICU admission. Each patient was categorized into one of four immunosuppression subgroups: ‘corticosteroid therapy,’ ‘monocytic alteration,’ ‘cellular immunosuppression,’ or ‘humoral immunosuppression.’ Survival analyses were performed, and confounding by indication was addressed using propensity score weighting with overlap. 383 patients were included, 50 were into the no-early-corticosteroids group and 333 in the early-corticosteroids group. In the overlap cohort, 118 were included (46 in the non-early-corticosteroids and 72 in the early-corticosteroids group). There was no association with day-60 mortality (IPTWoverlapHR = 0.97, 95% CI [0.51; 1.85], p = 0.92). There was also no association with the occurrence of nosocomial infections (IPTWoverlapSubHR = 2.59, CI 95% [0.77; 8.7], p = 0.13). We report that steroids had no benefit on mortality in immunocompromised patients admitted to ICU for severe COVID-19.

Background and AimsBreast cancer is the most common malignancy observed in patients with inflammatory bowel diseases (IBD). The aim of our study was to evaluate incident cancer rate (recurrence or new-onset cancer) in a cohort of IBD patients with a history of breast cancer according to the subsequent IBD treatment provided.MethodsA multicenter retrospective study included consecutive IBD patients with prior breast cancer. The inclusion date corresponded to the diagnosis of index malignancy. Follow-up lasted from cancer diagnosis until the occurrence of incident cancer.ResultsAmong 207 patients included (median disease duration: 13 years [IQR 6 - 21]), first line treatment (median interval of 28 months [IQR 7 - 64]) was a conventional immunosuppressant in 19.3 % of patients, anti-TNF in 19.8 %, vedolizumab in 7.2 % and ustekinumab in 1.9 %.After a median follow-up of 71 months [IQR, 34 - 148], 42 (20%) incident cancers were observed (34 breast cancer recurrences). Adjusted incidence rates per 1000 person-years were 10.2 (95%CI 6.0- 16.4) for the untreated arm and 28.9 (95%CI 11.6-59.6) for exposed patients (p= 0.0519). There was no significant difference between treated patients and controls regarding incident-cancer free survival rates (p=0.4796). In multivariable analysis, factors associated with incident cancer were stage T4d (p=0.036), triple negative tumor (p=0.016) and follow-up of less than 71 months (p=0.005).ConclusionWe did not find a statistically significant increase in incident breast cancer related to IBD treatment beyond the already known poor prognostic factors of breast cancer.

Aims: Although predominant in routine practice, non-ischaemic cardiogenic shock (NICS) remains underrepresented in past studies, mainly focused on ischaemic cardiogenic shock (CS). This study aims to describe the current NICS picture and define its independent correlates of short- and long-term outcomes.Methods and results: FRENSHOCK is a prospective registry including 772 CS patients from 49 centers. One-year mortality was the primary outcome. One-month mortality and the composite of 1-year mortality, heart transplantation (HTx), or ventricular assistance device (VAD) were secondary outcomes. Within 772 patients included, 492 (63.7%) were NICS. One-month and 1-year mortality rates were 25.6% and 45.7%, with a combined endpoint of 1-year mortality, HTx, or VAD of 53.9%. Multivariate analysis showed five independent factors for 1-year mortality: age (per year: aHR 1.03 [1.01-1.05], P &lt; 0.01), chronic kidney disease (CKD) (aHR 1.87 [1.25-2.80], P &lt; 0.01), norepinephrine use (aHR 1.52 [1.02-2.26], P = 0.04), active cancer (aHR 1.91 [1.07-3.42], P = 0.03) and acute renal replacement therapy (aHR 1.57 [1.01-2.46], P = 0.049). Age, CKD and norepinephrine were also predictive of 1-month mortality and 1-year mortality and/or HTx and/or VAD. Additionally, 1-month mortality was associated with septic triggers, and 1-year mortality and/or HTx and/or VAD with acute mechanical circulatory support, NYHA stage ≥ 3 and fluid administration.Conclusions: In this large study, NICS accounted for almost two-thirds of all CS cases, with substantial rates of short- and long-term mortality. Future studies should evaluate interventions to improve early stratification and management. NCT02703038.

Characterization of nanoscale formulations is a continuous challenge. Size, morphology and surface properties are the most common characterizations. However, physicochemical properties inside the nanoparticles, like viscosity, cannot be directly measured. Herein, we propose an original approach to measuring dynamic viscosity using a lipidic molecular rotor solubilized in the core of nano-formulations. These molecules undergo conformational changes in response to viscosity variations, leading to observable changes in fluorescence intensity and lifetime, able to sense the volume properties of dispersed nanodomains. The lipophilic molecular rotor (BOPIDY derivatives) was specifically synthesized and characterized as oil viscosity sensing in large volumes. A second part of the study compares these results with rBDP-Toco in nano-emulsions. The objective is to evaluate the impact of the formulation, droplet size and composition on the viscosity of the droplet's core. The lipophilic rotor showed a universal behavior whatever the oil composition, giving a master curve. Applied to nano-formulations, it reveals the viscosity inside the nanoemulsion droplets, enabling the detection of slight variations between reference oil samples and the nano-formulated ones. This new tool opens the way to the fine characterization of complex colloids and multi-domain nano and micro systems, potentially applied to hybrid materials and biomaterials.

BRAF V600E mutations occur in 2-5 % of advanced non-small cell lung cancer (NSCLC) patients. The dabrafenib-trametinib (D-T) combination was associated with improved and durable OS in patients in phase II. This study (IFCT-2004 BLaDE study) reported the efficacy of D-T combination in a large retrospective French real-world multicenter cohort of patients with advanced BRAF V600E-mutated NSCLC.

This protocol details an optimized method for the production of small stable spheroids, their culture, and 3D imaging, for the study of the endothelial and insulin-producing β cells interactions in a 3D model of pancreatic islets. The 150-200 μm spheroids, mirroring the lowest range of islet sizes, were prepared from a selected ratio combining 1 intra-islet endothelial cells (MS-1 cells) to 20 insulin-secreting cells (β-TC-6). Staining, clearing, and mounting challenges of small spheroids and their tackling by employing low-melting point agarose and the CUBIC clearing technique are detailed as well as key points for an efficient analysis of the 3D structure with different probes. Data indicate that NTPDASE-ectonucleotidase 3 does not colocalize with insulin in the spheroid model, suggesting varying maturity and functional levels of β-TC6 and that the complete procedure can also be applied to isolated pancreatic islets, with clear probing of intra-islet vessels. These findings underscore the effectiveness of the 3D imaging protocol in revealing complex pancreatic cell organization and interactions within the islet model.

Diagnosing coagulopathy in septic patients remains challenging in intensive care. Disseminated intravascular coagulation (DIC) indeed presents with complex pathophysiology, complicating timely diagnosis. Epidemiological data indicate a significant prevalence of DIC in septic patients, with mortality rates up to 60%. Despite advances, current biomarker-based diagnostic tools often fail to provide early and accurate detection. This review evaluates the utility and limitations of traditional and emerging biomarkers for diagnosing sepsis-induced coagulopathy (SIC) and DIC. We also assess the effectiveness of anticoagulant therapy guided by biomarker-based diagnostic criteria.

In this study, we introduce a rolled-up ring-shaped gastroretentive device, which enables controlled drug release via the radial position of a drug reservoir relative to its surface. The device was formed by rolling up a gelatin film, which was initially wrapped on the surface of an acrylic cylinder. Prior to rolling, a drug reservoir was formed at a predetermined position of the wrapped film. The device containing the drug was packed within gastric-dissolvable gelatin capsule shell. Upon contact with the simulated gastric medium, the prepared capsule was dissolved and rapidly released the ring-shaped device within two minutes. The deployed system then swelled and retained its shape, before eventually disintegration within 24 hours. The disintegration process can be accelerated, if necessary, via the design of "weak points" in the ring's structure, allowing for safe and programmed evacuation through the lower gastrointestinal tract. The rolled-up ring-shaped devices, containing riboflavin or captopril, allowed to control the release rates by the radial position of the drug reservoirs. The developed expandable gastroretentive device presents a promising solution for reducing daily dosages and enhancing personalized treatment.

Purpose: The aim of the present study was to evaluate the association between periodontitis and SARS-CoV-2 infection severity in a Turkish population.<p>Methods: Adult patients attending hospital consultation and testing positive for SARS-CoV-2 infection were consecutively enrolled in this study. Demographic variables, smoking status, COVID-19 symptoms, SpO 2 levels, and markers of inflammation (D-Dimer, lymphocytes and white blood cells count, CRP) were recorded. Patients suspected of periodontal disease were evaluated using self-reported questionnaires (OHIP-14, modified CDC/AAP questionnaire). Periodontal screening score (PESS) was calculated from the questionnaire. Univariate and multivariate logistic regression analyses were performed to evaluate the association between COVID-19-associated parameters and periodontitis.</p> <div>Results:<p>The study included 134 patients diagnosed with COVID-19. Nearly half of the participants were female (n = 68, 50.7%), and the mean age of the patients was 48.7 ± 18.2 years. A statistically significant majority of individuals (69.2%) were asymptomatic, while 22.3% experienced mild symptoms, and 8.5% reported moderate or severe symptoms. Oxygen saturation was found to be higher in asymptomatic patients (96.4 ± 2.8) compared to mild (90.4 ± 5.1) and moderate/severe patients (86.6 ± 8.9) (P &lt;0.001). There was no statistically significant difference concerning OHIP-14 score (P = 0.316), periodontitis (PESS ≥ 5) (P = 0.130), brushing habits (P = 0.901), and frequency of dental visits (P = 0.975) when considering SARS-CoV-2 infection severity. In multivariate logistic regression analysis, it was concluded that male gender (OR = 2.90, 95% CI: 1.04-8.04, P = 0.040), age 55 and above (OR = 5.94, 95% CI: 1.22-28.76, P = 0.026), and smoking (OR = 0.14, 95% CI: 0.02-0.75, P = 0.022) were statistically significant predictors of SARS-CoV-2 infection severity.</p></div> <div>Conclusions:<p>Even the association between SARS-CoV-2 infection severity and periodontitis, evaluated through self-reported outcome measures, were weak: male gender, age, and smoking were independent risk factors for SARS-CoV-2 infection severity in this patient cohort. Further research is warranted to explore these associations comprehensively.</p></div>

For a few decades, Type 2 Diabetes (T2D) has been recognized as a worldwide public health issue. T2D relies on systemic insulin resistance leading to Beta cell dysfunction. Nowadays, lifestyle modifications, such as improving eating habits and increasing physical activity, represent the first recommendations for managing T2D. Physical exercise, as a structured physical activity, is now considered as a non-pharmacological treatment with a wide range of beneficial effects, especially for people living with T2D. The review intends to summarize the current knowledge of physical exercise benefits in a context of T2D: from “unwanted” adipose tissue reduction to Beta cell health improvement. Moreover, we try to suggest an underlying mechanism explaining physical exercise beneficial effects in the context of T2D focusing on exerkines, molecules secreted in response to physical exercise. With this review, we highlight the beneficial impact of post-exercise secretions on Beta cell health and encourage research to continue in this direction. Identifying new exerkines with beneficial effects in the context of T2D could represent a promising approach for managing metabolic diseases.

Background: Cardiogenic shock (CS) is a severe hemodynamic condition with high mortality. Although extremely frequent in daily practice, the impact of anemia in CS is largely unknown. This study focuses on the consequences of low hemoglobin (Hb) level on the outcomes of CS patients. Methods: FRENSHOCK is a prospective registry including 772 CS patients from 49 centers. One-month and one-year mortalities were analyzed according to the admission level of Hb. Results: Among 754 patients, 71.8% were male, with a mean age of 65.8 (± 14.8) years, and 361 (47.9%) presenting with anemia. Four groups were defined, depending on admission Hb levels by quartiles: Q1: Hb &lt; 11.0 g/dL, Q2: Hb 11-12.6 g/dL, Q3: Hb &gt; 12.6-14 g/dL, and Q4: Hb &gt; 14.0 g/dL. Patients from the Q1 group required more frequent renal replacement therapy and norepinephrine. A significant increase in all-cause mortality was observed across Hb quartiles at 1 month (Ptrend = 0.035) and 1 year (Ptrend &lt; 0.01). Q1 patients had 1.64 times higher mortality at 1 month (1.09-2.47, p = 0.02) and 2.53 times higher mortality at 1 year (1.84-3.49, p &lt; 0.01) compared to Q4. The negative effect of low Hb level was confirmed in multivariate Cox regression adjusted for baseline characteristics, and was stronger in men, non-ischemic CS, patients without CKD and patients aged &lt; 67 years. Conclusion: Anemia is a common condition frequently intertwined with CS worsening both short- and long-term mortality. Further randomized studies are warranted to understand its mechanisms and adapt the transfusion strategy.

Abstract Aims Sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a cardioprotective effect in heart failure and myocardial infarction, pathologies often associated with low-grade inflammation. This cross-sectional study aims to investigate whether low-grade inflammation regulates SGLT2 expression and function in human vasculature, heart, and endothelial cells (ECs). Methods and results Human internal thoracic artery (ITA), left ventricle (LV) specimens, and cultured porcine coronary artery ECs were used. Expression of target molecules was assessed using RT-qPCR, western blot analysis, and immunofluorescence staining, and the generation of reactive oxygen species (ROS) and nitric oxide (NO) using fluorescent probes. The function of SGLT2 was investigated using empagliflozin and SGLT1 or 2 siRNA. SGLT2 mRNA and protein levels in ITA and LV specimens were correlated with the level of low-grade inflammation, markers of the angiotensin system, and EC activation. SGLT2 staining was observed in the ITA endothelium and smooth muscle, the coronary microcirculation, and cardiomyocytes. Elevated ROS formation in high SGLT2-expressing specimens was reduced by inhibition of the angiotensin system, SGLT2, and TNF-α. Exposure of ECs to IL-1ß, IL-6, and TNF-α led to an increase in SGLT1 and SGLT2 mRNA and protein expression, up-regulation of components of the angiotensin system, enhanced ROS and decreased NO formation, and activation of NF-κB. The stimulatory effect of TNF-α was prevented by N-acetylcysteine and inhibition of the angiotensin system, SGLT2 but not SGLT1, and NF-κB. Conclusion Low-grade inflammation is closely associated with SGLT2 expression in human vasculature and heart, and this response contributes to a feedforward mechanism with the AT1R/NADPH oxidase pathway to cause eNOS-NO/ROS imbalance.

<div><p>Background Periodontitis is an inflammatory disease causing destruction of periodontal tissues. Controlling inflammation is crucial for periodontitis treatment. Prohibitins (PHBs) are emerging targets in the treatment of inflammatory diseases. To identify compounds that would alleviate periodontitis, several small molecules that directly target PHBs and display various pharmacological activities were screened to decrease Porphyromonas gingivalis induced inflammation. Indeed, IN44, a new PHB ligand that has been shown to inhibit STAT3 and NF-kB signaling, suggesting that it may alleviate periodontitis. This study aimed to assess IN44's impact on inflammation elicited by P. gingivalis.</p></div> <div>Methods<p>In vitro, IN44 cytotoxicity was tested on periodontal cells with AlamarBlue and Live/Dead assays. Its effect on cytokines and mitochondrial ROS production were evaluated using ELISA and Mitosox assay. In mouse, systemic inflammation and experimental periodontitis were induced to assess IN44's therapeutic effects.</p></div> <div>Results<p>In vitro, IN44 (50 µM) showed no cytotoxicity on periodontal cells. It significantly reduced pro-inflammatory cytokine secretion and mitochondrial ROS in P. gingivalis-infected epithelial cells. Proteome analysis on infected epithelial cells revealed modulation of HSP60 and Akt expression by IN44. In vivo, IN44 demonstrated antiinflammatory effects in a mouse model of systemic inflammation induced by P. gingivalis, and it improved periodontal healing.</p></div> <div>Conclusion<p>These findings suggest that PHBs may warrant consideration as therapeutic targets for periodontitis and possibly other inflammatory disorders.</p></div>

<b>Background:</b> Electrocardiographic screening before subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation is unsuccessful in around 10% of cases. A personalized screening method, by slightly moving the electrodes, to obtain a better R/T ratio has been described to overcome traditional screening failure. <b>Objective:</b> The objectives of the SIS study were to assess to what extent a personalized screening method improves eligibility for S-ICD implantation and to evaluate the inappropriate shock rate after such screening success. <b>Methods:</b> All consecutive patients eligible for an S-ICD implantation were prospectively recruited across 20 French centers between December 2019 and January 2022. In case of traditional screening failure, patients received a second personalized screening. If at least 1 vector was positive, the personalized screening was considered successful, and the patient was eligible for implantation. <b>Results:</b> The study included 474 patients (mean age, 50.4 ± 14.1 years; 77.4% men). Traditional screening was successful in 456 (96.2%) cases. This figure rose to 98.3% (n = 466; P = .002) when personalized screening was performed. All patients implanted after successful personalized screening had correct signal detection on initial device interrogation. Nevertheless, after 1-year follow-up, 3 of the 7 patients (43%) implanted with personalized screening experienced inappropriate shock vs 18 of the 427 patients (4.2%) with traditional screening and S-ICD implantation (P = .003). <b>Conclusion:</b> Traditional S-ICD screening was successful in our study in a high proportion of patients. Considering the small improvement in success of screening and a higher rate of inappropriate shock, a strategy of personalized screening cannot be routinely recommended. <b>Clinicaltrials:</b> gov identifier: NCT04101253

Background: Diabetic foot ulcers are chronic, difficult to heal, and potentially life-threatening. Few medical devices have been studied in diabetic ulcers penetrating to bone or tendon. Methods: We conducted an international, open-label randomized controlled trial, randomly assigning patients with diabetic ulcers penetrating to bone, joint, or tendon 1:1 to intact fish skin graft or standard wound care, with assigned treatment applied through 14 weeks. The primary end point was the proportion of ulcers healed at 16 weeks, defined as reepithelization as identified by the investigator, and confirmed 14 days later. A blinded adjudication committee confirmed healing at both time points. Healing was also assessed at 20 and 24 weeks. Results: Between July 2020 and November 2022, 255 patients were randomly assigned to intact fish skin graft (n=129) or standard of care (n=126). Healing was achieved in 44% of patients at 16 weeks with intact fish skin graft compared with 26% for standard of care (P&lt;0.001, unadjusted), with additional healing at 20 weeks (46% vs. 32%) and 24 weeks (55% vs. 38%). Mean (SD) time to healing was 17.3 (0.69) weeks (95% confidence interval [CI], 15.5 to 18.7) for the intact fish skin graft group and 19.4 (0.66) weeks (95% CI, 18.1 to 20.7) for the standard of care group. In a Cox regression, intact fish skin graft was associated with faster time to healing (hazard ratio, 1.59; 95% CI, 1.07 to 2.36). Primary wound infections were the most common adverse event, occurring in 39 (30.2%) of patients in the intact fish skin graft group and 31 (24.6%) of patients in the standard of care group. Conclusions: Among patients with deep diabetic foot ulcers, treatment with intact fish skin graft was superior to standard of care in proportion of wounds healed at 16 weeks and was associated with faster time to healing. (Funded by European Commission Fast Track to Innovation Horizon 2020, and Kerecis Ltd. ClinicalTrials.gov NCT04257370.).

Background: Glanzmann thrombasthenia (GT) is a very rare autosomal inherited bleeding disease affecting megakaryocyte lineage with impacts on oral health such as gingival bleeding, which requires specific management protocols. Very few clinical cases have been published in the dental and hematologic literature. Objectives: This study focuses on a series of 21 patients affected specifically by GT and their hemorrhagic prophylaxis management with the use of recombinant activated factor VII (rFVIIa) for dental extractions and full-mouth debridement. Methods: Data were collected from medical and dental records. rFVIIa was administered prophylactically for oral procedures, following a standardized protocol. Each sessions were performed by experienced oral surgeons, and outcomes were analyzed with a focus on bleeding complications and adverse events. Results: Forty-one full-mouth debridements and 176 dental extractions were performed during 102 sessions of dental care in an outpatient setting. A total of 226 injections of rFVIIa was delivered. The mean number of injections was 2.2 (range, 1-4) per dental procedure. The overall rate of bleeding complications was 5.9% (n = 6). All 6 hemorrhagic complications were classified as minor bleeding. No thromboembolic event or allergic reaction was observed. Conclusion: The data presented in this retrospective observational study support the efficacy and safety of rFVIIa for the prevention of bleeding during invasive dental procedures in patients affected by GT. The rFVIIa protocol presented here seems to be a safe and efficient protocol for the prevention of bleeding during invasive oral procedures.

Abstract Background Intrahepatic cholangiocarcinoma is a public health threat because of its aggressiveness. Its genetic background differs from other biliary cancers. The aim of this study was to investigate the impact of genetic alterations on long-term outcomes. Methods PubMed, MEDLINE, Scopus, and Cochrane Library databases were systematically searched for studies assessing long-term outcomes after resection of intrahepatic cholangiocarcinoma according to genetic mutational profiling until 31 May 2022. The main outcome was the impact of genetic alterations on long-term outcomes in these patients. HR (95% c.i.) was used for effect size. Publication bias was investigated. Results A total of 24 retrospective studies were included. KRAS, IDH1/2, and TP53 were identified as the only three genes whose mutation correlated with survival (HR: 2.476, 95% c.i. 1.67–3.671, P &lt; 0.01 for KRAS; HR: 0.624, 95% c.i. 0.450–0.867, P &lt; 0.01 for IDH1/2; and HR: 2.771, 95% c.i. 2.034–3.775, P &lt; 0.01 for TP53). The prevalence of KRAS and IDH1/2 mutations differed between western and eastern studies (P &lt; 0.001 for both genes). Conclusion Determining the overall prevalence of the most common actionable and undruggable mutations may help to expand target therapy indications in the adjuvant setting. Inconsistent results have been found for some infrequent gene alterations; their rare involvement could potentially bias their prognostic meaning.

INTRODUCTION: Bilateral prosthetic hip or knee replacement in one surgical session is a procedure that has been widely validated in the literature, whereas hip and knee replacement in one surgical session remains poorly documented. This study reports on the results of these procedures by analyzing early post-operative complications in a retrospective multicenter study. MATERIAL AND METHODS: Between 2009 and 2023, 51 patients underwent hip and knee replacement surgery in a single surgical session at 4 French centers. They were 24 men and 27 women, with a mean age of 68.8 years (36-87); 7 patients were ASA 1, 30 were ASA 2 and 14 ASA 3. Prosthetic hip replacement was always performed first, associated 33 times with the ipsi-lateral knee and 18 times with the contralateral knee. All early complications, within the first 90 days post-operatively, were recorded: death, phlebitis, pulmonary embolism, myocardial infarction, surgical site infection (SSI), knee stiffness treated by mobilization under general anesthesia, urinary tract infection, acute urine retention or any other adverse event related to care. Transfusion rates were also reported. RESULTS: The rate of early complications was 9.8% (5/51). No deaths, no phlebitis, no pulmonary embolism and no SSI were observed. Complications included one myocardial infarction, one urinary tract infection, one superficial infection, one haematoma treated by surgical evacuation and one recurrent instability requiring revision surgery (hip arthroplasty). The transfusion rate was 17.6% (9/51). The complication rate of ASA 3 patients was higher than that of ASA 1 and 2 patients, while there was no difference related to age or BMI. DISCUSSION: Our results confirm the feasibility of single-stage hip and knee replacement, with a low complication rate in ASA 1 and 2 patients. This study adds to the few published works on the subject and reports comparable results. The small sample size and the heterogeneity of patients and centers limit the scope of the results, these limitations being relative to the volume expected for a rare procedure. CONCLUSION: Single-session hip and knee arthroplasty should be reserved for patients selected according to comorbidities: ASA score, age and body mass index. ASA 3 patients have a higher risk of complications. LEVEL OF EVIDENCE: IV; retrospective.

The rise of colistin-resistant <i>Acinetobacter baumannii</i> has severely limited treatment options for infections caused by this pathogen. While terpene alcohols and fatty acids have shown potential to enhance colistin’s efficacy, but their high lipophilicity limits their clinical application. To address this, we developed water-dispersible lipid nanoparticles (LNPs) in two sizes (40 nm and 130 nm), loaded with these compounds to act as colistin adjuvants. Among eleven LNP formulations, six significantly reduced colistin’s minimum inhibitory concentration (MIC) by 16- to 64-fold. The most effective, featuring (E,E)-farnesol and myristic acid, were further examined for bactericidal activity, membrane disruption, cytotoxicity, and <i>in vivo</i> efficacy in <i>Galleria mellonella</i> larvae. Time-kill studies demonstrated that at an adjuvant concentration of 60 mg/L, these LNPs eradicated bacteria when combined with 4 mg/L free colistin for resistant isolates (MIC = 128 mg/L) and 0.06 mg/L for susceptible isolates (MIC = 0.5 mg/L), without regrowth. Myristic acid-loaded LNPs combined with free colistin at 1/8 MIC resulted in a 4.2-fold higher mortality rate than the combination with (E,E)-farnesol-loaded LNPs in resistant strains. This result was correlated with a 45-fold faster increase in inner membrane permeability, measured by propidium iodide (PI) uptake, in the presence of myristic acid-loaded LNPs compared with a 13-fold faster increase with (E,E)-farnesol-loaded LNPs. DiSC3(5) assays revealed that LNPs alone depolarised the bacterial inner membrane, with enhanced effects when combined with colistin at 1/8 MIC, a result not observed with colistin alone at this concentration. As with PI uptake, this inner membrane depolarising effect was more pronounced with myristic acid-loaded LNPs than with (E,E)-farnesol-loaded LNPs in resistant strains, suggesting that the colistin adjuvant effect of these lipophilic compounds is due to their ability to help colistin destabilise the bacterial inner membrane. Cytotoxicity assays demonstrated no adverse effects on bone marrow macrophages after 6 h of exposure, although some toxicity was observed after 24 h. No mortality was observed in <i>Galleria mellonella</i> larvae over 7 days following three consecutive days of treatment with colistin and LNPs. Notably, the combination of (E,E)-farnesol-loaded LNPs and colistin significantly improved the survival of <i>Galleria</i> infected with <i>A. baumannii</i>. These results suggest that lipophilic-adjuvant-loaded LNPs may offer a promising strategy to enhance colistin efficacy and combat antibiotic-resistant <i>A. baumannii</i> infections.

Acute heart failure (AHF) is a complex, multifactorial syndromic condition that, until now, did not have a consensual definition [1], [2]. The difficulties in agreeing on a consensual definition of AHF also apply to research, since depending on the application of the field of investigation, the target populations concerned and the therapeutic goals or pathophysiological knowledge sought, the elements defining heart failure (HF) vary, especially among older patients. Thus, although the advent of echocardiography has made it possible to characterize disturbances in myocardial relaxation and altered ventricular filling, marking the birth of the concept of HF with preserved ejection fraction (HFpEF) versus HF with reduced ejection fraction (HFrEF), the different clinical presentations do not always make it possible to determine whether myocardial failure corresponds to a disease of ventricular filling of vascular origin [3].AHF is most often characterized by dyspnoea, lower limb oedema and/or intense asthenia. It is a common presentation in emergency departments (EDs) and has become a major public health problem as its incidence and prevalence rise in line with an aging population in all developed countries. AHF represents a growing medico-economic burden and is associated with high morbidity and mortality [4]. Currently, AHF is the main reason for hospital admissions in patients aged &gt; 65 years and acute cardiogenic pulmonary oedema accounts for approximately 1% of ED visits [3], [4], involving approximately 200,000 patients per year in France (including 5% of the French population aged 75–85 years and 10% of those aged &gt; 85 years) [5]. HF is a progressive pathology linked to aging, with mortality rising by 10% each year [6]. Indeed, the mortality rate remains appalling, reaching up to 12% during the hospital stay, 8–20% in the 2 months following hospitalization for an episode of AHF, and reaching 25–50% in the first 5 years after initial diagnosis. Moreover, mortality is increased in the presence of associated comorbidities such as anaemia, hypercholesterolemia or renal dysfunction, all of which become more frequent with age [3], [4], [6], [7].

Background: Cataract surgery requires a high level of dexterity and experience to avoid serious intra-and postoperative complications. Proper surgical training and evaluation during the learning phase are crucial to promote safety in the operating room (OR). This scoping review aims to report cataract surgery training efficacy for patient safety and trainee satisfaction in the OR when using virtual reality simulators (EyeSi [Haag-Streit, Heidelberg, Germany] or HelpMeSee [HelpMeSee foundation, Jersey city, New Jersey, United States]) or supervised surgical training on actual patients programs in residents. Methods: An online article search in the PubMed database was performed to identify studies proposing OR performance assessment after virtual-reality simulation (EyeSi or HelpMeSee) or supervised surgical training on actual patients programs. Outcome assessment was primarily based on patient safety (i.e., intra-and post-operative complications, OR performance, operating time) and secondarily based on trainee satisfaction (i.e., subjective assessment). Results: We reviewed 18 articles, involving 1515 participants. There were 13 using the EyeSi simulator, with 10 studies conducted in high-income countries (59%). One study used the HelpMeSee simulator and was conducted in India. The four remaining studies reported supervised surgical training on actual patients, mostly conducted in low-middleincome countries. Training programs greatly differed between studies and the level of certainty was considered low. Only four studies were randomized clinical trials. There were 17 studies (94%) proposing patient safety assessments, mainly through intraoperative complication reports (67%). Significant safety improvements were found in 80% of comparative virtual reality simulation studies. All three supervised surgery studies were observational and reported a high amount of cataract surgeries performed by trainees. However, intraoperative complication rates appeared to be higher than in virtual reality simulation studies. Trainee satisfaction was rarely assessed (17%) and did not correlate with training outcomes. Conclusions: Patient safety assessment in the OR remains a major concern when evaluating the efficacy of a training program. Virtual reality simulation appears to lead to safer outcomes compared to that of supervised surgical training on actual patients alone, which encourages its use prior to performing real cases. However, actual training programs need to be more consistent, while maintaining a balance between financial, cultural, geographical, and accessibility factors.

Islet transplantation is a promising approach for treating patients with unstable T1DM. However, it is confronted with numerous obstacles throughout the various stages of the transplantation procedure. Significant progress has been made over the last 25 years in understanding the mechanisms behind the loss of functional islet mass and in developing protective strategies. Nevertheless, at present, two to three pancreases are still needed to treat a single patient, which limits the maximal number of patients who can benefit from islet transplantation. Thus, this publication provides an overview of recent scientific findings on the various issues affecting islet transplantation. Specifically, we will focus on the understanding of the mechanisms involved and the strategies developed to alleviate these problems from the isolation stage to the post-transplantation phase. Finally, we hope that this review will highlight new avenues of action, enabling us to propose pancreatic islet transplantation to a maximum number of patients with T1DM.

This study aims to assess validity evidence of the new phacoemulsification module of the HelpMeSee [HMS] virtual reality simulator. Conducted at the Ophthalmology Department of Strasbourg University Hospital and Gepromed Education Department, Strasbourg, France, this cross-sectional study divided 20 surgeons into two groups based on their experience over or under 300 cataract surgeries. Surgeons filled out a background survey covering their phacoemulsification experience and prior simulator use before undergoing single-session simulations on the EyeSi [EYS] and HMS simulators. Handgrip strength was measured pre- and post-simulation to evaluate grip fatigue. Afterwards, surgeons rated the perceived realism on a seven-point Likert scale. Participants were predominantly right-handed males, with expert surgeons averaging 44 years and intermediate surgeons 29 years of age. Expert surgeons had completed around 2000 phacoemulsification surgeries compared to 150 by intermediates. Primary outcome was to assess the construct validity of HMS simulator based on the difference in total and modules scores between both groups. Significant performance differences were observed between the two groups, with experts scoring higher. HMS scores were 35.8±1.5 out of 46 points for experts and 27.2±2.3 for intermediates (p=0.006). For EYS, scores were 405.2±20.3 out of 500 points for experts and 327.8±25.2 for intermediates (p=0.028). Experts experienced significantly less grip fatigue post-simulation on HMS compared to intermediates. This research evaluates validity evidence of HMS’s phacoemulsification modules for the first time. It emphasizes the potential to broaden simulation-based training by targeting diverse populations.

In sepsis, inflammation, and nutrient deficiencies endanger cellular homeostasis and survival. Autophagy is primarily a mechanism of cellular survival under fasting conditions. However, autophagy-dependent cell death, known as autophagic cell death, is proinflammatory and can exacerbate sepsis. Autophagy also regulates various types of non-inflammatory and inflammatory cell deaths. Non-inflammatory apoptosis tends to suppress inflammation, however, inflammatory necroptosis, pyroptosis, ferroptosis, and autophagic cell death lead to the release of inflammatory cytokines and damage-associated molecular patterns (DAMPs) and amplify inflammation. The selection of cell death mechanisms is complex and often involves a mixture of various styles. Similarly, protective autophagy and lethal autophagy may be triggered simultaneously in cells. How cells balance the regulatory mechanisms of these processes is an area of interest that is still under investigation. Therapies aimed at modulating autophagy are considered promising. Enhancing autophagy helps clear and recycle damaged organelles and reduce the burden of inflammatory processes while inhibiting excessive autophagy, which could prevent autophagic cell death. In this review, we introduce recent advances in research and the complex regulatory system of autophagy in sepsis.

Abstract Background Despite scarce data, invasive mechanical ventilation (MV) is widely suggested as first-line ventilatory support in cardiogenic shock (CS) patients. We assessed the real-life use of different ventilation strategies in CS and their influence on short and mid-term prognosis. Methods FRENSHOCK was a prospective registry including 772 CS patients from 49 centers in France. Patients were categorized into three groups according to the ventilatory supports during hospitalization: no mechanical ventilation group (NV), non-invasive ventilation alone group (NIV), and invasive mechanical ventilation group (MV). We compared clinical characteristics, management, and occurrence of death and major adverse event (MAE) (death, heart transplantation or ventricular assist device) at 30 days and 1 year between the three groups. Results Seven hundred sixty-eight patients were included in this analysis. Mean age was 66 years and 71% were men. Among them, 359 did not receive any ventilatory support (46.7%), 118 only NIV (15.4%), and 291 MV (37.9%). MV patients presented more severe CS with more skin mottling, higher lactate levels, and higher use of vasoactive drugs and mechanical circulatory support. MV was associated with higher mortality and MAE at 30 days (HR 1.41 [1.05–1.90] and 1.52 [1.16–1.99] vs NV). No difference in mortality (HR 0.79 [0.49–1.26]) or MAE (HR 0.83 [0.54–1.27]) was found between NIV patients and NV patients. Similar results were found at 1-year follow-up. Conclusions Our study suggests that using NIV is safe in selected patients with less profound CS and no other MV indication. NCT02703038 Graphical abstract

Background : Islet transplantation has been associated with better metabolic control and quality of life than insulin treatment alone, but direct evidence of its effect on hard clinical endpoints is scarce. We aimed to assess the effect of islet transplantation on patient-graft survival in kidney transplant recipients with type 1 diabetes. Methods : In this retrospective cohort study, we enrolled all patients with type 1 diabetes who received a kidney graft in France during the study period, identified from the CRISTAL nationwide registry. Non-inclusion criteria included recipients from transplant centres that never proposed islet transplantation during the study period, recipients with a functional pancreas throughout the follow-up duration, recipients with more than two kidney transplants, HLA-sensitised recipients, recipients with less than 1 year of follow-up after kidney transplantation, misclassified recipients with type 2 diabetes, recipients aged over 65 years, recipients of kidney grafts from Donation after Circulatory Death donors, recipient with HIV or hepatitis, recipients with cancer, and recipients of combined liver-kidney transplants. Patients who also received islet-after-kidney (IAK) transplantation were compared with controls who received kidney transplantation alone according to a 1:2 matching method based on time-dependent propensity scores, ensuring patients comparability at the time of islet transplantation. The primary outcome was patient-graft survival, a composite outcome defined by death, re-transplantation, or return to dialysis. Findings : Between Jan 1, 2000, and Dec 31, 2017, 2391 patients with type 1 diabetes were identified as having received a kidney transplant, 47 patients of whom also received an islet transplantation. 2002 patients were not eligible for islet transplantation and 62 were excluded due to missing data. 327 eligible recipients from 15 centres were included in the study dataset for the target trial emulation. 40 patients who received IAK transplantation were successfully matched to 80 patients who received kidney transplantation alone. 13 (33%) of 40 patients in the IAK transplantation group returned to dialysis or died, compared with 36 (45%) of 80 patients in the kidney transplantation alone group. We found a significant benefit of islet transplantation compared with kidney transplantation alone on patient-graft survival, with a hazard ratio (HR) of 0·44 (95% CI 0·23–0·88; p=0·022), mainly explained by a protective effect on the risk of death (HR 0·41, 0·13–0·91; p=0·042). There was no meaningful association between IAK and death-censored graft survival (0·73, 0·30–1·89; p=0·36). Interpretation : In kidney transplant recipients with type 1 diabetes, IAK transplantation was associated with a significantly better patient-graft survival compared with kidney transplantation alone, mainly due to a protective effect on the risk of death. These results potentially serve as compelling grounds for advocating wider access to islet transplantation in patients with type 1 diabetes undergoing kidney transplant, as reimbursement of islet transplantation is provided in few countries worldwide.

<b>Introduction:</b> First-line oxygenation strategy in patients with acute hypoxaemic respiratory failure consists in standard oxygen or high-flow nasal oxygen therapy. Clinical practice guidelines suggest the use of high-flow nasal oxygen rather than standard oxygen. However, findings remain contradictory with a low level of certainty. We hypothesise that compared with standard oxygen, high-flow nasal oxygen may reduce mortality in patients with acute hypoxaemic respiratory failure. <b>Method and analysis:</b> The Standard Oxygen versus High-flow nasal Oxygen-trial is an investigator-initiated, multicentre, open-label, randomised controlled trial comparing high-flow nasal oxygen versus standard oxygen in patients admitted to an intensive care unit (ICU) for acute respiratory failure with moderate-to-severe hypoxaemia. 1110 patients will be randomly assigned to one of the two groups with a ratio of 1:1. The primary outcome is the number of patients who died 28 days after randomisation. Secondary outcomes include comfort, dyspnoea and oxygenation 1 hour after treatment initiation, the number of patients intubated at day 28, mortality in ICU, in hospital and until day 90, and complications during ICU stay. <b>Ethics and dissemination:</b>The study has been approved by the central Ethics Committee 'Sud Méditerranée III' (2020-07-05) and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals. <b>Trial registration:</b> number NCT04468126.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC) with a poor prognosis. Currently, chemotherapy and neoadjuvant chemotherapy continue to have limited efficacy in TNBC. With the deepening of research, nano targeted therapy shows a good application prospect in TNBC. Psoralen (PSO), an active component of Psoralea corylifolia, has significant advantages in inhibiting the growth of TNBC, but its poor solubility hampers its clinical practice. In this study, injectable psoralen polymer lipid nanoparticles (PSOPLNs) were developed to deliver the hydrophobic drug to the target site and improve bioavailability. These nanoparticles were fully characterized in terms of morphology, particle size, surface zeta potential, encapsulation efficiency, drug loading, stability, and in vitro release profile. Besides, structural characteristics were determined by ultraviolet (UV) and infrared spectroscopy. Finally, in vivo pharmacokinetic studies of PSO-PLNs were performed in rats. The characteristic absorption of PSO and PSO-PLNs appeared in UV, indicating that PSO-PLNs had encapsulated PSO; there was no obvious characteristic absorption of PSO in infrared spectra, indicating that PSO was mostly encapsulated in the nano-shell. PSO-PLNs could maintain stable physicochemical properties for 1.5 months when stored at 4 ◦C. PSO-PLNs selectively released PSO at pH 6.5, and the sustained and controlled release effect was significantly different from that of PSO (p &lt; 0.01). Pharmacokinetic studies in vivo demonstrated that PSO-PLNs could improve PSO bioavailability by increasing blood drug concentration and plasma protein binding rate. In summary, injectable PSO-PLNs could be considered as promising delivery system for advanced cancer therapeutics.

<div><p>Background: As the functional and aesthetical importance of the canine cannot be overstated, the management of a missing canine is challenging. This case report describes the treatment of an infra-occluded ankylosed maxillary canine in a patient with previously failed orthodontic treatment. Case description: A 20-year-old patient sought a second opinion for orthodontic treatment failure. The patient presented with an impacted, ankylosed, and severely infra-occluded right maxillary canine, as well as an iatrogenic clockwise cant of the maxillary occlusal plane and several root resorptions. The treatment corrected the cant of the occlusal plane while avoiding further root resorption, partially extracted the upper right canine, improved the quality and quantity of the soft tissue in the newly edentulous area, and provided a prosthetic rehabilitation using a lithium disilicate ceramic resin-bonded cantilever bridge. Conclusions: The use of a cantilevered bridge resulted in an aesthetically pleasing and minimally invasive rehabilitation. This technique is reversible, does not affect pulp vitality, and is a viable solution for rehabilitating the smiles of young patients. Clinical significance:</p><p>The smile rehabilitation for an ankylosed maxillary canine, especially in the case of a previously failed orthodontic treatment, is an important clinical challenge. A minimally invasive long-term restoration with a cantilever bridge is a viable solution. Functional and aesthetically pleasant results can be achieved with a multidisciplinary approach.</p></div>

<div><p>Reactive oxygen species, when produced in a controlled manner, are physiological modulators of healthy white adipose tissue (WAT) expansion and metabolic function.</p><p>By contrast, unbridled production of oxidants is associated with pathological WAT expansion and the establishment of metabolic dysfunctions, most notably insulin resistance and type 2 diabetes mellitus. NADPH oxidases (NOXs) produce oxidants in an orderly fashion and are present in adipocytes and in other diverse WATconstituent cell types. Recent studies have established several links between aberrant NOX-derived oxidant production, adiposity, and metabolic homeostasis. The objective of this review is to highlight the physiological roles attributed to diverse NOX isoforms in healthy WAT and summarize current knowledge of the metabolic consequences related to perturbations in their adequate oxidant production. We detail WAT-related alterations in preclinical investigations conducted in NOXdeficient murine models. In addition, we review clinical studies that have employed NOX inhibitors and currently available data related to human NOX mutations in metabolic disturbances. Future investigations aimed at understanding the integration of NOX-derived oxidants in the regulation of the WAT cellular redox network are essential for designing successful redox-related precision therapies to curb obesity and attenuate obesity-associated metabolic pathologies.</p></div>

The mortality rate of sepsis remains high and further increases when complicated by disseminated intravascular coagulation (DIC). Consequently, early detection and appropriate management of DIC will be helpful for the management of sepsis. Although overt DIC criteria are often used for diagnosing definitive DIC, it was not designed to detect early-phase DIC. The criteria and scoring system for sepsis-induced coagulopathy (SIC) were developed and introduced in 2017 to detect early-stage DIC, and they were subsequently adopted by the International Society on Thrombosis and Haemostasis in 2019. The objective of detecting SIC was not to miss the patients at high risk of developing overt DIC at an earlier time. Although anticoagulant therapies are potential options for the treatment of sepsis-associated DIC, their effectiveness has not been established, and further research is warranted. For that purpose, an international collaborative platform is required for future clinical trials, and SIC criteria have been suggested for such studies. Calculating the SIC score is straightforward and suitable for use in clinical settings. This review aims to introduce SIC criteria and its scoring system for better management of sepsis-associated DIC. We also intended to update the current knowledge regarding this novel diagnostic criterion.

Background International guidelines for locally advanced esophageal squamous cell carcinoma (ESCC) recommend both neoadjuvant chemoradiotherapy (nCRT) followed by planned surgery (P-surg) or definitive chemoradiotherapy (dCRT) with salvage surgery (S-surg). However, the optimal treatment remains unknown, and the ongoing pragmatic NEEDS randomized trial is assessing the efficacy of an organ-preserving strategy after dCRT (Nilsson, Front Oncol 2022). Real-world data on the management of non-metastatic ESCC is limited. This study aims to describe the treatment strategies and prognosis of patients with non-metastatic ESCC in a real-world setting. Methods We conducted a retrospective cohort study of patient treated for non-metastatic ESCC between 2014 and 2022. Data were extracted from the FREGAT database. For the entire population, different treatment strategies were described. We compared patients who received nCRT with those who received dCRT under real-life conditions (“Real-life” population) and according to the NEEDS randomized trial criteria (“NEEDS-like” population). Five-year overall survival (OS) and relapse-free survival (RFS) were compared between nCRT and dCRT patients using a Cox proportional hazard model adjusting for major confounders. In operated patients, the impact of surgery on OS and RFS was assessed using a time-dependent Cox proportional hazard model. Postoperative outcomes were compared between P-surg and S-surg using Fisher’s exact test. Results From 971 patients diagnosed with non-metastatic ESCC, 867 (89.3%) received a curative treatment including dCRT (41.0%), nCRT (28.0%), primary esophagectomy (9.8%), neoadjuvant chemotherapy (3.4%), or endoscopic resection (1.0%). Fifty-nine patients (6,1%) received supportive care or chemotherapy alone. Forty-five patients (4.6%) died during or before treatment. In the “real-life” population (n=659), 269 patients received nCRT and 390 patients received dCRT. A total of 229 patients (93.5%) in nCRT group underwent P-surg and S-surg was performed in 44 patients (11.3%) in dCRT group. After adjustment, dCRT was associated with a significantly poorer 5-year OS and RFS (respectively HR=1.83, 95%CI 1.44-2.33; HR=1.98, 95%CI 1.57-2.49). A complete clinical response (cCR) was observed in 21.6% and 29.5% of the nCRT and dCRT groups, respectively. Among cCR undergoing resection, 35.8% had residual disease on pathological specimen. Time between CRT and surgery was 58 days (IQR44-72) vs. 109 days (IQR71-278) for P-surge and S-Surg respectively. The 90-day mortality, major morbidity (Clavien-Dindo III/IV) and pulmonary complication rates were similar in both groups, except for a higher risk of anastomotic leakage after S-surg (p=0.05). In the “NEEDS-like” population (n=598), findings were consistent and comparable to those observed in the “real-life” population. Conclusion Among non-mestastatic ESCC included in the FREGAT database, 10.6% had a non-curative approach or died prematurely. Most patients underwent dCRT, with S-surg rate of only 11.3%. Neoadjuvant CRT followed by P-surg was associated with the best outcome in terms of OS and RFS in both “rela life” and “Needs-like” populations. In operated patients, postoperative outcomes were similar after nCRT and dCRT, except for a higher incidence of anastomotic leakage after S-surg. This study highlighted the therapeutic strategies used and their results in real-life conditions for non-metastatic ESCC inside the FREGAT database. The treatment option of nCRT followed by P-surg appears to remain the optimal curative treatment regimen.

Background: Factors to accurately stratify patients with early-stage non-small cell lung cancer (NSCLC) in different prognostic groups are still needed. This study aims to investigate 1) the prognostic potential of circulating cell-free (CF) and extracellular vesicles (EVs)-derived microRNA (miRNAs), and 2) their added value with respect to known prognostic factors (PFs). Methods: The RESTING study is a multicentre prospective observational cohort study on resected stage IA-IIIA patients with NSCLC. The primary end-point was disease-free survival (DFS), and the main analyses were carried out separately for CF-and EV-miRNAs. CF-and EV-miRNAs were isolated from plasma, and miRNA-specific libraries were prepared and sequenced. To reach the study aims, three statistical models were specified: one using the miRNA data only (Model 1); one using both miRNAs and known PFs (age, gender, and pathological stage) (Model 2), and one using the PFs alone (Model 3). Five-fold cross-validation (CV) was used to assess the predictive performance of each. Standard Cox regression and elastic net regularized Cox regression were used. Results: A total of 222 patients were enrolled. The median follow-up time was 26.3 (95% CI 25.4-27.6) months. From Model 1, three CF-miRNAs and 21 EV-miRNAs were associated with DFS. In Model 2, two CF-miRNAs (miR-29c-3p and miR-877-3p) and five EV-miRNAs (miR-181a-2-3p, miR-182-5p, miR-192-5p, miR-532-3p and miR-589-5p) remained associated with DFS. From pathway enrichment analysis, TGF-beta and NOTCH were the most involved pathways. Conclusion: This study identified promising prognostic CF-and EV-miRNAs that could be used as a non-invasive, cost-effective tool to aid clinical decision-making. However, further evaluation of the obtained miRNAs in an external cohort of patients is warranted.

Aims/hypothesis: Our study aims to uncover glycaemic phenotype heterogeneity in type 1 diabetes. Methods: In the Study of the French-speaking Society of Type 1 Diabetes (SFDT1), we characterised glycaemic heterogeneity thanks to a set of complementary metrics: HbA1c, time in range (TIR), time below range (TBR), CV, Gold score and glycaemia risk index (GRI). Applying the Discriminative Dimensionality Reduction with Trees (DDRTree) algorithm, we created a phenotypic tree, i.e. a 2D visual mapping. We also carried out a clustering analysis for comparison. Results: We included 618 participants with type 1 diabetes (52.9% men, mean age 40.6 years [SD 14.1]). Our phenotypic tree identified seven glycaemic phenotypes. The 2D phenotypic tree comprised a main branch in the proximal region and glycaemic phenotypes in the distal areas. Dimension 1, the horizontal dimension, was positively associated with GRI (coefficient [95% CI]) (0.54 [0.52, 0.57]), HbA1c (0.39 [0.35, 0.42]), CV (0.24 [0.19, 0.28]) and TBR (0.11 [0.06, 0.15]), and negatively with TIR (-0.52 [-0.54, -0.49]). The vertical dimension was positively associated with TBR (0.41 [0.38, 0.44]), CV (0.40 [0.37, 0.43]), TIR (0.16 [0.12, 0.20]), Gold score (0.10 [0.06, 0.15]) and GRI (0.06 [0.02, 0.11]), and negatively with HbA1c (-0.21 [-0.25, -0.17]). Notably, socioeconomic factors, cardiovascular risk indicators, retinopathy and treatment strategy were significant determinants of glycaemic phenotype diversity. The phenotypic tree enabled more granularity than traditional clustering in revealing clinically relevant subgroups of people with type 1 diabetes. Conclusions/interpretation: Our study advances the current understanding of the complex glycaemic profile in people with type 1 diabetes and suggests that strategies based on isolated glycaemic metrics might not capture the complexity of the glycaemic phenotypes in real life. Relying on these phenotypes could improve patient stratification in type 1 diabetes care and personalise disease management.

Background: Cardiogenic shock and sepsis are severe haemodynamic states that are frequently present concomitantly, leading to substantial mortality. Despite its frequency and clinical significance, there is a striking lack of literature on the outcomes of combined sepsis and cardiogenic shock. Methods: FRENSHOCK was a prospective registry including 772 patients with cardiogenic shock from 49 centres. The primary endpoint was 1-month all-cause mortality. Secondary endpoints included heart transplantation, ventricular assistance device and all-cause death rate at 1 year. Results: Among the 772 patients with cardiogenic shock included, 92 cases were triggered by sepsis (11.9%), displaying more frequent renal and hepatic acute injuries, with lower mean arterial pressure. Patients in the sepsis group required broader use of dobutamine (90.1% vs 81.2%; P = 0.16), norepinephrine (72.5% vs 50.8%; P &lt; 0.01), renal replacement therapy (29.7% vs 14%; P &lt; 0.01), non-invasive ventilation (36.3% vs 24.4%; P = 0.09) and invasive ventilation (52.7% vs 35.9%; P = 0.02). Sepsis-triggered cardiogenic shock resulted in higher 1-month (41.3% vs 24.0%; adjusted hazard ratio 1.94, 95% confidence interval 1.36–2.76; P &lt; 0.01) and 1-year (62.0% vs 42.9%; adjusted hazard ratio 1.75, 95% confidence interval 1.32–2.33; P &lt; 0.01) all-cause death rates. No significant difference was found at 1 year for heart transplantation or ventricular assistance device (8.7% vs 10.3%; adjusted odds ratio 0.72, 95% confidence interval 0.32–1.64; P = 0.43). In patients with sepsis-triggered cardiogenic shock, neither the presence of a pre-existing cardiomyopathy nor the co-occurrence of other cardiogenic shock triggers had any additional impact on death. Conclusions: The association between sepsis and cardiogenic shock represents a common high-risk scenario, leading to higher short- and long-term death rates, regardless of the association with other cardiogenic shock triggers or the presence of pre-existing cardiomyopathy.

<div>HIGHLIGHTS<p>Subclinical leaflet thrombosis was recently linked to higher rates of stroke and transient ischemic attack after TAVR. EVs have emerged as a surrogate marker of endothelial dysfunction and cardiovascular risk. This study demonstrates the role of EVs trapped within the native aortic valve in valvular dysfunction and thrombogenicity, and points at the contribution of the local angiotensin system/NADPH oxidases/SGLT2 pro-oxidant pathway.</p></div>

Background: At present, the diagnosis of acute coronary syndrome (ACS) can be made by emergency physicians using the usual complementary tests, since the current troponin and electrocardiogram (ECG) protocols have been extensively tested for their safety. However, the detection of coronary calcifications on CT associated with coronary obstruction may be of interest for the diagnostic strategy in the emergency department (ED). The aim of this study was to evaluate a strategy combining a non-ischemic ECG with an initial normal troponin assay and the diagnostic accuracy of chest CT in detecting coronary calcifications to rule out the presence of an acute coronary event in patients presenting with chest pain in the ED. Methods: This was a retrospective, single-center study carried out in an ED in France and included all patients over 18 years of age presenting with chest pain between 1 June 2021 and 31 December 2021 with a non-ischemic ECG and a negative first troponin assay. The primary endpoint was the diagnostic performance of the combing strategy in ruling out ACS. The secondary endpoints were the sensitivity and specificity of calcifications in acute coronary syndrome, comparison with the diagnostic performance of a second troponin assay and the rate of reconsultation, rehospitalisation and investigations within 2 months of the ED. Results: Of the 280 patients included, 141 didn't have calcifications. A total of 14 events were found with a negative predictive value for the combining strategy of 99.8% [95%CI: 98.2 -100]. Sensitivity and specificity were 98.4% [95%CI: 83.8 -100] and 53% [95%CI: 47 -58.9], respectively. Among patients with no calcification, 8.2% were admitted to hospital and none suffered an acute coronary event. A total of 36 patients (12.8%) consulted a doctor within 2 months, with 23 investigations, all of which were negative in the non-calcification group. Conclusions: A strategy combining the detection of coronary calcifications on chest CT in patients with a nonischemic ECG and a single troponin assay is effective to rule out ACS in the ED, and may perform better then ECG and troponin alone.

Background and purpose Castration‐resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first‐line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC. Experimental approach Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC. Key results Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient‐derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells. Conclusion and implications Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa.

<div><p>Background CHA 2 DS 2 -VASc score-related differences have been reported in atrial fibrotic remodeling and prognosis of atrial fibrillation (AF) patients after ablation. There are currently no data on the efficacy of low voltage zone (LVZ)guided ablation in persistent AF patients according to CHA 2 DS 2 -VASc score. We assessed in a cohort of persistent AF patients the extent of LVZ, the regional distribution of LA voltage and the outcome of LA voltage-guided substrate ablation in addition to PVI according to CHA 2 DS 2 -VASc score.</p><p>Methods 138 consecutive persistent AF patients undergoing a first voltage-guided catheter ablation were enrolled. 58 patients with CHAD 2 DS 2 -VASc score ≥ 3 and 80 patients with CHAD 2 DS 2 -VASc score ≤ 2 were included. LA voltage maps were obtained using 3D-electroanatomical mapping system in sinus rhythm. LVZ was defined as &lt; 0.5 mV.</p></div> <div>Results<p>In the high CHAD 2 DS 2 -VASc score group, LA voltage was lower (1.5 [1.1-2.5] vs. 2.3 [1.5-2.8] mV, p = 0.02) and LVZs were more frequently identified (40% vs. 18%), p &lt; 0.01). Female with CHA 2 DS 2 -VASc score ≥ 3 (p = 0.031), LA indexed volume (p = 0.009) and P-wave duration ≥ 150 ms (p = 0.001) were predictors of LVZ. After a 36-month follow-up, atrial arrhythmia-free survival was similar between the two groups (logrank test, P = 0.676).</p><p>Conclusions AF patients with CHAD 2 DS 2 -VASc score ≥ 3 display more LA substrate remodeling with lower voltage and more LVZs compared with those with CHAD 2 DS 2 -VASc score ≤ 2. Despite this atrial remodeling, they had similar and favorable 36 months results after one single procedure. Unlike male with CHAD 2 DS 2 -VASc score ≥ 3, female with CHAD 2 DS 2 -VASc score ≥ 3 was predictor of LVZ occurrence.</p></div>

This article reports the successful one-step synthesis of two micron-sized composite powders consisting of chitosan and amorphous calcium phosphate. These composite materials are prepared by spray drying of a solution containing chitosan and calcium phosphate precursors. The co-precipitation of chitosan and calcium phosphate precursors during the process induces a highly homogeneous distribution of the phases. The mineral phase identified as spherical nanoparticles dispersed in chitosan showed no chemical bonding with the polymer. As demonstrated by electron microscopy, small angle X-ray scattering and spectroscopies, variation in chitosan concentrations significantly influences the size and spatial distribution of the mineral phase. These results present a promising approach for the preparation of chitosan/amorphous calcium phosphate composite powders with controlled and tunable properties with potential applications in the field of biomaterial engineering such as bone substitutes.

Abstract OBJECTIVES To determine safety and survival outcomes associated with lobectomy, segmentectomy and wedge resection for early-stage lung cancer by quiring the French population-based registry EPIdemiology in THORacic surgery (EPITHOR). METHODS Retrospective analysis of 19 452 patients with stage c IA lung carcinoma who underwent lobectomy, segmentectomy or wedge resection between 2016 and 2022 with curative-intent. Main outcome measures were 90-day mortality and 5-year overall survival estimates. Proportional hazards regression and propensity score matching were used to adjust outcomes for key patient, tumour and practice environment factors. RESULTS The treatment distribution was 72.2% for lobectomy, 21.5% for segmentectomy and 6.3% for wedge. Unadjusted 90-day mortality rates were 1.6%, 1.2% and 1.1%, respectively (P = 0.10). Unadjusted 5-year overall survival estimates were 80%, 78% and 70%, with significant inter-group survival curves differences (P &lt; 0.0001). Multivariable proportional hazards regression showed that wedge was associated with worse overall survival [adjusted hazard ratio (AHR), 1.23 (95% confidence interval 1.03–1.47); P = 0.021] compared with lobectomy, while no significant difference was disclosed when comparing segmentectomy to lobectomy (1.08 [0.97–1.20]; P = 0.162). The three-way propensity score analyses confirmed similar 90-day mortality rate for wedge resection and segmentectomy compared with lobectomy (hazard ratio: 0.43; 95% confidence interval 0.16–1.11; P = 0.081 and 0.99; 0.48–2.10; P = 0.998, respectively), but poorer overall survival (1.45; 1.13–1.86; P = 0.003 and 1.31; 1–1.71; P = 0.048, respectively). CONCLUSIONS Wedge resection was associated with comparable 90-day mortality but lower overall survival when compared to lobectomy. Overall, all types of sublobar resections may not offer equivalent oncologic effectiveness in real-world settings.

Skeletal defects are the second-leading cause of disability worldwide, prompting the development of smart solutions for treatment. Calcium glycerophosphate (Ca–GP), chitosan (CS), hydroxyapatite (HA), and zein (ZN) were used to fabricate these thermo-responsive hydrogels. Ca–GP, an economically viable and bioactive glycerophosphate source, remains relatively underexplored. Natural protein ZN and the gold standard bone regenerative biomaterial HA were incorporated as reinforcing agents. The resulting composite hydrogels (HGs) exhibit a sol phase at 4 °C–10 °C and transition to gels at body temperature within 4–6 min. Their good injectability and the ability to be easily shaped into complex structures further support their great potential as minimally invasive solutions for treatment. The addition of ZN significantly improved the mechanical and biological properties of the HGs. The highest ZN concentration resulted in the strongest mechanical strength, measuring 52.2 MPa at 40% strain. HGs exhibited optimal swelling and degradation rates. Scanning electron microscopy analysis supported their porous nature. In vitro cell culture assays and wound healing assays demonstrated their excellent biocompatibility and regenerative potential. Drug-loaded HGs exhibited up to 90% drug release and antibacterial activity. All these results support their promising potential to support the regeneration of skeletal defects in a minimally invasive manner.

Many strategies for regenerating the damaged tissues or degenerating cells are employed in regenerative medicine. Stem cell technology is a modern strategy of the recent approaches, particularly the use of mesenchymal stem cells (MCSs). The ability of MSCs to differentiate as well as their characteristic behaviour as paracrine effector has established them as key elements in tissue repair. Recently, extracellular vesicles (EVs) shed by MSCs have emerged as a promising cell free therapy. This comprehensive review encompasses MSCs-derived exosomes and their therapeutic potential as nanotherapeutics. We also discuss their potency as drug delivery nano-carriers in comparison with liposomes. A better knowledge of EVs behaviour in vivo and of their mechanism of action are key to determine parameters of an optimal formulation in pilot studies and to establish industrial processes.

Background: The Sequential Organ Failure Assessment (SOFA) score is an important tool in diagnosing sepsis and quantifying organ dysfunction. However, despite emerging evidence of differences in sepsis pathophysiology between women and men, sex is currently not being considered in the SOFA score. We aimed to investigate potential sex-specific differences in organ dysfunction, as measured by the SOFA score, in patients with sepsis or septic shock and explore outcome associations. Methods: Retrospective analysis of sex-specific differences in the SOFA score of prospectively enrolled ICU patients with sepsis or septic shock admitted to one of 85 certified Swiss ICUs between 01/2021 and 12/2022. Results: Of 125,782 patients, 5947 (5%) were admitted with a clinical diagnosis of sepsis (2244, 38%) or septic shock (3703, 62%). Of these, 5078 (37% women) were eligible for analysis. A statistically significant difference of the total SOFA score on admission was found between women (mean 7.5 ± SD 3.6 points) and men (7.8 ± 3.6 points, Wilcoxon rank-sum p &lt; 0.001). This was driven by differences in the coagulation (p = 0.008), liver (p &lt; 0.001) and renal (p &lt; 0.001) SOFA components. Differences between sexes were more prominent in younger patients &lt; 52 years of age (women 7.1 ± 4.0 points vs men 8.1 ± 4.2 points, p = 0.004). No sex-specific differences were found in ICU length of stay (women median 2.6 days (IQR 1.3-5.3) vs men 2.7 days (IQR 1.2-6.0), p = 0.13) and ICU mortality (women 14% vs men 15%, p = 0.17). Conclusion: Sex-specific differences exist in the SOFA score of patients admitted to a Swiss ICU with sepsis or septic shock, particularly in laboratory-based components. Although the clinical meaningfulness of these differences is unclear, a reevaluation of sex-specific thresholds for SOFA score components is warranted in an attempt to make more accurate and individualised classifications.

No abstract available

Background Our objective is twofold: determining if simulation allows residents to reach proficient surgeons' performance concerning fundamental technical skills of endovascular surgery (FEVS) while investigating effects of the program on surgeons’ stress. Methods Using a FEVS training simulator, 8 endovascular FEVS were performed by vascular surgery residents (simulator-naive or simulator-experienced residents [SER]) and seniors. Total time needed to complete the 8 tasks, called total completion time (TCT), was the main evaluation criterion. Analgesia Nociception Index (ANI) was monitored during simulation. Likert scale questionnaire was filled out after each simulation. Results For each task, TCT was significantly lower for SER and seniors than simulator-naive residents (P = 0.0163). After only 5 simulations, SER were able to reach and even exceed the seniors' level in terms of TCT, with a median time of 10.8 min for SER and 11.9 min for seniors, and wire's movements with a median distance during cannulation of 4.44 m for SER and 4.17 m for seniors. Seniors remained better than SER in terms of precise wire manipulation (wire movement after cannulation), 4.17 m against 4.44 m (3.72–5.96), respectively. Based on the Likert scale stress analysis, seniors felt less stressed than both residents' groups (P = 0.0618). Seniors’ initial ANI and mean ANI over the session were significantly lower than those of the residents, P = 0.0358 and P = 0.0250, respectively. Conclusions We showed that 5 simulation sessions allowed residents to reach experienced surgeons’ capacities on FEVS concerning TCT. Subjectively, seniors felt less stressed than residents, contrary to the results of our objective measures of stress.

Cartilage, an important connective tissue, provides structural support to other body tissues, and serves as a cushion against impacts throughout the body. Found at the end of the bones, cartilage decreases friction and averts bone-on-bone contact during joint movement. Therefore, defects of cartilage can result from natural wear and tear, or from traumatic events, such as injuries or sudden changes in direction during sports activities. Overtime, these cartilage defects which do not always produce immediate symptoms, could lead to severe clinical pathologies. The emergence of induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine, providing a promising platform for generating various cell types for therapeutic applications. Thus, chondrocytes differentiated from iPSCs become a promising avenue for non-invasive clinical interventions for cartilage injuries and diseases. In this review, we aim to highlight the current strategies used for in vitro chondrogenic differentiation of iPSCs and to explore their multifaceted applications in disease modeling, drug screening, and personalized regenerative medicine. Achieving abundant functional iPSC-derived chondrocytes requires optimization of culture conditions, incorporating specific growth factors, and precise temporal control. Continual improvements in differentiation methods and integration of emerging genome editing, organoids, and 3D bioprinting technologies will enhance the translational applications of iPSC-derived chondrocytes. Finally, to unlock the benefits for patients suffering from cartilage diseases through iPSCs-derived technologies in chondrogenesis, automatic cell therapy manufacturing systems will not only reduce human intervention and ensure sterile processes within isolator-like platforms to minimize contamination risks, but also provide customized production processes with enhanced scalability and efficiency.

Background: Lung transplantation (LTx) is a life-extending therapy for specific patients with terminal lung diseases. This study aimed to evaluate the associations and causes of 1-year mortality after lung transplantation at Strasbourg University Hospital, France, between 2012 and 2021. <div>Material/Methods:<p>We carried out a retrospective analysis on 425 patients who underwent LTx at Strasbourg University Hospital between January 1, 2012, and December 31, 2021. Pre-transplant, perioperative, and postoperative data were collected from the electronic medical records.</p></div> <div>Results:<p>Among all patients, 94.6% had a LTx, 4.0% a heart-lung transplantation, and 1.4% underwent pancreatic isletlung transplantation. The median age at transplantation was 57 years, with 55.3% male patients. The main native lung disease leading to LTx was chronic obstructive pulmonary disease in 51.1% of patients; 16.2% needed super-urgent LTx.</p><p>The 1-year mortality rate was 11.5%. Most deaths were either caused by multi-organ failure or septic shock.</p><p>In our multivariate analysis, we identified 3 risk factors significantly related to 1-year mortality after LTx: body mass index (BMI) between 25 and 30 kg/m 2 vs BMI between 18.5 and 25 kg/m 2 (P=0.032), postoperative extracorporeal membrane oxygenation support (P=0.034), and intensive care unit length of stay after transplantation (P&lt;0.001). Two other factors were associated with a significantly lower 1-year mortality risk: longer hospital stay after LTx (P=0.024) and tacrolimus prescription (P=0.004).</p></div> <div>Conclusions:<p>Our study reported a 1-year mortality rate of 11.5% after LTx. Although LTx candidates are carefully selected, additional data are required to improve understanding of the risk factors for post-LTx mortality.</p></div>

Purpose: The efficacy of the 1-h bundle for emergency department (ED) patients with suspected sepsis, which includes lactate measurement, blood culture, broad-spectrum antibiotics administration, administration of 30 mL/kg crystalloid fluid for hypotension or lactate ≥ 4 mmol/L, remains controversial. Methods: We carried out a pragmatic stepped-wedge cluster-randomized trial in 23 EDs in France and Spain. Adult patients with Sepsis-3 criteria or a quick sequential organ failure assessment (SOFA) score ≥ 2 or a lactate &gt; 2 mmol/L were eligible. The intervention was the implementation of the 1-h sepsis bundle. The primary outcome was in-hospital mortality truncated at 28 days. Secondary outcomes included volume of fluid resuscitation at 24 h, acute heart failure at 24 h, SOFA score at 72 h, intensive care unit (ICU) length of stay, number of days on mechanical ventilation or renal replacement therapy, vasopressor free days, unnecessary antibiotic administration, and mortality at 28 days. 1148 patients were planned to be analysed; the study period ended after 873 patients were included. Results: 872 patients (mean age 66, 42% female) were analyzed: 387 (44.4%) in the intervention group and 485 (55.6%) in the control group. Median SOFA score was 3 [1-5]. Median time to antibiotic administration was 40 min in the intervention group vs 113 min in the control group (difference - 73 [95% confidence interval (CI) - 93 to - 53]). There was a significantly higher rate, volume, and shorter time to fluid resuscitation within 3 h in the intervention group. There were 47 (12.1%) in-hospital deaths in the intervention group compared to 61 (12.6%) in the control group (difference in percentage - 0.4 [95% CI - 5.1 to 4.2], adjusted relative risk (aRR) 0.81 [95% CI 0.48 to 1.39]). There were no differences between groups for other secondary endpoints. Conclusions: Among patients with suspected sepsis in the ED, the implementation of the 1-h sepsis bundle was not associated with significant difference in in-hospital mortality. However, this study may be underpowered to report a statistically significant difference between groups.

Background: There is no reliable indicator that can assess the treatment effect of anticoagulant therapy for sepsisassociated disseminated intravascular coagulation (DIC) in the short term. The aim of this study is to develop and validate a prognostic index identifying 28-day mortality in septic DIC patients treated with antithrombin concentrate after a 3-day treatment. Methods: The cohort for derivation was established utilizing the dataset from post-marketing surveys, while the cohort for validation was acquired from Japan’s nationwide sepsis registry data. Through univariate and multivariate analyses, variables that were independently associated with 28-day mortality were identified within the derivation cohort. Risk variables were then assigned a weighted score based on the risk prediction function, leading to the development of a composite index. Subsequently, the area under the receiver operating characteristic curve (AUROC). 28-day survival was compared by Kaplan–Meier analysis. Results: In the derivation cohort, 252 (16.9%) of the 1492 patients deceased within 28 days. Multivariable analysis identified DIC resolution (hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.22–0.45, P &lt; 0.0001) and rate of Sequential Organ Failure Assessment (SOFA) score change (HR: 0.42, 95% CI: 0.36–0.50, P &lt; 0.0001) were identified as independent predictors of death. The composite prognostic index (CPI) was constructed as DIC resolution (yes: 1, no: 0) + rate of SOFA score change (Day 0 SOFA score–Day 3 SOFA score/Day 0 SOFA score). When the CPI is higher than 0.19, the patients are judged to survive. Concerning the derivation cohort, AUROC for survival was 0.76. As for the validation cohort, AUROC was 0.71. Conclusion: CPI can predict the 28-day survival of septic patients with DIC who have undergone antithrombin treatment. It is simple and easy to calculate and will be useful in practice.

Objectives: In the protocol for cleaning and sterilizing dental handpieces (DHs), water retention within the instrument poses a challenge and may compromise the sterilization process. This study aimed to assess the reliability and reproducibility of the sterilization protocol regarding the dryness of DHs. It evaluated the presence of residual water in these instruments after various conditions of treatment through multiple dryness tests. Methods: This comparative study examined the dryness of seven different DHs following five washing-disinfection and/or sterilization protocols. Dabbing tests, shaking by hand, or compressed air tests through DHs and over absorbent paper were employed to ascertain the thorough dryness of DHs after treatment. As soon as the first sign of water appeared on the absorbent paper, the DH was deemed to be not dry. Results: Upon completion of the washing-disinfection protocol without sterilization, five out of seven DHs were deemed dry using the dabbing test, yet none were fully dry when subjected to shaking or compressed air. However, in the four protocols incorporating final sterilization, all DHs were dry according to the three drying tests. Conclusion: This study underscores the essential role of the sterilization step in eliminating residual water from DHs, thereby ensuring optimal conditions for effective sterilization in terms of dryness. Furthermore, the study recommends against relying solely on the dabbing drying test, emphasizing the importance of shaking or using compressed air to confirm instrument dryness.

Background : Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring mechanical ventilation suffer from a high incidence of ventilator associated pneumonia (VAP), mainly related to Enterobacterales. Data regarding extended-spectrum beta-lactamase producing Enterobacterales (ESBL-E) VAP are scarce. We aimed to investigate risk factors and outcomes of ESBL-E related VAP among critically ill coronavirus infectious disease-19 (COVID-19) patients who developed Enterobacterales related VAP. Patients and methods: We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU) that included 4929 COVID-19 critically ill patients. For the present analysis, only patients with complete data regarding resistance status of the first episode of Enterobacterales related VAP (ESBL-E and/or carbapenem-resistant Enterobacterales, CRE) and outcome were included. Results: We included 591 patients with Enterobacterales related VAP. The main causative species were Enterobacter sp (n = 224) , E. coli (n = 111) and K. pneumoniae (n = 104). One hundred and fifteen patients (19%), developed a first ESBL-E related VAP, mostly related to Enterobacter sp (n = 40), K. pneumoniae (n = 36), and E. coli (n = 31). Eight patients (1%) developed CRE related VAP. In a multivariable analysis, African origin (North Africa or Sub-Saharan Africa) (OR 1.7 [1.07–2.71], p = 0.02), time between intubation and VAP (OR 1.06 [1.02–1.09], p = 0.002), PaO 2 /FiO 2 ratio on the day of VAP (OR 0.997 [0.994–0.999], p = 0.04) and trimethoprim-sulfamethoxazole exposure (OR 3.77 [1.15–12.4], p = 0.03) were associated with ESBL-E related VAP. Weaning from mechanical ventilation and mortality did not significantly differ between ESBL-E and non ESBL-E VAP. Conclusion: ESBL-related VAP in COVID-19 critically-ill patients was not infrequent. Several risk factors were identified, among which some are modifiable and deserve further investigation. There was no impact of resistance of the first Enterobacterales related episode of VAP on outcome.

Hematological malignancies may require rapid-onset treatment because of their short doubling time, notably observed in acute leukemias and specific high-grade lymphomas. Furthermore, in targeted onco-hematological scenarios, chemotherapy is deemed necessary as an emergency measure when facing short-term, life-threatening complications associated with highly chemosensitive hematological malignancies. The risks inherent in the disease itself, or in the initiation of treatment, may then require admission to the intensive care unit (ICU) to optimize monitoring and initial management protocols. Hyperleukocytosis and leukostasis in acute leukemias, tumor lysis syndrome, and disseminated intravascular coagulation are the most frequent onco-hematological complications requiring the implementation of emergency chemotherapy in the ICU. Chemotherapy must also be started urgently in secondary hemophagocytic lymphohistiocytosis. Tumor-induced microangiopathic hemolytic anemia and plasma hyperviscosity due to malignant monoclonal gammopathy represent infrequent yet substantial indications for emergency chemotherapy. In all cases, the administration of emergency chemotherapy in the ICU requires close collaboration between intensivists and hematology specialists. In this review, we provide valuable insights that aid in the identification and treatment of patients requiring emergency chemotherapy in the ICU, offering diagnostic tools and guidance for their overall initial management.

In this study, we present a new type of polymer-free hydrogel made only from nonionic surfactants, oil, and water. Such a system is produced by taking advantage of the physicochemical behavior and interactions between nonionic surfactants and oil and water phases, according to a process close to spontaneous emulsification used in the production of nano-emulsions. Contrary to the classical process of emulsion-based gel formulation, we propose a simple one-step approach. Beyond the originality of the concept, these nanoemulgels appear as very promising systems able to encapsulate and deliver various molecules with different solubilities. In the first section, we propose a comprehensive investigation of the gel formation process and its limits through oscillatory rheological characterization, characterization of the sol/gel transitions, and gel strength. The second section is focused on the follow-up of the release of an encapsulated model hydrophilic molecule and on the impact of the rheological gel properties on the release profiles.

Background: Solitary Bone Cyst (SBC), also known as a simple bone cyst, hemorrhagic cyst, or traumatic cyst is classified by the WHO among non-odontogenic benign lesions of the jaw. The article explores the use of a static 3D-printed surgical guide to treat mandibular SBC, emphasizing a minimally surgical approach for this lesion. Case Presentation: A 20-year-old woman was referred for a persistent mandibular SBC lacuna, without specific complaints. Her medical history included a previous bone trepanation for a SBC in the same area, radiologically and surgically confirmed. X-ray assessment showed a well-defined unilocular radiolucency surrounding the root of the first left lower molar (tooth #36), measuring 10 × 10 mm. Pulp sensitivity was normal. CBCT data and STL files of dental cast were obtained preoperatively and registered. A 3D-printed surgical guide was used for minimally invasive trepanation of the buccal cortical. The simulation used a targeted endodontic microsurgery approach in order to determine axis and diameter of the trephine. Surgery was performed under local anesthesia. The guide was tooth supported integrating tubes and a fork for guiding precise trepanation. A 3.5 mm round bone window was created, leaving an empty cavity confirming SBC diagnosis and permitting bone curettage. A blood clot was obtained to promote bone healing. Complete reossification was observed after 6 months. The follow-up at 2 years confirmed a complete bone healing with normal pulp sensitivity. Discussion: The 3D-printed windowed surgical guide with dental support offers big advantages, including improved visibility and reduced errors. Compared to traditional guides, it eliminates visual hindrance and allows easier and quick access to confined areas as well as an improved irrigation during drilling process. The article also highlights the importance of preoperative planning while acknowledging potential limitations and errors and surgical complications. Conclusion The use of the 3D-printed surgical guide could be used in routine for minimally invasive intervention of SBC. This case also demonstrates the potential utility of this approach in various procedures in oral and maxillofacial surgery. The technique provides precise localization, reducing complications and enhances operative efficiency.

Historically, heparin has had the longest historical use as an anticoagulant and continues this day to be the primary therapeutic option for preventing thrombosis and thromboembolism in critically ill hospitalized patients. Heparin is also used to treat sepsis and sepsis-associated disseminated intravascular coagulation (DIC) in various countries. However, the efficacy and safety of heparin for this indication remains controversial, as adequately powered randomized clinical studies have not demonstrated as yet a survival benefit in sepsis and sepsis-associated DIC, despite meta-analyses and propensity analyses reporting improved outcomes without increasing bleeding risk. Further, activated protein C and recombinant thrombomodulin showed greater improvements in outcomes compared with heparin, although these effects were inconclusive. In summary, further research is warranted, despite the ongoing clinical use of heparin for sepsis and sepsis-associated DIC. Based on Japanese guidelines, antithrombin or recombinant thrombomodulin may be a preferable choice if they are accessible.

Objective The contribution of the mitochondrial electron transfer system to insulin secretion involves more than just energy provision. We identified a small RNA fragment (mt-tRF-LeuTAA) derived from the cleavage of a mitochondrially-encoded tRNA that is conserved between mice and humans. The role of mitochondrially-encoded tRNA-derived fragments remains unknown. This study aimed to characterize the impact of mt-tRF-LeuTAA, on mitochondrial metabolism and pancreatic islet functions. Methods We used antisense oligonucleotides to reduce mt-tRF-LeuTAA levels in primary rat and human islet cells, as well as in insulin-secreting cell lines. We performed a joint transcriptome and proteome analysis upon mt-tRF-LeuTAA inhibition. Additionally, we employed pull-down assays followed by mass spectrometry to identify direct interactors of the fragment. Finally, we characterized the impact of mt-tRF-LeuTAA silencing on the coupling between mitochondrial metabolism and insulin secretion using high-resolution respirometry and insulin secretion assays. Results Our study unveils a modulation of mt-tRF-LeuTAA levels in pancreatic islets in different Type 2 diabetes models and in response to changes in nutritional status. The level of the fragment is finely tuned by the mechanistic target of rapamycin complex 1. Located within mitochondria, mt-tRF-LeuTAA interacts with core subunits and assembly factors of respiratory complexes of the electron transfer system. Silencing of mt-tRF-LeuTAA in islet cells limits the inner mitochondrial membrane potential and impairs mitochondrial oxidative phosphorylation, predominantly by affecting the Succinate (via Complex II)-linked electron transfer pathway. Lowering mt-tRF-LeuTAA impairs insulin secretion of rat and human pancreatic β-cells. Conclusions Our findings indicate that mt-tRF-LeuTAA interacts with electron transfer system complexes and is a pivotal regulator of mitochondrial oxidative phosphorylation and its coupling to insulin secretion.

Background: This study aimed to characterize the demographics, microbiology, management and treatment outcomes of mediastinitis according to the origin of the infection. Methods: This retrospective observational study enrolled patients who had mediastinitis diagnosed according to the criteria defined by the Centers for Disease Control and Prevention and were treated in Strasbourg University Hospital, France, between 1 January 2010 and 31 December 2020. Results: We investigated 151 cases, including 63 cases of poststernotomy mediastinitis (PSM), 60 cases of mediastinitis due to esophageal perforation (MEP) and 17 cases of descending necrotizing mediastinitis (DNM). The mean patient age (standard deviation) was 63 (14.5) years, and 109 of 151 patients were male. Microbiological documentation varied according to the origin of the infection. When documented, PSM cases were mostly monomicrobial (36 of 53 cases [67.9%]) and involved staphylococci (36 of 53 [67.9%]), whereas MEP and DNM cases were mostly plurimicrobial (38 of 48 [79.2%] and 8 of 12 [66.7%], respectively) and involved digestive or oral flora microorganisms, respectively. The median duration of anti-infective treatment was 41 days (interquartile range, 21-56 days), and 122 of 151 patients (80.8%) benefited from early surgical management. The overall 1-year survival rate was estimated to be 64.8% (95% confidence interval, 56.6%-74.3%), but varied from 80.1% for DNM to 61.5% for MEP. Conclusions: Mediastinitis represents a rare yet deadly infection. The present cohort study exhibited the different patterns observed according to the origin of the infection. Greater insight and knowledge on these differences may help guide the management of these complex infections, especially with respect to empirical anti-infective treatments. Keywords: descending necrotizing mediastinitis; esophageal perforation; infectious mediastinitis; sternotomy.

Onco-virotherapy is an emergent treatment for cancer based on viral vectors. The therapeutic activity is based on two different mechanisms including tumor-specific oncolysis and immunostimulatory properties. In this study, we evaluated onco-virotherapy in vitro responses on immunocompetent non-small cell lung cancer (NSCLC) patient-derived tumoroids (PDTs) and healthy organoids. PDTs are accurate tools to predict patient’s clinical responses at the in vitro stage. We showed that onco-virotherapy could exert specific antitumoral effects by producing a higher number of viral particles in PDTs than in healthy organoids. In the present work, we used multiplex protein screening, based on proximity extension assay to highlight different response profiles. Our results pointed to the increase of proteins implied in T cell activation, such as IFN-γ following onco-virotherapy treatment. Based on our observation, oncolytic viruses-based therapy responders are dependent on several factors: a high PD-L1 expression, which is a biomarker of greater immune response under immunotherapies, and the number of viral particles present in tumor tissue, which is dependent to the metabolic state of tumoral cells. Herein, we highlight the use of PDTs as an alternative in vitro model to assess patient-specific responses to onco-virotherapy at the early stage of the preclinical phases.

Metal ion-catalyzed overproduction of reactive oxygen species (ROS) is believed to contribute significantly to oxidative stress and be involved in several biological processes, from immune defense to development of diseases. Among the essential metal ions, copper is one of the most efficient catalysts in ROS production in the presence of O2 and a physiological reducing agent such as ascorbate. To control this chemistry, Cu ions are tightly coordinated to biomolecules. Free or loosely bound Cu ions are generally avoided to prevent their toxicity. In the present report, we aim to find stable Cu-ligand complexes (Cu-L) that can efficiently catalyze the production of ROS in the presence of ascorbate under aerobic conditions. Thermodynamic stability would be needed to avoid dissociation in the biological environment, and high ROS catalysis is of interest for applications as antimicrobial or anticancer agents. A series of Cu complexes with the well-known tripodal and tetradentate ligands containing a central amine linked to three pyridyl-alkyl arms of different lengths were investigated. Two of them with mixed arm length showed a higher catalytic activity in the oxidation of ascorbate and subsequent ROS production than Cu salts in buffer, which is an unprecedented result. Despite these high catalytic activities, no increased antimicrobial activity toward Escherichia coli or cytotoxicity against eukaryotic AGS cells in culture related to Cu-L-based ROS production could be observed. The potential reasons for discrepancy between in vitro and in cell data are discussed.

To create robust and adaptable methods for lung pneumonia diagnosis and the assessment of its severity using chest Xrays (CXR), access to well-curated, extensive datasets is crucial. Many current severity quantification approaches require resource-intensive training for optimal results. Healthcare practitioners require efficient computational tools to swiftly identify COVID-19 cases and predict the severity of the condition. In this research, we introduce a novel image augmentation scheme as well as a neural network model founded on Vision Transformers (ViT) with a small number of trainable parameters for quantifying COVID-19 severity and other lung diseases. Our method, named Vision Transformer Regressor Infection Prediction (ViTReg-IP), leverages a ViT architecture and a regression head. To assess the model’s adaptability, we evaluate its performance on diverse chest radiograph datasets from various open sources. We conduct a comparative analysis against several competing deep learning methods. Our results achieved a minimum Mean Absolute Error (MAE) of 0.569 and 0.512 and a maximum Pearson Correlation Coefficient (PC) of 0.923 and 0.855 for the geographic extent score and the lung opacity score, respectively, when the CXRs from the RALO dataset were used in training. The experimental results reveal that our model delivers exceptional performance in severity quantification while maintaining robust generalizability, all with relatively modest computational requirements. The source codes used in our work are publicly available at https://github. com/bouthainas/ViTReg-IP.

Functional assessment before lung cancer resection was originally based on resting pulmonary function tests. In the 1980s, the maximal oxygen uptake (VO2max, approached in routine through peakVO2) measured during symptom-limited exercise was shown to be a better predictor of operative mortality than ventilatory function tests. Today, peakVO2 is integrated in most algorithms for risk stratification. One aim of exercise tests is to stress the whole cardiopulmonary system to estimate the physiological reserve and, thus, to evaluate the ability of patients to survive the physical stress of surgery. Loewen et al. [1] in a prospective multi-institutional study validated the use of peakVO2 to assess operability and also showed that a subset of patients with low peakVO2 values (<15 ml/min/kg) had good tolerance to lung resection. In addition, it has been shown that low peakVO2 was not associated with an increased surgical risk after video-assisted thoracoscopic lobectomy, contrary to open-surgery lobectomy [2]. Besides peakVO2, the minute ventilation (VE)/carbon dioxide output (VCO2) slope demonstrated to be a strong predictor of mortality in heart failure [3], chronic obstructive pulmonary disease and pulmonary hypertension. The VE/VCO2 slope evaluates the ventilatory cost of CO2 removal from the blood, justifying the name of ‘ventilatory efficiency’. The VE/VCO2 slope gives insights into the ventilation-perfusion matching efficiency in the lung and also of gas exchange during physical effort, which may be impaired before pulmonary mechanics in lung disorders. Therefore, it provides additional information to peakVO2, which reflects the integrity of O2 transport chain and utilization during exercise, from ambient air to mitochondria.

<div><p>Background: Obesity is a risk factor for atrial fibrillation (AF). Data regarding left atrial (LA) remodeling in obese patients are scarce. Whether obesity favors AF recurrence after catheter ablation (CA) is still controversial. We assessed the distribution of epicardial atrial fat on computed tomography (CT), LA bipolar voltage, low-voltage zone (LVZ) extent, and the outcome of voltage-guided ablation of persistent AF in obese and non-obese patients. Methods: A total of 139 patients with persistent AF undergoing a first voltage-guided ablation were enrolled and divided into two groups: 74 were non-obese and 65 were obese. Epicardial adipose tissue (EAT) was assessed on a CT scanner. LA endocardial voltage maps were obtained using a 3D mapping system in sinus rhythm. LVZ was defined as a bipolar peak-to-peak voltage amplitude &lt;0.5 mV. Results: LA volume, voltage, and EAT amount were similar in the two groups. LVZ was less frequent in obese patients [12 (18.8%) vs. 26 (35.1%), p = 0.05], particularly on the anterior wall. The posterior and lateral EATs were correlated with posterior and lateral LVZ extent, respectively, in obese patients. After 36 months of follow-up, the AF-free survival rate was similar. Lateral EAT [odds ratio (OR) 1.21, 95% confidence interval (CI) 1-1.4, p = 0.04] and P-wave duration (OR 1.03, 95% CI 1-1.05, p = 0.03), but not body mass index (BMI), were predictors of AF recurrence after CA. Conclusion: In obese patients, LVZ was less marked than in non-obese patients with similar LA volumes, voltage, and EAT amounts. In obese patients, posterior and lateral EATs were correlated with posterior and lateral LVZ extents. Obese patients had a similar and favorable 36-month outcome after AF ablation. BMI was not predictive of AF recurrence.</p></div>

Background: The aim of the study was to describe and investigate the effect of pulmonary arterial hypertension (PAH) therapies in a cohort of patients with severe precapillary pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD; PH-COPD), and to assess factors predictive of treatment response and mortality. Material and methods: We retrospectively included patients with severe incident PH-COPD who received PAH therapy and underwent RHC at diagnosis and on treatment. Results: From 2015 to 2022, 35 severe PH-COPD patients, with clinical features of pulmonary vascular phenotype, were included. Seventeen (48.5%) patients were treated with combined PAH therapy. PAH therapy led to a significant improvement in hemodynamics (PVR -3.5 Wood Units (-39.3%); p &lt; 0.0001), and in the simplified four-strata risk-assessment score, which improved by at least one category in 21 (60%) patients. This effect was more pronounced in patients on dual therapy. Kaplan-Meier estimated survival rates at 1, 3 and 5 years were 94%, 65% and 42% respectively. Univariate analysis showed a significant reduction in survival in patients with a higher simplified risk score at follow-up (Hazard ratio (HR) 2. 88 [1.16-7.15]; p = 0.02). Hypoxemia &lt;50 mmHg was correlated to mortality in multivariate analysis (HR 4.33 [1.08-17.42]; p = 0.04). Conclusions: Our study confirms the poor prognosis of patients with COPD and a pulmonary vascular phenotype and the potential interest of combined PAH therapy in this population, with good tolerability and greater clinical and hemodynamic improvement than monotherapy. Using the simplified risk score during follow-up could be of interest in this population.

Purpose: We aimed to identify ocular comorbidities and reasons of blindness in monocular patients and to compare visual outcomes of cataract surgery between monocular and binocular patients. Methods: A single-center case-control study was conducted between November 2011 and May 2019 to compare consecutive series of patients needing cataract surgery in Strasbourg University Hospitals, France. Cases were patients with permanent monocular vision loss. Controls were binocularly sighted patients. All patients underwent cataract surgery using phacoemulsification technique. Chart analysis included demographic data, medical history, and surgical determinants data. Student's t tests and Fisher's exact tests were the main methods used for statistical analysis. Results: Each group included 80 patients. The mean age at the time of surgery was significantly higher in monocular than binocular patients (77 vs. 71 years, p &lt; 0.001). Thirty-two monocular patients (40%) had ocular comorbidities, compared to only 19 (23%) in the control group (p &lt; 0.05). The leading cause of monocular status was amblyopia caused by strabismus (22 patients, 27.5%). Age-related macular degeneration, open-angle glaucoma, and diabetic retinopathy were the three main ocular comorbidities that were observed in the monocular group. Monocular patients had significantly lower visual acuity than the control group (p &lt; 0.01) before and after cataract surgery. Conversely, improvement in visual acuity after surgery was not statistically different between groups (p = 0.054). There was no statistically significant difference in the rate of surgical complications between groups (p = 0.622). Conclusions: This study illustrates that cataract surgery in monocular patients is not more complicated than in binocular patients, but that it is significantly delayed.

Pheniramine is an over-the-counter antihistamine drug. Its accessibility and low cost made it more popular among drug abusers in Pakistan. In this study, pheniramine was quantified in both conventional and alternative specimens of twenty chronic drug abusers, aged 16-50 years, who were positive for pheniramine in comprehensive toxicological screening for drugs by gas chromatography with mass spectral detection in positive electron impact mode. Pheniramine was extracted from biological specimens using solid phase extraction and liquid chromatography tandem mass spectrometry was employed for quantification. Chromatographic separation was carried out on a Poroshell120EC-18 (2.1 mm × 50 mm × 2.7 µm) column using water-acetonitrile in formic acid (0.1%) mobile phase in gradient elution mode with 500 μL/min flow rate. Positive electrospray ionization mode and multi-reaction monitoring with ion transitions m/z 241.3 → 195.8 and 167.1 for pheniramine and m/z m/z 247.6 → 173.1 for pheniramine-d6 were employed. The quantification method showed good linear ranges of 2-1000 ng/mL in blood, urine, and oral fluid; 2-1000 ng/mg in hair and 5-1000 ng/mg in nail with ≥ 0.985% coefficient of linearity. The retention time of pheniramine was 3.0 ± 0.1 min. The detection and lower quantification limits were 1 ng/mL and 2 ng/mL for blood, urine, oral fluid and hair whereas 2.5 ng/mg and 5 ng/mg for nail, respectively. Mean extraction recovery and ionization suppression ranged 86.3-95.1% and -4.6 to -14.4% in the studied matrices. Intra-day and inter-day precision were 4.1-9.3% and 2.8-11.2%, respectively. Pheniramine levels in specimens of drug abusers were 23-480 ng/mL in blood, 72-735 ng/mL in urine, 25-379 ng/mL in oral fluid, 10-170 ng/mg in hair and 8-86 ng/mg in nail specimens. Alternative specimens are of utmost significance in clinical and medico-legal cases. In this study, authors compared matrix-matched calibration curves to blood calibration curve and obtained results within ± 10%; thereby justifying the use of blood calibration curve for urine, oral fluid, hair, and nail specimens.

Background: Extracorporeal membrane oxygenation (ECMO) is associated with a high risk of bleeding complications. The specific impact of ECMO on fibrinolysis remains unexplored. The objective of the current pilot observational prospective study was to investigate the longitudinal dynamics of fibrinolytic markers— i.e. , changes over time—in the context of bleeding events in patients on ECMO. Methods: Longitudinal dynamics of contact phase components (kininogen and bradykinin) and fibrinolysis markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1], their complexes [tPA•PAI-1], plasmin–antiplasmin complexes, plasminogen, and D-dimer) were measured in patients undergoing venovenous and venoarterial ECMO, before implantation, at 0, 6, and 12 h after implantation, and daily thereafter. Results: The cohort consisted of 30 patients (214 ECMO days). The concentrations of tPA, D-dimer, plasmin–antiplasmin complexes, PAI-1, and tPA•PAI-1 complexes were increased, whereas plasminogen decreased compared to normal values. A noteworthy divergence was observed between hemorrhagic and nonhemorrhagic patients: in bleeding patients, D-dimer, plasmin–antiplasmin, tPA, PAI-1, and tPA•PAI-1 followed an increasing kinetics before hemorrhage and then decreased to their baseline level; conversely, nonbleeding patients showed a decreasing kinetics in these markers. Also, D-dimer and tPA followed an increasing kinetics in bleeding patients compared to nonbleeding patients (median values for D-dimer dynamics: 1,080 vs . –440 ng/ml, P = 0.05; tPA dynamics: 0.130 vs . 0.100 nM, P = 0.038), and both markers significantly increased the day before hemorrhage. A tPA concentration above 0.304 nM was associated with bleeding events (odds ratio, 4.92; 95% CI, 1.01 to 24.08; P = 0.049). Conclusions: Contact activation induces fibrinolysis in ECMO patients, especially in patients experiencing bleeding. This finding supports the role of this mechanism as a possible causal factor for hemorrhages during ECMO and open new avenues for novel therapeutic perspectives. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Neutrophils serve as the frontline defenders in the host's response to infections. However, the available methods for assessing the activated status of neutrophils are still limited. The immature cells that appear during sepsis are large with complex cytoplasmic components and rich nucleic acids, making them diagnosable by cell population data analysis using the automated cell counter. The changes are expressed as increased forward scattered light, side fluorescence light, and side fluorescence distribution width. Additionally, changes in side fluorescence light may indicate the neutrophil extracellular trap formation and can be useful for the diagnosis of sepsis-associated disseminated intravascular coagulation.

Hard tissue regenerative mesoporous bioactive glass (MBG) has traditionally been synthesized using costly and toxic alkoxysilane agents and harsh conditions. In this study, MBG was synthesized using the cheaper reagent SiO 2 by using a co-precipitation approach. The surface properties of MBG ceramic were tailored by functionalizing with amino and carboxylic groups, aiming to develop an efficient drug delivery system for treating bone infections occurring during or after reconstruction surgeries. The amino groups were introduced through a salinization reaction, while the carboxylate groups were added via a chain elongation reaction. The MBG, MBG-NH2, and MBG-NH-COOH were analyzed by using various techniques: x-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Brunauer–Emmett–Teller (BET), scanning electron microscopy and energy-dispersive x-ray spectroscopy. The XRD results confirmed the successful preparation of MBG, and the FTIR results indicated successful functionalization. BET analysis revealed that the prepared samples were mesoporous, and functionalization tuned their surface area and surface properties. Cefixime, an antibiotic, was loaded onto MBG, MBG-NH2, and MBG-NH-COOH to test their drug-carrying capacity. Comparatively, MBG-NH-COOH showed good drug loading and sustained release behavior. The release of the drug followed the Fickian diffusion mechanism. All prepared samples displayed favorable biocompatibility at higher concentration in the Alamar blue assay with MC3T3 cells and exhibited the good potential for hard tissue regeneration, as carbonated hydroxyapatite formed on their surfaces in simulated body fluid.

Introduction: Toll-like receptors play crucial roles in the sepsis-induced systemic inflammatory response. Septic shock mortality correlates with overexpression of neutrophilic TLR2 and TLR9, while the role of TLR4 overexpression remains a debate. In addition, TLRs are involved in the pathogenesis of viral infections such as COVID-19, where the single-stranded RNA of SARS-CoV-2 is recognized by TLR7 and TLR8, and the spike protein activates TLR4. Methods: In this study, we conducted a comprehensive analysis of TLRs 1–10 expressions in white blood cells from 71 patients with bacterial and viral infections. Patients were divided into 4 groups based on disease type and severity (sepsis, septic shock, moderate, and severe COVID-19) and compared to 7 healthy volunteers. Results: We observed a significant reduction in the expression of TLR4 and its co-receptor CD14 in septic shock neutrophils compared to the control group (p &lt; 0.001). Severe COVID-19 patients exhibited a significant increase in TLR3 and TLR7 levels in neutrophils compared to controls (p &lt; 0.05). Septic shock patients also showed a similar increase in TLR7 in neutrophils along with elevated intermediate monocytes (CD14+CD16+) compared to the control group (p &lt; 0.005 and p &lt; 0.001, respectively). However, TLR expression remained unchanged in lymphocytes. Conclusion: This study provides further insights into the mechanisms of TLR activation in various infectious conditions. Additional analysis is needed to assess their correlation with patient outcome and to evaluate the impact of TLR-pathway modulation during septic shock and severe COVID-19.

Background The effects of pharmacological therapy on cardiogenic shock (CS) survivors have not been extensively studied. Thus, this study investigated the association between guideline‐directed heart failure (HF) medical therapy (GDMT) and one‐year survival rate in patients who are post‐CS. Methods and Results FRENSHOCK (French Observatory on the Management of Cardiogenic Shock in 2016) registry was a prospective multicenter observational survey, conducted in metropolitan French intensive care units and intensive cardiac care units. Of 772 patients, 535 patients were enrolled in the present analysis following the exclusion of 217 in‐hospital deaths and 20 patients with missing medical records. Patients with triple GDMT (beta‐blockers, renin‐angiotensin system inhibitors, and mineralocorticoid receptor antagonists) at discharge (n=112) were likely to have lower left ventricular ejection fraction on admission and at discharge compared with those without triple GDMT (n=423) (22% versus 28%, P &lt;0.001 and 29% versus 37%, P &lt;0.001, respectively). In the overall cohort, the one‐year mortality rate was 23%. Triple GDMT prescription was significantly associated with a lower one‐year all‐cause mortality compared with non‐triple GDMT (adjusted hazard ratio 0.44 [95% CI, 0.19–0.80]; P =0.007). Similarly, 2:1 propensity score matching and inverse probability treatment weighting based on the propensity score demonstrated a lower incidence of one‐year mortality in the triple GDMT group. As the number of HF drugs increased, a stepwise decrease in mortality was observed (log rank; P &lt;0.001). Conclusions In survivors of CS, the one‐year mortality rate was significantly lower in those with triple GDMT. Therefore, this study suggests that intensive HF therapy should be considered in patients following CS.

Background: Chronic kidney disease (CKD) is one of the leading causes of death worldwide, closely interrelated with cardiovascular diseases, ultimately leading to the failure of both organs - the so-called "cardiorenal syndrome". Despite this burden, data related to cardiogenic shock outcomes in CKD patients are scarce.Methods: FRENSHOCK (NCT02703038) was a prospective registry involving 772 patients with cardiogenic shock from 49 centres. One-year outcomes (rehospitalization, death, heart transplantation, ventricular assist device) were analysed according to history of CKD at admission and were adjusted on independent predictive factors.Results: CKD was present in 164 of 771 patients (21.3%) with cardiogenic shock; these patients were older (72.7 vs. 63.9years) and had more comorbidities than those without CKD. CKD was associated with a higher rate of all-cause mortality at 1month (36.6% vs. 23.2%; hazard ratio 1.39, 95% confidence interval 1.01-1.9; P=0.04) and 1year (62.8% vs. 40.5%, hazard ratio 1.39, 95% confidence interval 1.09-1.77; P&lt;0.01). Patients with CKD were less likely to be treated with norepinephrine/epinephrine or undergo invasive ventilation or receive mechanical circulatory support, but were more likely to receive renal replacement therapy (RRT). RRT was associated with a higher risk of all-cause death at 1month and 1year regardless of baseline CKD status.Conclusions: Cardiogenic shock and CKD are frequent "cross-talking" conditions with limited therapeutic options, resulting in higher rates of death at 1month and 1year. RRT is a strong predictor of death, regardless of preexisting CKD. Multidisciplinary teams involving cardiac and kidney physicians are required to provide integrated care for patients with failure of both organs.

<div><p>Platinum-based drugs remain the reference treatment for gastric cancer (GC). However, the frequency of resistance, due to mutations in TP53 or alterations in the energy and redox metabolisms, impairs the efficacy of current treatments, highlighting the need for alternative therapeutic options.</p><p>Here, we show that a cycloruthenated compound targeting the redox metabolism, RDC11, induces higher cytotoxicity than oxaliplatin in GC cells and is more potent in reducing tumor growth in vivo. Detailed investigations into the mode of action of RDC11 indicated that it targets the glutathione (GSH) metabolism, which is an important drug resistance mechanism. We demonstrate that cycloruthenated complexes regulate the expression of enzymes of the transsulfuration pathway via the Unfolded Protein Response (UPR) and its effector ATF4. Furthermore, RDC11 induces the expression of SLC7A11 encoding for the cystine/glutamate antiporter xCT. These effects lead to a lower cellular GSH content and elevated oxygen reactive species production, causing the activation of a caspase-independent apoptosis. Altogether, this study provides the first evidence that cycloruthenated complexes target the GSH metabolism, neutralizing thereby a major resistance mechanism towards platinum-based chemotherapies and anticancer immune response.</p><p>1.</p></div>

Abstract Background Both critically ill patients with coronavirus disease 2019 (COVID-19) and patients receiving extracorporeal membrane oxygenation (ECMO) support exhibit a high incidence of healthcare-associated infections (HAI). However, data on incidence, microbiology, resistance patterns, and the impact of HAI on outcomes in patients receiving ECMO for severe COVID-19 remain limited. We aimed to report HAI incidence and microbiology in patients receiving ECMO for severe COVID-19 and to evaluate the impact of ECMO-associated infections (ECMO-AI) on in-hospital mortality. Methods For this study, we analyzed data from 701 patients included in the ECMOSARS registry which included COVID-19 patients supported by ECMO in France. Results Among 602 analyzed patients for whom HAI and hospital mortality data were available, 214 (36%) had ECMO-AI, resulting in an incidence rate of 27 ECMO-AI per 1000 ECMO days at risk. Of these, 154 patients had bloodstream infection (BSI) and 117 patients had ventilator-associated pneumonia (VAP). The responsible microorganisms were Enterobacteriaceae (34% for BSI and 48% for VAP), Enterococcus species (25% and 6%, respectively) and non-fermenting Gram-negative bacilli (13% and 20%, respectively). Fungal infections were also observed (10% for BSI and 3% for VAP), as were multidrug-resistant organisms (21% and 15%, respectively). Using a Cox multistate model, ECMO-AI were not found associated with hospital death (HR = 1.00 95% CI [0.79–1.26], p = 0.986). Conclusions In a nationwide cohort of COVID-19 patients receiving ECMO support, we observed a high incidence of ECMO-AI. ECMO-AI were not found associated with hospital death. Trial registration number NCT04397588 (May 21, 2020).

Background : Long-term outcomes of lung transplantation (LTx) remain hampered by chronic lung allograft dysfunction (CLAD). Matrix metalloproteinase 9 (MMP-9) is a secretory endopeptidase identified as a key mediator in fibrosis processes associated with CLAD. The objective of this study was to investigate whether plasma MMP9 levels may be prognostic of CLAD development. Methods : Participants were selected from the Cohort in Lung Transplantation (COLT) for which a biocollection was associated. We considered two time points, year 1 (Y1) and year 2 (Y2) post-transplantation, for plasma MMP-9 measurements. We analysed stable recipients at those time points, comparing those who would develop a CLAD within the 2 years following the measurement to those who would remain stable 2 years after. Results : MMP-9 levels at Y1 were not significantly different between the CLAD and stable groups (230 ng/ml vs. 160 ng/ml, p = 0.4). For the Y2 analysis, 129 recipients were included, of whom 50 developed CLAD within 2 years and 79 remained stable within 2 years. MMP-9 plasma median concentrations were higher in recipients who then developed CLAD than in the stable group (230 ng/ml vs. 118 ng/ml, p = 0.003). In the multivariate analysis, the Y2 MMP-9 level was independently associated with CLAD, with an average increase of 150 ng/ml (95% CI [0–253], p = 0.05) compared to that in the stable group. The Y2 ROC curve revealed a discriminating capacity of blood MMP-9 with an area under the curve of 66%. Conclusion : Plasmatic MMP-9 levels measured 2 years after lung transplantation have prognostic value for CLAD.

Background and importance: Endotracheal intubation is a lifesaving procedure that is reportedly associated to a significant risk of adverse events. Recent trials have reported that the use of videolaryngoscope and of a stylet might limit this risk during emergency intubation. Objectives: The objective of this study was to provide a national description of intubation practices in French Emergency Departments (EDs). Settings and participants: We conducted an online nationwide survey by sending an anonymous 37-item questionnaire via e-mail to 629 physicians in French EDs between 2020 and 2022. Intervention: A single questionnaire was sent to a sole referent physician in each ED. Outcome measures and analysis: The primary endpoint was to assess the proportion of French EDs in which videolaryngoscopy was available for emergency intubation and its use in routine practice. Secondary endpoints included the presence of local protocol or standard of procedure for intubation, availability of capnography, and routine use of a stylet. Main results: Of the surveyed EDs, 342 (54.4%) returned the completed questionnaire. A videolaryngoscope was available in 193 (56%) EDs, and direct laryngoscopy without a stylet was majorly used as the primary approach in 280 (82%) EDs. Among the participating EDs, 74% had an established protocol for intubation and 92% provided a capnography device for routine verification of tube position. In cases of difficult intubation, the use of a bougie was recommended in 227 (81%) EDs, and a switch to a videolaryngoscope in 16 (6%) EDs. The most frequently used videolaryngoscope models were McGrath Mac Airtraq (51%), followed by Airtraq (41%), and Glidescope (14%). Conclusion: In this large French survey, the majority of EDs recommended direct laryngoscopy without stylet, with seldom use of videolaryngoscopy.

The p53 protein plays a major role in cancer prevention, and over 50% of cancer diagnoses can be attributed to p53 malfunction. p53 incorporates a structural Zn site that is required for proper protein folding and function, and in many cases point mutations can result in loss of the Zn2+ ion, destabilization of the tertiary structure, and eventual amyloid aggregation. Herein, we report a series of compounds designed to act as small molecule stabilizers of mutant p53, and feature Zn-binding fragments to chaperone Zn2+ to the metal depleted site and restore wild-type (WT) function. Many Zn metallochaperones (ZMCs) have been shown to generate intracellular reactive oxygen species (ROS), likely by chelating redox-active metals such as Fe2+/3+ and Cu+/2+ and undergoing associated Fenton chemistry. High levels of ROS can result in off-target effects and general toxicity, and thus, careful tuning of ligand Zn2+ affinity, in comparison to the affinity for other endogenous metals, is important for selective mutant p53 targeting. In this work we show that by using carboxylate donors in place of pyridine we can change the relative Zn2+/Cu2+ binding ability in a series of ligands, and we investigate the impact of donor group changes on metallochaperone activity and overall cytotoxicity in two mutant p53 cancer cell lines (NUGC3 and SKGT2).

<div><p>Developing diffusion barrier layer on material interfaces has potential applications in various fields like packaging materials, pharmaceuticals, chemical filtration, microelectronics, medical devices. Although numerous physical and chemical methods have been proposed to generate the diffusion barrier layer, the complexity of fabrication techniques and high manufacturing costs limit their practical utility. Here, we propose an innovative approach to fabricate the diffusion barrier layer by irradiating poly(dimethylsiloxane) (PDMS) with a midinfrared (m) CO 2 laser. This process directly creates a diffusion barrier layer on the PDMS surface by forming heavily crosslinked network in the polymer matrix. The optimal irradiation conditions were investigated by modulating the defocusing distance, laser power,</p></div>

Pseudoxanthoma Elasticum (PXE) is an inherited disease characterized by elastic fiber calcification in the eyes, the skin and the cardiovascular system. PXE results from mutations in ABCC6 that encodes an ABC transporter primarily expressed in the liver and kidneys. It took nearly 15 years after identifying the gene to better understand the etiology of PXE. ABCC6 function facilitates the efflux of ATP, which is sequentially hydrolyzed by the ectonucleotidases ENPP1 and CD73 into pyrophosphate (PPi) and adenosine, both inhibitors of calcification. PXE, together with General Arterial Calcification of Infancy (GACI caused by ENPP1 mutations) as well as Calcification of Joints and Arteries (CALJA caused by NT5E/CD73 mutations), forms a disease continuum with overlapping phenotypes and shares steps of the same molecular pathway. The explanation of these phenotypes place ABCC6 as an upstream regulator of a purinergic pathway (ABCC6 → ENPP1 → CD73 → TNAP) that notably inhibits mineralization by maintaining a physiological Pi/PPi ratio in connective tissues. Based on a review of the literature and our recent experimental data, we suggest that PXE (and GACI/CALJA) be considered as an authentic “purinergic disease”. In this article, we recapitulate the pathobiology of PXE and review molecular and physiological data showing that, beyond PPi deficiency and ectopic calcification, PXE is associated with wide and complex alterations of purinergic systems. Finally, we speculate on the future prospects regarding purinergic signaling and other aspects of this disease.

Flurbiprofen (FBP), a nonsteroidal anti-inflammatory drug (NSAID), is commonly used to treat the pain of rheumatoid arthritis, but in prolonged use it causes gastric irritation and ulcer. To avoid these adverse events of NSAIDs, the simultaneous administration of H2 receptor antagonists such as ranitidine hydrochloride (RHCl) is obligatory. Here, we developed composite oral fast-disintegrating films (ODFs) containing FBP along with RHCl to provide a gastroprotective effect as well as to enhance the solubility and bioavailability of FBP. The ternary solid dispersion (TSD) of FBP was fabricated with Syloid® 244FP and poloxamer® 188 using the solvent evaporation technique. The synthesized FBP-TSD (coded as TSD) was loaded alone (S1) and in combination with plain RHCl (S2) in the composite ODFs based on hydroxypropyl methyl cellulose E5 (HPMC E5). The synthesized composite ODFs were evaluated by in vitro (thickness, folding endurance, tensile strength, disintegration, SEM, FTIR, XRD and release study) and in vivo (analgesic, anti-inflammatory activity, pro-inflammatory cytokines and gastroprotective assay) studies. The in vitro characterization revealed that TSD preserved its integrity and was effectively loaded in S1 and S2 with optimal compatibility. The films were durable and flexible with a disintegration time ≈15 s. The release profile at pH 6.8 showed that the solid dispersion of FBP improved the drug solubility and release when compared with pure FBP. After in vitro studies, it was observed that the analgesic and anti-inflammatory activity of S2 was higher than that of pure FBP and other synthesized formulations (TSD and S1). Similarly, the level of cytokines (TNF-α and IL-6) was also markedly reduced by S2. Furthermore, a gastroprotective assay confirmed that S2 has a higher safety profile in comparison to pure FBP and other synthesized formulations (TSD and S1). Thus, composite ODF (S2) can effectively enhance the FBP solubility and its therapeutic efficacy, along with its gastroprotective effect.

A large amount of research in orthopedic and maxillofacial domains is dedicated to the development of bioactive 3D scaffolds. This includes the search for highly resorbable compounds, capable of triggering cell activity and favoring bone regeneration. Considering the phosphocalcic nature of bone mineral, these aims can be achieved by the choice of amorphous calcium phosphates (ACPs). Because of their metastable property, these compounds are however to-date seldom used in bulk form. In this work, we used a non-conventional “cold sintering” approach based on ultrafast low-pressure RT compaction to successfully consolidate ACP pellets while preserving their amorphous nature (XRD). Complementary spectroscopic analyses (FTIR, Raman, solid-state NMR) and thermal analyses showed that the starting powder underwent slight physicochemical modifications, with a partial loss of water and local change in the HPO42- ion environment. The creation of an open porous structure, which is especially adapted for non-load bearing bone defects, was also observed. Moreover, the pellets obtained exhibited sufficient mechanical resistance allowing for manipulation, surgical placement and eventual cutting/reshaping in the operation room. Three-dimensional porous scaffolds of cold-sintered reactive ACP, fabricated through this low-energy, ultrafast consolidation process, show promise toward the development of highly bioactive and tailorable biomaterials for bone regeneration, also permitting combinations with various thermosensitive drugs.

Abstract Tissue engineering as an interdisciplinary field of biomedical sciences has raised many hopes in the treatment of cardiovascular diseases as well as development of in vitro three-dimensional (3D) cardiac models. This study aimed to engineer a cardiac microtissue using a natural hybrid hydrogel enriched by granulocyte colony-stimulating factor (G-CSF), a bone marrow-derived growth factor. Cardiac ECM hydrogel (Cardiogel: CG) was mixed with collagen type I (ColI) to form the hybrid hydrogel, which was tested for mechanical and biological properties. Three cell types (cardiac progenitor cells, endothelial cells and cardiac fibroblasts) were co-cultured in the G-CSF-enriched hybrid hydrogel to form a 3D microtissue. ColI markedly improved the mechanical properties of CG in the hybrid form with a ratio of 1:1. The hybrid hydrogel demonstrated acceptable biocompatibility and improved retention of encapsulated human foreskin fibroblasts. Co-culture of three cell types in G-CSF enriched hybrid hydrogel, resulted in a faster 3D structure shaping and a well-cellularized microtissue with higher angiogenesis compared to growth factor-free hybrid hydrogel (control). Immunostaining confirmed the presence of CD31+ tube-like structures as well as vimentin+ cardiac fibroblasts and cTNT+ human pluripotent stem cells-derived cardiomyocytes. Bioinformatics analysis of signaling pathways related to the G-CSF receptor in cardiovascular lineage cells, identified target molecules. The in silico-identified STAT3, as one of the major molecules involved in G-CSF signaling of cardiac tissue, was upregulated in G-CSF compared to control. The G-CSF-enriched hybrid hydrogel could be a promising candidate for cardiac tissue engineering, as it facilitates tissue formation and angiogenesis.

Purpose: To compare the clinical performance of the combination of enamel matrix derivatives and bone substitutes (EMD+BG) with bone substitutes (BG) alone in the surgical treatment of periodontal intrabony and furcation defects. Materials and Methods: Electronic databases (Medline, Embase and Web of Science) were searched for randomised controlled trials in humans that investigated the combination of EMD+BG vs BG alone in either intrabony or furcation defects with a minimal follow-up of 6 months. A random-effect meta-analysis was conducted according to the type of defect (intrabony or furcation defects) and the follow-up time (6 or ≥ 12 months). Results: From a total of 1583 entries, 9 randomised controlled clinical trials (RCTs) were retrieved and included in the qualitative and quantitative synthesis. All of them were included in the meta-analysis. The meta-analysis detected an additional clinical attachment level (CAL) gain in intrabony defects treated with EMD+BG compared to BG alone in studies with ≥ 12-month follow-up (mean difference = 0.67 mm, 95% CI [0.44 ; 0.90], p &lt; 0.00001). No additional benefit was found in furcation defects in terms of CAL gain or probing depth (PD) reduction. Conclusion: The addition of EMD may improve the clinical outcomes of intrabony defects treated with bone substitutes. These findings may support the use of this combined therapy, particularly in large and non-contained defects.

Silicate-based bioactive glass nano/microspheres hold significant promise for bone substitution by facilitating osteointegration through the release of biologically active ions and the formation of a biomimetic apatite layer. Cu-doping enhances properties such as pro-angiogenic and antibacterial behavior. While sol-gel methods usually yield homogeneous spherical particles for pure silica or binary glasses, synthesizing poorly aggregated Cu-doped ternary glass nano/microparticles without a secondary CuO crystalline phase remains challenging. This article introduces an alternative method for fabricating Cu-doped ternary microparticles using sol-gel chemistry combined with spray-drying. The resulting microspheres exhibit well-defined, poorly aggregated particles with spherical shapes and diameters of a few microns. Copper primarily integrates into the microspheres as Cu$^0$ nanoparticles and as Cu$^{2+}$ within the amorphous network. This doping affects silica network connectivity, as calcium and phosphorus are preferentially distributed in the glass network (respectively as network modifiers and formers) or involved in amorphous calcium phosphate nano-domains depending on the doping rate. These differences affect the interaction with simulated body fluid. Network depolymerization, ion release (SiO$_4^{4-}$, Ca$^{2+}$), PO$_4^{3-}$, Cu$^{2+}$), and apatite nanocrystal layer formation are impacted, as well as copper release. The latter is mainly provided by the copper involved in the silica network and not from metal nanoparticles, most of which remain in the microspheres after interaction. This understanding holds promising implications for potential therapeutic applications, offering possibilities for both short-term and long-term delivery of a tunable copper dose.

Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) down-regulates angiotensin-converting enzyme 2, potentially increasing angiotensin II. We hypothesized that losartan compared to usual care decreases mortality and is safe in patients hospitalized with coronavirus disease 2019 (COVID-19). We aimed to evaluate the effect of losartan versus usual care on 28-day mortality in patients hospitalized for acute COVID-19. Methods. Eligibility criteria included adults admitted for acute COVID-19. Exclusion criteria were hypotension, hyperkalemia, acute kidney injury, and use of angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors within 7 days. Participants were randomized to losartan 25-100 mg/day orally for the hospital duration or 3 months or the control arm (usual care) in 29 hospitals in Canada and France. The primary outcome was 28-day mortality. Secondary outcomes were hospital mortality, organ support, and serious adverse events (SAEs). Results. The trial was stopped early because of a serious safety concern with losartan. In 341 patients, any SAE and hypotension were significantly higher in the losartan versus usual care groups (any SAE: 39.8% vs 27.2%, respectively, P = .01; hypotension: 30.4% vs 15.3%, respectively, P &lt; .001) in both ward and intensive care patients. The 28-day mortality did not differ between losartan (6.5%) versus usual care (5.9%) (odds ratio, 1.11 [95% confidence interval, .47-2.64]; P = .81), nor did organ dysfunction or secondary outcomes. Conclusions. Caution is needed in deciding which patients to start or continue using ARBs in patients hospitalized with pneumonia to mitigate risk of hypotension, acute kidney injury, and other side effects. ARBs should not be added to care of patients hospitalized for acute COVID-19.

In critically ill patients, endotracheal intubation (ETI) is lifesaving but carries a high risk of adverse events, notably hypoxemia. Preoxygenation is performed before introducing the tube to increase the safe apnea time. Oxygenation is monitored by pulse oximeter measurement of peripheral oxygen saturation (SpO2). However, SpO2 is unreliable at the high oxygenation levels produced by preoxygenation and, in the event of desaturation, may not decrease sufficiently early to allow preventive measures. The oxygen reserve index (ORI) is a dimensionless parameter that can also be measured continuously by a fingertip monitor and reflects oxygenation in the moderate hyperoxia range. The ORI ranges from 0 to 1 when arterial oxygen saturation (PaO2) varies between 100 to 200 mmHg, as occurs during preoxygenation. No trial has assessed the potential effects of ORI monitoring to guide preoxygenation for ETI in unstable patients. We designed a multicenter, two-arm, parallel-group, randomized, superiority, open trial in 950 critically ill adults requiring ETI. The intervention consists in monitoring ORI values and using an ORI target for preoxygenation of at least 0.6 for at least 1 minute. In the control group, preoxygenation is guided by SpO2 values recorded by a standard pulse oximeter, according to the standard of care, the goal being to obtain 100% SpO2 during preoxygenation, which lasts at least 3 minutes. The standard-of-care ETI technique is used in both arms. Baseline parameters, rapid-sequence induction medications, ETI devices, and physiological data are recorded. The primary outcome is the lowest SpO2 value from laryngoscopy to 2 minutes after successful ETI. Secondary outcomes include cognitive function on day 28. Assuming a 10% standard deviation for the lowest SpO2 value in the control group, no missing data, and crossover of 5% of patients, with the bilateral alpha risk set at 0.05, including 950 patients will provide 85% power for detecting a 2% between-group absolute difference in the lowest SpO2 value. Should ORI monitoring with a target of ≥0.6 be found to increase the lowest SpO2 value during ETI, then this trial may change current practice regarding preoxygenation for ETI. Trial registration: Registered on ClinicalTrials.gov (NCT05867875) on April 27, 2023.

© Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society 2023.Background: Clinician-reported outcome (ClinRO) measures are emerging as useful contributors to assessments of treatment benefits. The objective of this study was to collect ClinRO measures of physical and cognitive impairments after convulsive status epilepticus (CSE) requiring intensive care unit admission. Methods: We conducted a post hoc analysis of the data from HYBERNATUS, a multicenter open-label controlled trial that randomized 270 critically ill patients with CSE requiring mechanical ventilation in 11 French intensive care units to therapeutic hypothermia (32u201334 °C for 24 h) plus standard care or standard care alone. We included all patients who attended a day 90 in-person neurologist visit with measurement of the functional independence measure (FIM) score (range from 18 [total assistance] to 126 [total independence]), Mini-Mental State Examination (MMSE) score (range 0u201330), and Glasgow outcome scale (GOS) score (1, death; 2, vegetative state; 3, severe disability; 4, moderate disability; and 5, mild or no disability). These three scores were compared across groups defined by several patient and CSE characteristics. Results: Of 229 patients with GOS scores ≥ 3 on day 90 (male sex, 58.2%; median age, 56 years [47u201367]), 67 (29%) attended an in-person neurologist visit. Twenty-nine (43%) patients had a previous history of epilepsy, and 16 (24%) patients had a primary brain insult. CSE was refractory in 22 (33%) patients. On day 90 after CSE onset, median FIM and MMSE scores were 121 (112u2013125) and 26.0 (24.0u201328.8), respectively. The GOS score was 3 in 16 (33.8%) patients, 4 in 9 (13.4%) patients, and 5 in 42 (62.7%) patients. Worse GOS score values were significantly associated with worse FIM and MMSE scores. Conclusions: In patients attending the in-person neurologist visit on day 90 after CSE onset, ClinRO measures indicated that the main impairments were cognitive. FIM and MMSE scores were associated with GOS scores. Further studies are needed to evaluate the possible impact of neuroprotective and rehabilitation strategies on disability and cognitive impairments in survivors of CSE. Clinical trial registration NCT01359332.

Introduction: Although largely used, the place of oxygen therapy and its devices in patients with acute hypoxemic respiratory failure (ARF) deserves to be clarified. The French Intensive Care Society (Société de Réanimation de Langue Française, SRLF) and the French Emergency Medicine Society (Société Française de Médecine d'Urgence, SFMU) organized a consensus conference on oxygen therapy in ARF (excluding acute cardiogenic pulmonary oedema and hypercapnic exacerbation of chronic obstructive diseases) in December 2023. Methods: A committee without any conflict of interest (CoI) with the subject defined 7 generic questions and drew up a list of sub questions according to the population, intervention, comparison and outcomes (PICO) model. An independent work group reviewed the literature using predefined keywords. The quality of the data was assessed using the GRADE methodology. Fifteen experts in the field from both societies proposed their own answers in a public session and answered questions from the jury (a panel of 16 critical-care and emergency medicine physicians, nurses and physiotherapists without any CoI) and the public. The jury then met alone for 48 h to write its recommendations. Results: The jury provided 22 statements answering 11 questions: in patients with ARF (1) What are the criteria for initiating oxygen therapy? (2) What are the targets of oxygen saturation? (3) What is the role of blood gas analysis? (4) When should an arterial catheter be inserted? (5) Should standard oxygen therapy, high-flow nasal cannula oxygen therapy (HFNC) or continuous positive airway pressure (CPAP) be preferred? (6) What are the indications for non-invasive ventilation (NIV)? (7) What are the indications for invasive mechanical ventilation? (8) Should awake prone position be used? (9) What is the role of physiotherapy? (10) Which criteria necessarily lead to ICU admission? (11) Which oxygenation device should be preferred for patients for whom a do-not-intubate decision has been made? Conclusion: These recommendations should optimize the use of oxygen during ARF.

Endothelial dysfunction is a pivotal early event in the development of major cardiovascular diseases including hypertension, atherosclerosis, diabetes, and aging. The alteration of the endothelial function is often triggered by an imbalance between the endothelial formation of vasoprotective factors, including nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH), and vasocontracting factors, such as arachidonic acid-derived mediators generated by cyclooxygenases, and an increased level of oxidative stress. Recently, endothelial senescence was reported to be an early trigger of endothelial dysfunction. Preclinical studies indicate that polyphenol-rich food, including anthocyanin-rich products, can activate pathways promoting an increased formation of vasoprotective factors and can prevent the induction of endothelial dysfunction in endothelial cells and isolated blood vessels. Similarly, intake of anthocyanin-rich products has been associated with the prevention and/or the improvement of an endothelial dysfunction in several experimental models of cardiovascular diseases, including physiological aging. Moreover, clinical data indicate that polyphenol-rich and anthocyanin-rich products can improve endothelial function and vascular health in humans with cardiovascular diseases. The present review will discuss both experimental and clinical evidence indicating that several polyphenol-rich foods and natural products, and especially anthocyanin-rich products, can promote endothelial and vascular health, as well as the underlying mechanisms.

Les études épidémiologiques identifient la parodontite, maladie inflammatoire chronique des tissus de soutien des dents, comme un facteur contribuant au risque cardiovasculaire. Bien que la nature de l’association entre parodontite et maladies cardio-vasculaires (MCV) reste à définir (causalité ou corrélation), l’inflammation systémique de bas grade et les bactériémies chroniques qui sont associées aux parodontites apparaissent impliquées dans le développement de l’athérosclérose et des maladies cardio-vasculaires associées. Le traitement parodontal semble contribuer à l’amélioration des paramètres de la santé cardiovasculaire. Dès lors, une approche de prévention bidirectionnelle, impliquant à la fois la gestion de la parodontite et des facteurs de risque cardiovasculaire, pourrait permettre une réduction de la morbidité et de la mortalité liées aux MCV.

Purpose: Multiple myeloma (MM) is the second most common neoplastic blood disease worldwide. Belantamab mafodotin is a new antibody conjugate anti-B-cell maturation antigen effective against refractory myelomas. It induces intracorneal microcysts leading to refractive fluctuations. The aim of this study is to assess the value of monitoring refractive fluctuations based on the location of microcystic-like epithelial changes (MECs) to facilitate patient follow-up. Methods: This observational and multicentric study was conducted using data collected from several French centers contacted through secure email through a standardized data collection table. Results: The fluctuation of objective refraction in spherical equivalent confirms a significant myopic shift from peripheral to central forms. A decrease in the best-corrected visual acuity (BCVA), an increase in keratometry, and an increase in central epithelial pachymetry have also been observed when MECs migrate toward the center. Conclusion: The myopization found in our study in patients with central and paracentral MECs is consistent with current literature. Fluctuations in BCVA, keratometry, and epithelial pachymetry are also consistent. This study is the first real-world study and highlights heterogeneity in follow-up, emphasizing the need to establish multidisciplinary follow-up strategies. The analysis of refractive fluctuations appears to be a reproducible and noninvasive screening method that could facilitate patient follow-up without the need for consultation focused on corneal diseases.

Background: The assessment of acute heart failure (AHF) prognosis is primordial in emergency setting. Although AHF management is exhaustively codified using mortality predictors, there is currently no recommended scoring system for assessing prognosis. The European Society of Cardiology (ESC) recommends a comprehensive assessment of global AHF prognosis, considering in-hospital mortality, early rehospitalization rates and the length of hospital stay. Objective: We aimed to prospectively evaluate the performance of the Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF (MEESSI-AHF) score in estimating short prognosis according to the ESC guidelines. Design, settings and patients: A multicenter study was conducted between November 2020, and June 2021. Adult patients who presented to eleven French hospitals for AHF were prospectively included. Outcome measures and analysis: According to MEESSI-AHF score, patients were stratified in four categories corresponding to mortality risk: low-, intermediate-, high- and very high-risk groups. The primary outcome was the number of days alive and out of the hospital during the 30-day period following admission to the Emergency Department (ED). Results: In total, 390 patients were included. The number of days alive and out of the hospital decreased significatively with increasing MEESSI-AHF risk groups, ranging from 21.2 days (20.3–22.3 days) for the low-risk, 20 days (19.3–20.5 days) for intermediate risk,18.6 days (17.6–19.6 days) for the high-risk and 17.9 days (16.9–18.9 days) very high-risk category. Conclusion: Among patients admitted to ED for an episode of AHF, the MEESSI-AHF score estimates with good performance the number of days alive and out of the hospital.

Importance : Tracheal intubation is recommended for coma patients and those with severe brain injury, but its use in patients with decreased levels of consciousness from acute poisoning is uncertain. Objective : To determine the effect of intubation withholding vs routine practice on clinical outcomes of comatose patients with acute poisoning and a Glasgow Coma Scale score less than 9. Design, Setting, and Participants : This was a multicenter, randomized trial conducted in 20 emergency departments and 1 intensive care unit (ICU) that included comatose patients with suspected acute poisoning and a Glasgow Coma Scale score less than 9 in France between May 16, 2021, and April 12, 2023, and followed up until May 12, 2023. Intervention : Patients were randomized to undergo conservative airway strategy of intubation withholding vs routine practice. Main Outcomes and Measures : The primary outcome was a hierarchical composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Key secondary outcomes included adverse events resulting from intubation as well as pneumonia within 48 hours. Results : Among the 225 included patients (mean age, 33 years; 38% female), 116 were in the intervention group and 109 in the control group, with respective proportions of intubations of 16% and 58%. No patients died during the in-hospital stay. There was a significant clinical benefit for the primary end point in the intervention group, with a win ratio of 1.85 (95% CI, 1.33 to 2.58). In the intervention group, there was a lower proportion with any adverse event (6% vs 14.7%; absolute risk difference, 8.6% [95% CI, −16.6% to −0.7%]) compared with the control group, and pneumonia occurred in 8 (6.9%) and 16 (14.7%) patients, respectively (absolute risk difference, −7.8% [95% CI, −15.9% to 0.3%]). Conclusions and Relevance : Among comatose patients with suspected acute poisoning, a conservative strategy of withholding intubation was associated with a greater clinical benefit for the composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Trial Registration : ClinicalTrials.gov Identifier: NCT04653597

<b>Importance:</b> International guidelines recommend body temperature control below 37.8&nbsp;°C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33&nbsp;°C might lead to better outcomes when the initial rhythm is nonshockable. <b>Objective:</b> To assess whether hypothermia at 33&nbsp;°C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm. <b>Data Sources:</b> Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis. <b>Study Selection:</b> The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33&nbsp;°C) or normothermia (target temperature 36.5 to 37.7&nbsp;°C), according to different study protocols, for at least 24&nbsp;hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score. <b>Data Extraction and Synthesis:</b> Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2&nbsp;studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation. <b>Main Outcomes and Measures:</b> The primary outcome was mortality at 3&nbsp;months; secondary outcomes included unfavorable functional outcome at&nbsp;3 to 6&nbsp;months, defined as a Cerebral Performance Category score of&nbsp;3 to&nbsp;5. <b>Results:</b> A total of 912&nbsp;patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571&nbsp;patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3&nbsp;months, 354 of 442&nbsp;patients in the hypothermia group (80.1%) and 386 of 470&nbsp;patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of&nbsp;429 in the hypothermia group (90.0%) and 413 of&nbsp;463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P&nbsp;=&nbsp;.97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups. <b>Conclusions and Relevance:</b> In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33&nbsp;°C did not significantly improve survival or functional outcome.

European countries have become host countries for migrants and unaccompanied minors. However, many migrants arrive without identity documents. Many methods exist to estimate age; among them, several methods using dental age have been proposed. Our objective was to evaluate the accuracy of biological age determination in a multiethnic sample using dental age estimated using three methods: Nolla, Demirjian, and the London Atlas. Orthopantomograms collected for 324 patients of various ethnicities aged from 4 to 20 years old were included. Then, for each orthopantomogram, a blind trained examiner used the three methods of age estimation. For each method, the estimated mean age was greater than the real mean age (p &lt; 0.0001). The accuracy after 18 years old with a 1-year margin was under 50%. Demirjian's method gave a less accurate estimated age than Nolla's method (p &lt; 0.0001) or the London Atlas (p &lt; 0.001). The most accurate methods were those of Nolla and the London Atlas, with average absolute deviations of 1.3 and 1.2 years, respectively. Demirjian's method was much less accurate, with a deviation of around 2 years. The evaluated methods are unable to provide reliable information to determine if an individual is a minor.

Reconstructing the meniscus is not currently possible due to its intricate and heterogeneous structure. In this forum, we first discuss the shortcomings of current clinical strategies in meniscus repair. Then, we describe a new promising cell-based, ink-free 3D biofabrication technology to produce tailor-made large-scale functional menisci.

Background: Disseminated intravascular coagulation (DIC) worsens the prognosis of septic shock and contributes to multiple organ failure. To date, no data linking DIC and acute kidney injury (AKI) occurrence, severity, and evolution in this setting are available. We aimed at analyzing the association between AKI occurrence, severity and evolution in patients with septic shock-induced DIC. In a prospective monocentric cohort study, consecutive patients, 18 years and older, admitted in the ICU of Strasbourg University Hospital in the setting of systemic hypotension requiring vasopressor related to an infection, without history of terminal chronic kidney disease were eligible. AKI was defined according to the KDIGO classification. DIC diagnosis was based on the International Society on Thrombosis and Haemostasis (ISTH) score. Evolution of AKI was evaluated through the composite endpoint of major adverse kidney events. Only patients with DIC that occurred before or at the time of AKI diagnosis were considered. Univariate and multivariate analysis were performed to determine factors associated with renal outcomes. Results: 350 patients were included, of whom 129 experienced DIC. Patients with DIC were more seriously ill (median SAPS II 64 vs. 56, p &lt; 0.001), and had higher 28-day mortality (43.3% vs. 26.2%, p &lt; 0.001). AKI was more frequent in patients with DIC (86.8% vs. 74.2%, p &lt; 0.005), particularly for the more severe stage of AKI [KDIGO 3 in 58.1% of patients with DIC vs. 30.8% of patients without DIC, p &lt; 0.001, AKI requiring renal replacement therapy (RRT) in 47.3% of patients with DIC vs. 21.3% of patients without DIC, p &lt; 0.001]. After adjustment for confounding factors, DIC occurrence remained associated with the risk of having the more severe stage of AKI with an odds ratio (OR) of 2.74 [IC 95% (1.53-4.91), p &lt; 0.001], and with the risk of requiring RRT during the ICU stay [OR 2.82 (1.53-5.2), p &lt; 0.001]. Conclusion: DIC appears to be strongly associated with the risk of developing the more severe form of AKI (stage 3 of the KDIGO classification, RRT requirement), even after adjustment for severity and other relevant factors.

La première Journée de santé publique dentaire, en 2001, a été non seulement le point de départ de la création de l’association des Acteurs de la santé publique bucco-dentaire (ASPBD), mais aussi celui de l’identification en France de cette spécialité, alors qu’elle était déjà reconnue comme telle par l’Association dentaire américaine dès 1950. L’ASPBD organise, depuis annuellement une journée nationale de santé publique bucco-dentaire. L’ASPBD rassemble la grande majorité des odontologistes, enseignants-chercheurs hospitalo-universitaires français, mais aussi les autres hospitalo-universitaires francophones. Nous oeuvrons tout au long de l’année à faire travailler ensemble le dentaire et le non-dentaire, principalement le monde institutionnel et associatif avec les usagers, les libéraux et les salariés, l’Organisation mondiale de la santé et la Société française de santé publique. À l’image du binôme qui préside chacune de nos journées depuis vingt-deux ans. Notre association a pour vocation de rassembler tous les acteurs concernés pour oeuvrer à l’intégration de la santé orale dans toutes les politiques de santé et dispositifs de promotion de la santé et de prévention. Nous pensons qu’il est indispensable de former à la santé orale tant les personnels médicaux et paramédicaux que ceux de l’éducation et de l’animation. De même, nous agissons pour que la prévention s’organise à l’échelon territorial, au plus près des populations en fonction de leurs besoins. C’est le sens de notre participation active à la lutte contre les inégalités sociales et territoriales de santé, la santé orale étant un marqueur fort d’inégalités sociales de santé.Article disponible en ligne à l'adresse

Background: Evaluate the impact of the MiniMed™ 780G advanced hybrid closed-loop (AHCL) system on the glucose profile of pregnant women with type 1 diabetes (T1D) and maternal–neonatal complications. Methods: From April 2021 to September 2022, pregnant women with T1D treated with the AHCL system were included in an observational multicenter retrospective study. Continuous glucose monitoring parameters were analyzed monthly during pregnancy as well as maternal–neonatal complications. Results: Thirteen pregnant women, including a twin pregnancy (age: 33 ± 3 years, hemoglobin A1c [HbA1c]: 7.3% ± 0.7%, insulin doses: 0.72 ± 0.21 U/kg/day) were analyzed. At delivery, gestational age was 37 ± 2 weeks. During first 2 weeks of pregnancy, time in range (TIR, 63–140 mg/dL) was 46% (34–55) and increased to 54% (51–59) (P &lt; 0.01), 64% (48–68) (P &lt; 0.01), and 66% (60–70) (P &lt; 0.001) during the first, second, and third trimester, respectively. During the night, TIR (63–140 mg/dL) was &gt;70% throughout pregnancy. Time below the range &lt;63 mg/dL increased from 0.5% (0–2) to 1.3% (0.7–2.2), 2% (1.2–3.5) (P &lt; 0.05), and 1.3% (1.31–3) (P &lt; 0.05) during the first, second, and third trimester, respectively. At delivery, insulin doses increased to 0.89 ± 0.35 IU/kg/day (P &lt; 0.01), and HbA1c decreased to 6.4% ± 0.6% (P = 0.005). The reported carbohydrate amount increased from 167 ± 363 g/d during early pregnancy to 243 ± 106 g/d (P &lt; 0.01) at delivery. The birthweight was 3134 ± 711 g, with 5/14 macrosomia and 2/14 neonatal hypoglycemia. Moreover, 5/13 patients had a preeclampsia and 9/13 a cesarean section, including three cases of scarred uterus. The Clinical Trial Registration number is: CE-2022-55. Conclusion: The AHCL system provided good glucose control during pregnancy and recommendation targets were reached during the nocturnal period only. The maternal and neonatal complications remained high.

Wilms tumors are highly curable in up to 90% of cases with a combination of surgery and radio-chemotherapy, but treatment-resistant types such as diffuse anaplastic Wilms tumors pose significant therapeutic challenges. Our multi-omics profiling unveils a distinct desert-like diffuse anaplastic Wilms tumor subtype marked by immune/stromal cell depletion, TP53 alterations, and cGAS-STING pathway downregulation, accounting for one-third of all diffuse anaplastic cases. This subtype, also characterized by reduced CD8 and CD3 infiltration and active oncogenic pathways involving histone deacetylase and DNA repair, correlates with poor clinical outcomes. These oncogenic pathways are found to be conserved in anaplastic Wilms tumor cell models. We identify histone deacetylase and/or WEE1 inhibitors as potential therapeutic vulnerabilities in these tumors, which might also restore tumor immunogenicity and potentially enhance the effects of immunotherapy. These insights offer a foundation for predicting outcomes and personalizing treatment strategies for aggressive pediatric Wilms tumors, tailored to individual immunological landscapes.

Background: Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. Methods: In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed. Results: A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (83%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI], 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group. Conclusions: Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).

Objectives: Giant cell tumor of bone (GCTB) is defined as a rare intermediate-grade mesenchymal tumor. The firstline treatment was surgery but since the 2010s, denosumab is a medical therapeutic option that can stop progression of GCTBs with a high efficiency. Osteochimionecrosis of the jaw (ONJ) is a well-documented oral complication associated to denosumab implying careful oro-dental follow-up. So far, GCTB patients constitute a particular subgroup of denosumab-treated patients for whom very few studies about orodental care are described. Materials and methods: All patients diagnosed with GCTB and treated by denosumab therapy and who had orodental follow-up were included. Nine patients received denosumab as adjuvant and/or neoadjuvant treatment of surgery and one patient received denosumab as an exclusive therapy. Denosumab was temporary stopped in case of a serious adverse event like ONJ. Results: Of the 10 patients enrolled in this study, 8 started denosumab after undergoing one or more GCTB resection surgeries, and 1 patient was started on denosumab early on because surgery was considered too harmful. Only one patient benefited from denosumab treatment without tumor resection. All patients except one received an oral examination prior to initiation of denosumab treatment, the mean DMFT index was 9.8 and 4 patients had a poor periodontal status. In 5 of our 10 patients, denosumab therapy have been disturbed in order to manage one ONJ and 7 tooth extraction. Conclusion: Oro-dental status can strongly influence denosumab therapy in GCTB patients that’s why a close collaboration is required between oncologist and oral surgeon.

Objectives: The COVID-19 epidemic upset the standards in terms of hygiene and protection in the dental office, bringing additional precautions for dentists. The objective of our study was to draw the "new normal" of hygiene measures at the end of the COVID-19 epidemic. Materials and methods: A self-administered questionnaire about transitional recommendations for oral care in the context of the COVID-19 epidemic was published online in private groups dedicated to French dentists. Results: The 246 respondents understood the reasons behind those recommendations, since 10 out of 11 measures reached a mean score greater than 2.5 on a 0 (not at all) to 4 (absolutely) scale when it came to determining whether the measure made the practitioner feel safe and ensured patient safety. Besides, more of the respondents intended to maintain the measures than they were to apply them before the epidemic. Conclusions: The COVID-19 epidemic reshaped the relationship to hygiene and protection measures in the context of dental practices. The "new normal" of hygiene measures at the end of the COVID-19 epidemic will probably involve more protective measures than before. Clinical relevance: These results constitute interesting avenues for public health deliberation, which would make it possible to best adapt future health recommendations in order to define the "new normal" of hygiene measures in dental practices at the end of the COVID-19 epidemic. Therefore, it could have an impact on all practitioners in their clinical activities.

Introduction: Giant cell tumor of bone (GCTB) is a very rare tumor encountered in the jaws and its histology is quite similar to the more common giant cell granuloma of the jaws (GCGJ). These two entities can be easily confused in maxillofacial region. They are classically managed surgically, but in some localizations and in specific medical-surgical contexts, neoadjuvant therapy with denosumab may be indicated. This report tends to reinforce existing evidence in favor of the use of a neoadjuvant approach, particularly for localization of GCTB in the orofacial region. Presentation of case: This is a 57-year-old female patient, an alcoholic smoker, in whom a voluminous mandibular radiolucent lesion was discovered during a routine X-ray by her dentist. After medical imaging assessment and incisional biopsy, diagnosis of GCTB was established. A neoadjuvant denosumab therapy was proposed first followed by a secondary surgical curettage. After 4 years' follow-up, complete healing was observed with no recurrence of the lesion. Discussion: Surgical management of aggressive GCTB is risky particularly in localizations involving the sacrum, spine or craniofacial skeleton with a high residual recurrence rate. The use of denosumab to stop tumor progression and facilitate secondary excision surgery is a recent approach that is now well documented in the literature showing promising results with a low rate of side effects. Conclusion: This case of mandibular GCTB is to our knowledge the unique case described in this localization and treated by denosumab neoadjuvant therapy followed by surgery with a 4-year follow-up showing a complete healing.

BACKGROUND: Deconvoluting the heterogenous prognosis of Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) is crucial for enhancing patient care, given its rapidly increasing incidence in western countries and the adverse side effects of OSCC treatments. METHODS: Transcriptomic data from HPV-positive OSCC samples were analyzed using unsupervised hierarchical clustering, and clinical relevance was evaluated using Kaplan-Meier analysis. HPV-positive OSCC cell line models were used in functional analyses and phenotypic assays to assess cell migration and invasion, response to cisplatin, and phagocytosis by macrophages in vitro. RESULTS: We found, by transcriptomic analysis of HPV-positive OSCC samples, a ΔNp63 dependent molecular signature that is associated with patient prognosis. ΔNp63 was found to act as a tumor suppressor in HPV-positive OSCC at multiple levels. It inhibits cell migration and invasion, and favors response to chemotherapy. RNA-Seq analysis uncovered an unexpected regulation of genes, such as DKK3, which are involved in immune response-signalling pathways. In agreement with these observations, we found that ΔNp63 expression levels correlate with an enhanced anti-tumor immune environment in OSCC, and ΔNp63 promotes cancer cell phagocytosis by macrophages through a DKK3/NF-κB-dependent pathway. CONCLUSION: Our findings are the first comprehensive identification of molecular mechanisms involved in the heterogeneous prognosis of HPV-positive OSCC, paving the way for much-needed biomarkers and targeted treatment.

<b>Aims:</b> Characteristics, management, and outcomes of patients with active cancer admitted for cardiogenic shock remain largely unknown. This study aimed to address this issue and identify the determinants of 30-day and 1-year mortality in a large cardiogenic shock cohort of all etiologies. <b>Methods and results:</b> FRENSHOCK is a prospective multicenter observational registry conducted in French critical care units between April and October 2016. "Active cancer" was defined as a malignancy diagnosed within the previous weeks with planned or ongoing anticancer therapy. Among the 772 enrolled patients (mean age 65.7 ± 14.9 years; 71.5% male), 51 (6.6%) had active cancer. Among them, the main cancer types were solid cancers (60.8%), and hematological malignancies (27.5%). Solid cancers were mainly urogenital (21.6%), gastrointestinal (15.7%), and lung cancer (9.8%). Medical history, clinical presentation, and baseline echocardiography were almost the same between groups. In-hospital management significantly differed: patients with cancers received more catecholamines or inotropes (norepinephrine 72 vs 52%, p=0.005 and norepinephrine-dobutamine combination 64.7 vs 44.5%, p=0.005), but had less mechanical circulatory support (5.9 vs 19.5%, p=0.016). They presented similar 30-day mortality rate (29 vs 26%) but a significantly higher mortality at one-year (70.6 vs 45.2%, p&lt;0.001). In multivariable analysis, active cancer was not associated with 30-day mortality but was significantly associated with 1-year mortality in 30-day survivors (HR 3.61 [1.29 - 10.11], p=0.015). <b>Conclusion: </b>Active cancer patients accounted for almost 7% of all cases of cardiogenic shock. Early mortality was the same regardless active cancer or not, whereas long-term mortality was significantly increased in patients with active cancer.

Water-in-oil (W/O) Pickering emulsions (PEs) as delivery systems have recently attracted important research efforts. The lack of food-grade hydrophobic particulate as emulsion stabilizers is the most important challenge in this field. This study investigates the surface modification of silica (SiO2) nanoparticles (SNPs) by chitosan and their role in formulation and stabilization of PEs; namely, the adsorption of chitosan on the surface of SNPs through electrostatic attraction with different chitosan/SiO2 ratio and pH values. The ability of SNPs to stabilize water in oil PEs regarding this modification was then investigated. The interaction between SNPs and chitosan was characterized by zeta potential, wettability, FTIR, Energy dispersive X-ray mapping analysis (EDX- MAP) and nitrogen absorption/desorption isotherm. The results confirmed that the surface modification of SNPs by chitosan had a significant impact on zeta potential and on the wettability of SNPs. Finally, modified SNPs were applied to the formulation of PEs; we identified the optimized conditions that increase the emulsion formulation process and stability. Therefore, modified SNPs by chitosan in this study could act as food-grade W/O Pickering stabilizers to fabricate environmental-friendly emulsion products.

Purpose: To determine the impact of an artificial intelligence software predicting malignancy in the management of incidentally discovered lung nodules. Materials and methods: In this retrospective study, all lung nodules ≥ 6 mm and ≤ 30 mm incidentally discovered on emergency CT scans performed between June 1, 2017 and December 31, 2017 were assessed. Artificial intelligence software using deep learning algorithms was applied to determine their likelihood of malignancy: most likely benign (AI score &lt; 50%), undetermined (AI score 50-75%) or probably malignant (AI score &gt; 75%). Predictions were compared to two-year follow-up and Brock's model. Results: Ninety incidental pulmonary nodules in 83 patients were retrospectively included. 36 nodules were benign, 13 were malignant and 41 remained indeterminate at 2 years follow-up. AI analysis was possible for 81/90 nodules. The 34 benign nodules had an AI score between 0.02% and 96.73% (mean = 48.05 § 37.32), while the 11 malignant nodules had an AI score between 82.89% and 100% (mean = 93.9 § 2.3). The diagnostic performance of the AI software for positive diagnosis of malignant nodules using a 75% malignancy threshold was: sensitivity = 100% [95% CI 72%-100%]; specificity = 55.8% [38 -73]; PPV = 42.3% [23-63]; NPV = 100% [82-100]. With its apparent high NPV, the addition of an AI score to the initial CT could have avoided a guidelines-recommended follow-up in 50% of the benign pulmonary nodules (6/12 nodules). Conclusion: Artificial intelligence software using deep learning algorithms presents a strong NPV (100%, with a 95% CI 82-100), suggesting potential use for reducing the need for follow-up of nodules categorized as benign.

NTPDase1/CD39, the major vascular ectonucleotidase, exerts thrombo-immunoregulatory function by controlling endothelial P2 receptor activation. Despite the well-described release of ATP from endothelial cells, few data are available regarding the potential role of CD39 as a regulator of arterial diameter. We thus investigated the contribution of CD39 in short-term diameter adaptation and long-term arterial remodeling in response to flow using Entpd1−/− male mice. Compared to wild-type littermates, endothelial-dependent relaxation was modified in Entpd1−/− mice. Specifically, the vasorelaxation in response to ATP was potentiated in both conductance (aorta) and small resistance (mesenteric and coronary) arteries. By contrast, the relaxing responses to acetylcholine were supra-normalized in thoracic aortas while decreased in resistance arteries from Entpd1−/− mice. Acute flow-mediated dilation, measured via pressure myography, was dramatically diminished and outward remodeling induced by in vivo chronic increased shear stress was altered in the mesenteric resistance arteries isolated from Entpd1−/− mice compared to wild-types. Finally, changes in vascular reactivity in Entpd1−/− mice were also evidenced by a decrease in the coronary output measured in isolated perfused hearts compared to the wild-type mice. Our results highlight a key regulatory role for purinergic signaling and CD39 in endothelium-dependent short- and long-term arterial diameter adaptation to increased flow.

NTPDase1/CD39, the major vascular ectonucleotidase, exerts thrombo-immunoregulatory function by controlling endothelial P2 receptor activation. Despite the well-described release of ATP from endothelial cells, few data are available regarding the potential role of CD39 as a regulator of arterial diameter. We thus investigated the contribution of CD39 in short-term diameter adaptation and long-term arterial remodeling in response to flow using Entpd1−/− male mice. Compared to wild-type littermates, endothelial-dependent relaxation was modified in Entpd1−/− mice. Specifically, the vasorelaxation in response to ATP was potentiated in both conductance (aorta) and small resistance (mesenteric and coronary) arteries. By contrast, the relaxing responses to acetylcholine were supra-normalized in thoracic aortas while decreased in resistance arteries from Entpd1−/− mice. Acute flow-mediated dilation, measured via pressure myography, was dramatically diminished and outward remodeling induced by in vivo chronic increased shear stress was altered in the mesenteric resistance arteries isolated from Entpd1−/− mice compared to wild-types. Finally, changes in vascular reactivity in Entpd1−/− mice were also evidenced by a decrease in the coronary output measured in isolated perfused hearts compared to the wild-type mice. Our results highlight a key regulatory role for purinergic signaling and CD39 in endothelium-dependent short- and long-term arterial diameter adaptation to increased flow.

The population of older adults (≥65 years) with type 2 diabetes mellitus (T2DM) is diverse, encompassing individuals with varying functional capabilities, living arrangements, concomitant medical conditions, and life expectancies. Hence, their categorization into different patient profiles (ie, good health, intermediate health, poor health) may aid in clinical decision-making when establishing glycemic goals and pharmacological treatment strategies. Further granularity in assessing each patient profile through interdisciplinary collaboration may also add precision to therapeutic and monitoring decisions. In this review, we discuss with a multidisciplinary approach how to deliver the best benefit from advanced diabetes therapies and technologies to older adults with T2DM according to each patient profile. There remain however several areas that deserve further research in older adults with T2DM, including the efficacy and safety of continuous glucose monitoring and automated insulin delivery systems, the switch to once-weekly insulin, the effectiveness of multidisciplinary care models, and the use of supported telemedicine and remote blood glucose monitoring in the oldest-old (≥85 years) who particularly require the assistance of others.

Introduction: In the context of budgetary constraints faced by healthcare systems, the medical-economic evaluation of care strategies becomes essential. In particular, valuing consumed resources in the overcrowded emergency departments (EDs) has become a priority to adopt more efficient approaches in treating the growing number of patients. However, precisely measuring the cost of care is challenging. While bottom-up micro-costing is considered the gold standard, its practical application remains limited. Objective: The objective was to accurately estimate the ED care cost for patients consulting in a French ED for suspected lower respiratory tract infection. Methods: The authors conducted a cost analysis using a bottom-up micro-costing method. Patients were prospectively included between January 1, and March 31, 2023. The primary endpoint was the mean cost of ED care. Resources consumed were collected using direct observation method and cost data were obtained from information available at Strasbourg University Hospital. Results: The mean cost of ED care was €411.68 (SD = 174.49). The cost elements that made the greatest contribution to the total cost were laboratory tests, labor, latency time, imaging and consumables. Considering this cost and the current epidemiological data on respiratory infections in France, the absence of valuation for outpatient care represents an annual loss of over 17 million euros for healthcare facilities. Conclusion: Micro-costing is a key element in valuing healthcare costs. The importance of accurately measuring costs, along with measuring the health outcomes of a defined care pathway, is to enhance the relevance of health economic evaluations and thus ensure efficient care.

This work describes a patient-derived tumoroid model (PDTs) to support precision medicine in lung oncology. The use of human adipose tissue-derived microvasculature and patient-derived peripheral blood mononuclear cells (PBMCs) permits to achieve a physiologically relevant tumor microenvironment. This study involved ten patients at various stages of tumor progression. The vascularized, immune-infiltrated PDT model could be obtained within two weeks, matching the requirements of the therapeutic decision. Histological and transcriptomic analyses confirmed that the main features from the original tumor were reproduced. The 3D tumor model could be used to determine the dynamics of response to antiangiogenic therapy and platinum-based chemotherapy. Antiangiogenic therapy showed a significant decrease in vascular endothelial growth factor (VEGF)-A expression, reflecting its therapeutic effect in the model. In an immune-infiltrated PDT model, chemotherapy showed the ability to decrease the levels of lymphocyte activation gene-3 protein (LAG-3), B and T lymphocyte attenuator (BTLA), and inhibitory receptors of T cells functions.

Objectives: Staphylococcus epidermidis (SE) is a supposedly low-virulence agent, which may cause proven bloodstream infections (BSIs), with little-known consequences on intensive care unit (ICU) patients. We aimed at studying ICU patients diagnosed with BSIs caused by SE (SE-BSIs). Methods: We constituted a retrospective cohort in two medical ICUs. SE-BSIs were defined by two or more independent SE-positive blood cultures of the same strain, within 48 hours, without concurrent infection. Results: We included 59 patients; 58% were men (n = 34), with median age of 67 (interquartile range 60-74) years and a simplified acute physiology score II of 59 (36-74) points, and 56% were immunocompromised (n = 33). Among the 37 (63%) patients requiring norepinephrine initiation or increase at the onset of SE-BSI versus patients not requiring vasopressors (37%; n = 22), concomitant arterial lactate levels reached 2.8 (1.9-5.8) versus 1.5 (1.3-2.2) mmol/l (P &lt;0.01), whereas the mean blood pressure was 49 (42-54) versus 61 (56-65) mm Hg (P = 0.01) and the mortality was 46% (n = 17) vs 14% (n = 3) at day 28 (P = 0.01), respectively. Regarding antibiotics, the susceptibility rates toward linezolid and vancomycin were 71% (n = 41/58) and 100% (n = 54/54), respectively. At the time of SE-BSI, all but one patient had a central venous access device. Conclusion: This work highlights SE-BSIs as a cause of septic shock, mostly in immunocompromised ICU patients, with increasing concerns about resistance to antibiotics and central line management. Keywords: Critical care; Immunocompromised host; Lymphopenia; Neoplasms; Septic shock; Staphylococcus epidermidis.

BACKGROUND and AIMS: After a prolonged intensive care unit (ICU) stay patients experience increased mortality and morbidity. The primary aim of this study was to assess the prognostic value of nutritional status, body mass composition and muscle strength, as assessed by body mass index (BMI), bioelectrical impedance analysis (BIA), handgrip (HG) test, and that of the biological features to predict one-year survival at the end of a prolonged ICU stay. METHODS: This was a multicenter prospective observational study. Survivor patients older than 18 years with ICU length of stay &gt;72 h were eligible for inclusion. BIA and HG were performed at the end of the ICU stay. Malnutrition was defined by BMI and fat-free mass index (FFMI). The primary endpoint was one-year mortality. Multivariable logistic regression was performed to determine parameters associated with mortality. RESULTS: 572 patients were included with a median age of 63 years [53.5; 71.1], BMI of 26.6 kg/m(2) [22.8; 31.3], SAPS II score of 43 [31; 58], and ICU length of stay of 9 days [6; 15]. Malnutrition was observed in 142 (24.9%) patients. During the 1-year follow-up after discharge, 96 (18.5%) patients died. After adjustment, a low HG test score (aOR = 1.44 [1.11; 1.89], p = 0.01) was associated with 1-year mortality. Patients with low HG score, malnutrition, and Albuminemia &lt;30 g/L had a one-year death rate of 41.4%. Conversely, patients with none of these parameters had a 1-year death rate of 4.1%. CONCLUSION: BIA to assess FFMI, HG and albuminemia at the end of ICU stay could be used to predict 1-year mortality. Their ability to identify patients eligible for a structured recovery program could be studied.

Background Cardiac arrest is the most life-threatening complication of attempted suicide by hanging. However, data are scarce on its characteristics and outcome predictors. Methods This retrospective observational multicentre study in 31 hospitals included consecutive adults admitted after cardiac arrest induced by suicidal hanging. Factors associated with in-hospital mortality were identified by multivariate logistic regression with multiple imputations for missing data and adjusted to the temporal trends over the study period. Results Of 450 patients (350 men, median age, 43 [34–52] years), 305 (68%) had a psychiatric history, and 31 (6.9%) attempted hanging while hospitalized. The median time from unhanging to cardiopulmonary resuscitation was 0 [0–5] min, and the median time to return of spontaneous circulation (ROSC) was 20 [10–30] min. Seventy-nine (18%) patients survived to hospital discharge. Three variables were independently associated with higher in-hospital mortality: time from collapse or unhanging to ROSC&gt;20 min (odds ratio [OR], 4.71; 95% confidence intervals [95%CIs], 2.02–10.96; p = 0.0004); glycaemia &gt;1.4 g/L at admission (OR, 6.38; 95%CI, 2.60–15.66; p &lt; 0.0001); and lactate &gt;3.5 mmol/L at admission (OR, 6.08; 95%CI, 1.71–21.06; p = 0.005). A Glasgow Coma Scale (GCS) score of &gt;5 at admission was associated with lower in-hospital mortality (OR, 0.009; 95%CI, 0.02–0.37; p = 0.0009). Conclusion In patients with hanging-induced cardiac arrest, time from collapse or unhanging to return of spontaneous circulation, glycaemia, arterial lactate, and coma depth at admission were independently associated with survival to hospital discharge. Knowledge of these risk factors may help guide treatment decisions in these patients at high risk of hospital mortality.

<b>Objectives: </b>The clinical profile and outcomes of patients with Coronavirus Disease 2019 (COVID-19) who require veno-arterial extracorporeal membrane oxygenation (VA-ECMO) or veno-arterial-venous extracorporeal membrane oxygenation (VAV-ECMO) are poorly understood. We aimed to describe the characteristics and outcomes of these patients and to identify predictors of both favourable and unfavourable outcomes.<b>Methods:</b> ECMOSARS is a multicentre, prospective, nationwide French registry enrolling patients who require veno-venous extracorporeal membrane oxygenation (ECMO)/VA-ECMO in the context of COVID-19 infection (652 patients at 41 centres). We focused on 47 patients supported with VA- or VAV-ECMO for refractory cardiogenic shock.<b>Results:</b> The median age was 49. Fourteen percent of patients had a prior diagnosis of heart failure. The most common aetiologies of cardiogenic shock were acute pulmonary embolism (30%), myocarditis (28%) and acute coronary syndrome (4%). Extracorporeal cardiopulmonary resuscitation (E-CPR) occurred in 38%. In-hospital survival was 28% in the whole cohort, and 43% when E-CPR patients were excluded. ECMO cannulation was associated with significant improvements in pH and FiO2 on day 1, but non-survivors showed significantly more severe acidosis and higher FiO2 than survivors at this point (P = 0.030 and P = 0.006). Other factors associated with death were greater age (P = 0.02), higher body mass index (P = 0.03), E-CPR (P = 0.001), non-myocarditis aetiology (P = 0.02), higher serum lactates (P = 0.004), epinephrine (but not noradrenaline) use before initiation of ECMO (P = 0.003), haemorrhagic complications (P = 0.001), greater transfusion requirements (P = 0.001) and more severe Survival after Veno-Arterial ECMO (SAVE) and Sonographic Assessment of Intravascular Fluid Estimate (SAFE) scores (P = 0.01 and P = 0.03).<b>Conclusions:</b> We report the largest focused analysis of VA- and VAV-ECMO recipients in COVID-19. Although relatively rare, the need for temporary mechanical circulatory support in these patients is associated with poor prognosis. However, VA-ECMO remains a viable solution to rescue carefully selected patients. We identified factors associated with poor prognosis and suggest that E-CPR is not a reasonable indication for VA-ECMO in this population.

<b>Aims:</b> Impact of skin mottling has been poorly studied in patients admitted for cardiogenic shock. This study aimed to address this issue and identify determinants of 30-day and 1-year mortality in a large cardiogenic shock cohort of all etiologies. <b>Methods and results: </b>FRENSHOCK is a prospective multicenter observational registry conducted in French critical care units between April and October, 2016. Among the 772 enrolled patients (mean age 65.7 ± 14.9 years; 71.5% male), 660 had skin mottling assessed at admission (85.5%) with almost 39% of patients in cardiogenic shock presenting mottling. The need for invasive respiratory support was significantly higher in patients with mottling (50.2% vs. 30.1%, p &lt; 0.001) and likewise for the need for renal replacement therapy (19.9% vs. 12.4%, p = 0.09). However, the need for mechanical circulatory support was similar in both groups. Patients with mottling at admission presented a higher length of stay (19 vs. 16 days, p = 0.033), a higher 30-day mortality rate (31% vs. 23.3%, p = 0.031), and also showed significantly higher mortality at 1-year (54% vs. 42%, p = 0.003). The subgroup of patients in whom mottling appeared during the first 24 h after admission had the worst prognosis at 30 days. <b>Conclusion: </b>Skin mottling at admission in patients with cardiogenic shock was statistically associated with prolonged length of stay and poor outcomes. As a perfusion-targeted resuscitation parameter, mottling is a simple, clinical-based approach and may thus help to improve and guide immediate goal-directed therapy to improve cardiogenic shock patients' outcomes.

Background: Respiratory mechanics is a key element to monitor mechanically ventilated patients and guide ventilator settings. Besides the usual basic assessments, some more complex explorations may allow to better characterize patients' respiratory mechanics and individualize ventilation strategies. These advanced respiratory mechanics assessments including esophageal pressure measurements and complete airway closure detection may be particularly relevant in critically ill obese patients. This study aimed to comprehensively assess respiratory mechanics in obese and non-obese ICU patients with or without ARDS and evaluate the contribution of advanced respiratory mechanics assessments compared to basic assessments in these patients. Methods: All intubated patients admitted in two ICUs for any cause were prospectively included. Gas exchange and respiratory mechanics including esophageal pressure and end-expiratory lung volume (EELV) measurements and low-flow insufflation to detect complete airway closure were assessed in standardized conditions (tidal volume of 6 mL kg -1 predicted body weight (PBW), positive end-expiratory pressure (PEEP) of 5 cmH 2 O) within 24 h after intubation. Results: Among the 149 analyzed patients, 52 (34.9%) were obese and 90 (60.4%) had ARDS (65.4% and 57.8% of obese and non-obese patients, respectively, p = 0.385). A complete airway closure was found in 23.5% of the patients. It was more frequent in obese than in non-obese patients (40.4% vs 14.4%, p &lt; 0.001) and in ARDS than in non-ARDS patients (30% vs. 13.6%, p = 0.029). Respiratory system and lung compliances and EELV/PBW were similarly decreased in obese patients without ARDS and obese or non-obese patients with ARDS. Chest wall compliance was not impacted by obesity or ARDS, but end-expiratory esophageal pressure was higher in obese than in nonobese patients. Chest wall contribution to respiratory system compliance differed widely between patients but was not predictable by their general characteristics. Conclusions: Most respiratory mechanics features are similar in obese non-ARDS and non-obese ARDS patients, but end-expiratory esophageal pressure is higher in obese patients. A complete airway closure can be found in around 25% of critically ill patients ventilated with a PEEP of 5 cmH2O. Advanced explorations may allow to better characterize individual respiratory mechanics and adjust ventilation strategies in some patients.

Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance. SIGNIFICANCE: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma. Humans Gene Expression Profiling Prognosis Kidney Neoplasms Immunotherapy Tumor Microenvironment Clinical Trials as Topic

Patient reported outcomes measures (PROMS) are important endpoints to measure patient health status in the perioperative setting. However, there are no good tools to measure PROMS in the pediatric surgical population. Patients 7 to 17 years old undergoing surgery were included and followed up for 1 day after surgery (POD1). At POD1 the patients were asked to rate their overall postoperative recovery using a 100-mm visual analog scale (VAS). The primary outcome was the pediatric QoR-15 score on postoperative day 1 (POD1). 150 patients completed the study. The mean (SD) pediatric QoR-15F scores were 132.1 (14.1) and 111.0 (27.0), preoperatively and on POD1, respectively. Convergent validity confirmed with Pearson (r) correlation between the postoperative pediatric QoR-15F and the patient-rated global recovery assessment was 0.72 (95% confidence interval [0.63-0.79]; p < 10-16). Concerning reliability, internal consistency of the pediatric QoR-15 assessed by Cronbach's alpha was 0.90. The test-retest concordance correlation coefficient was 0.92; 95% CI [0.83-0.96]. Split-half alpha was 0.74. The pictorial pediatric version of the QoR-15F showed good validity, reliability, responsiveness, acceptability and feasibility. This PROMS should be considered for clinical care and research in the perioperative pediatric patient setting.Trial Registration: NCT04453410 on clinicaltrials.gov.

Background: Gender-related differences have been reported in atrial fibrotic remodeling and prognosis of atrial fibrillation (AF) patients after ablation. We assessed in persistent AF the regional distribution of left atrial (LA) bipolar voltage and the extent of low-voltage zones (LVZ) according to gender as well as the results of a voltage-guided substrate ablation. Methods: Consecutive patients who underwent a voltage-guided AF ablation were enrolled. LA endocardial voltage maps were obtained using a 3D electroanatomical mapping system in sinus rhythm. LVZ was defined as &lt;0.5 mV. Results: A total of 115 patients were enrolled (74 men, 41 women). The LA bipolar voltage amplitude was twice lower in the whole LA ( p &lt; 0.01) and in each atrial region in women compared with men, whereas the LA indexed volume was similar. LVZ were found in 56.1% of women and 16.2% of men ( p &lt; 0.01). LVZ were also more extensive in women ( p = 0.01), especially in the anterior LA. Atrial voltage alteration occurred earlier in women than in men. In a multivariate analysis, the female sex (OR 12.99; 95% CI, 3.23-51.63, p = 0.0001) and LA indexed volume (OR 1.09; 95% CI, 1.04-1.16, p = 0.001) were predictive of LVZ. Atrial arrhythmia-free survival was similar in men and women 36 months after a single ablation procedure. <div>Conclusion:<p>The study reports a strong relationship between the female gender and atrial substrate remodeling. The female gender was significantly associated with higher incidence, earlier occurrence, and greater extent of LVZ compared with men. Despite the female-specific characteristics in atrial remodeling, LVZ-guided ablation may improve the AF ablation outcome in women.</p></div>

Background and Objectives: Chest radiography remains the most frequently used examination in emergency departments (ED) for the diagnosis of community-acquired pneumonia (CAP), despite its poor diagnostic accuracy compared with ultra-low-dose (ULD) chest computed tomography (CT). However, although ULD CT appears to be an attractive alternative to radiography, its organizational impact in ED remains unknown. Our objective was to compare the relevant timepoints in ED management of CT and chest radiography. Materials and Methods: We conducted a retrospective study in two ED of a University Hospital including consecutive patients consulting for a CAP between 1 March 2019 and 29 February 2020 to assess the organizational benefits of ULD chest CT and chest radiography (length of stay (LOS) in the ED, time of clinical decision after imaging). Overlap weights (OW) were used to reduce covariate imbalance between groups. Results: Chest radiography was performed for 1476 patients (mean age: 76 years [63; 86]; 55% men) and ULD chest CT for 133 patients (mean age: 71 [57; 83]; 53% men). In the weighted population with OW, ULD chest CT did not significantly alter the ED LOS compared with chest radiography (11.7 to 12.2; MR 0.96 [0.85; 1.09]), although it did significantly reduce clinical decision time (6.9 and 9.5 h; MR 0.73 [0.59; 0.89]). Conclusion: There is real-life evidence that a strategy with ULD chest CT can be considered to be a relevant approach to replace chest radiography as part of the diagnostic workup for CAP in the ED without increasing ED LOS.

Objective: Dentists need a high level of awareness to limit the spread of COVID-19 (Coronavirus disease 2019). This study aimed to evaluate the level of awareness and attitude regarding the risk associated with dental procedures among dentists. Material and Methods: An online questionnaire was submitted to dentists between April-May 2020. The questionnaire form included questions related to demographic data, the transmission characterization of SARS-CoV-2, and treatment of COVID-19 patients. Data were analyzed using IBM SPSS V23 and chi-square test (p ≤ 0.05). Results: A total of 3825 participants (29.1± 7.6 years) were included. In COVID-19, the riskiest dental branch in terms of the risk of contamination through saliva was considered to be Periodontics (32.2%), while the least risky branch was Orthodontics (0.2%). Specific dental treatment procedures considered at high risk of contamination were tooth preparation (69.4%), scaling and root planing (63.5%), filling (53.4%), and pulpectomy (40.5%). The parameters of the study that differed according to gender and professional status were the viability of the virus, the risk assessment, saliva contamination risk, and aerosol-generating activities for COVID-19 (p &lt; 0.05). Conclusion: Dentists were aware of the risk assessment and extra precautionary methods. However, they had limited knowledge about the viability of the virus. Dentists should be aware of recommended approaches and update their knowledge about COVID-19 to limit the spread of the disease. Since dentistry is an area suitable for the transmission of the COVID-19, the fact that dentists have information about the viability of this virus will be lifesaving in clinical applications.

Abstract Background Anticoagulants are widely used but can lead to iatrogenic events such as bleeding. Limited data exists regarding the characteristics and management of patients admitted to intensive care units (ICU) for severe anticoagulant-related extracranial bleeding. Methods A retrospective observational study was conducted in five French ICUs. From January 2007 to December 2018, all patients aged over 18 years admitted to ICU for extracranial bleeding while receiving therapeutic anticoagulation were included. Results 486 patients were included, mainly male (61%) with an average age of 73 ± 13 years. Most patients had comorbidities, including hypertension (68%), heart disease (49%) and diabetes (33%). Patients were treated by vitamin K antagonists (VKA, 54%), heparins (25%) and direct oral anticoagulants (DOAC, 7%). The incidence of patients admitted to ICU for anticoagulant-related bleeding increased from 3.2/1000 admissions in 2007 to 5.8/1000 in 2018. This increase was particularly high for DOAC class. Upon admission, patients exhibited severe organ failure, as evidenced by a high SOFA score (7 ± 4) and requirement for organ support therapies such as vasopressors (31.5%) and invasive mechanical ventilation (34%). Adherence to guidelines for the specific treatment of anticoagulant-related bleeding was generally low. ICU mortality was 27%. In multivariate analysis, five factors were independently associated with mortality: chronic hypertension, need for vasopressors, impaired consciousness, hyperlactatemia and prolonged aPTT > 1.2. Conclusion Anticoagulant-related extracranial bleeding requiring ICU admission is a serious complication responsible for organ failure and significant mortality. Its incidence is rising. The therapeutic management is suboptimal and could be improved by educational programs.

Objective: To develop a multidisciplinary French reference that addresses initial pre- and in-hospital management of a mild traumatic brain injury patient. Design: A panel of 22 experts was formed on request from the French Society of Emergency Medicine (SFMU) and the French Society of Anaesthesiology and Critical Care Medicine (SFAR). A policy of declaration and monitoring of links of interest was applied and respected throughout the process of producing the guidelines. Similarly, no funding was received from any company marketing a health product (drug or medical device). The expert panel had to respect and follow the Grade® (Grading of Recommendations Assessment, Development and Evaluation) methodology to evaluate the quality of the evidence on which the recommendations were based. Given the impossibility of obtaining a high level of evidence for most of the recommendations, it was decided to adopt a "Recommendations for Professional Practice" (RPP) format, rather than a Formalized Expert Recommendation (FER) format, and to formulate the recommendations using the terminology of the SFMU and SFAR Guidelines. Methods: Three fields were defined: 1) pre-hospital assessment, 2) emergency room management, and 3) emergency room discharge modalities. The group assessed 11 questions related to mild traumatic brain injury. Each question was formulated using a PICO (Patients Intervention Comparison Outcome) format. Results: The experts' synthesis work and the application of the GRADE® method resulted in the formulation of 14 recommendations. After two rounds of rating, strong agreement was obtained for all recommendations. For one question, no recommendation could be made. Conclusion: There was strong agreement among the experts on important, transdisciplinary recommendations, the purpose of which is to improve management practices for patients with mild head injury.

While treated dentin matrix (TDM) has been used for regeneration of dental tissues, the quality and quantity of regenerated periodontal tissue structure are suboptimal. Te present study was undertaken to test whether the combined use of the TDM with dental follicle cells (DFCs) and Hertwig's epithelial root sheath (HERS) cells enhances the regeneration of periodontal structures in a nondental microenvironment. TDMs were fabricated from 3-month-old Sprague-Dawley (SD) rats. DFCs and HERS cells were isolated from postnatal 7-day SD rats. Purifed DFCs and HERS cells, both in combination or alone, were seeded and cultured on TDM in vitro and characterized. Te cell-seeded TDMs were subsequently implanted into a 3-month-old rat greater omentum for 6 weeks, and further histological evaluation was performed. Te results showed that cells grew well on the surface of TDMs, and mineralized nodules could be seen, especially in the HERS + DFCs group. After transplantation in rat omentum, periodontal ligament-like fbers and cementum-like structures were observed around the TDM in 1/3 of the samples in both the HERS group and the DFCs group and in 2/3 of the samples in the HERS + DFCs group, while almost no attached tissue formation was found in the TDM only group. Te formed cementum width and the periodontal ligament length were signifcantly larger in the HERS + DFCs group. Te periodontal ligament-like fbers in the HERS + DFCs group were orderly arranged and attached to the cementum-like tissues, which resembled the cementum-periodontal structure. Terefore, the combined use of DFCs, TDM, and HERS cells may be a promising strategy for the regeneration of the periodontal structures, especially in the nondental microenvironment.

Background and Objective: In thoracic surgery, different modalities of extracorporeal life support (ECLS) can be used for cardiorespiratory support in complex scenarios. Decades of learning in clinical practice and physiology associated with technological development led to a great variety of ECLS technologies available. Thoracic surgery procedures with difficult or impossible single lung ventilation may still be performed using different ECLS modalities. The aim of this review is to describe the use of ECLS, with its different modalities, as a solution to perform complex surgeries in a patient with difficult or impossible single lung ventilation. Methods: A literature review was conducted using the terms "extracorporeal life support pulmonary resection" and "extracorporeal life support thoracic surgery", and articles were selected according to defined criteria. Key Content and Findings: To support lung function during thoracic surgery, the most efficient and popular variety of ECLS is venovenous extracorporeal membrane oxygenation. Lung resection on a single lung after pneumonectomy, surgery in a patient with severe hypercapnia and/or low respiratory reserve, carinal and airway surgery, and severe thoracic trauma are the main examples of situations where ECLS may be the solution to provide a safe surgical environment in patients who cannot tolerate single lung ventilation. Multidisciplinarity, selection of patients and careful surgical planning are cornerstones in defining the situations that may benefit from ECLS support. Conclusions: Knowledge on techniques of ECLS are essential for every thoracic surgeon. Although rarely used, these techniques of cardiorespiratory support should be considered when planning complex cases with difficulties in ventilation and emergent situations.

Dynamin 2 (DNM2) is a ubiquitously expressed GTPase regulating membrane trafficking and cytoskeleton dynamics. Heterozygous dominant mutations in DNM2 cause centronuclear myopathy (CNM), associated with muscle weakness and atrophy and histopathological hallmarks as fiber hypotrophy and organelles mis-position. Different severities range from the severe neonatal onset form to the moderate form with childhood onset and to the mild adult onset form. No therapy is approved for CNM. Here we aimed to validate and rescue a mouse model for the moderate form of DNM2-CNM harboring the common DNM2 R369W missense mutation. Dnm2(R369W/+) mice presented with increased DNM2 protein level in muscle and moderate CNM-like phenotypes with force deficit, muscle and fiber hypotrophy, impaired mTOR signaling, and progressive mitochondria and nuclei mis-position with age. Molecular analyses revealed a fiber type switch toward oxidative metabolism correlating with decreased force and alteration of mitophagy markers paralleling mitochondria structural defects. Normalization of DNM2 levels through intramuscular injection of AAV-shDnm2 targeting Dnm2 mRNA significantly improved histopathology and muscle and myofiber hypotrophy. These results showed that the Dnm2(R369W/+) mouse is a faithful model for the moderate form of DNM2-CNM and revealed that DNM2 normalization after a short 4-week treatment is sufficient to improve the CNM phenotypes.

Irreversible pulpitis is an extremely painful dental pathology. Its emergency treatment, pulpotomy, should include the use of a pulp dressing in the pulp chamber until the final treatment. Various antalgic products have been suggested as efficient medications to relieve the patient's pain and are commonly used, but data for scientific validation are scarce. Objective: We evaluated the efficacy of articaine or eugenol in the diminution of pain after pulpotomy. Design: We included 100 patients with irreversible pulpitis and evaluated their initial pain levels. Pain was measured using a 0-10 numeric rating scale. After treatment through pulpotomy, we randomized them into two groups using either articaine or eugenol as a pulp dressing and evaluated their pain level at 1, 3 and 7 days. Results: Initial pain levels were severe (7.53). The use of painkillers was not associated with lower levels of pain. Both treatments showed great efficiency on day 1, with stronger efficiency of eugenol than articaine, showing a decrease of 6.24 versus 4.89 (p = 0.025). Both treatments were efficient, whatever the age or sex of the patient, the initial pain level, and the causal tooth. Conclusion: Pulpotomy is an efficient way to relieve pain, using either articaine or eugenol. When choosing a pulp dressing, eugenol should be the first choice.

Transcatheter aortic valve implantation (TAVI) has become an alternative to surgical aortic valve replacement for patients with symptomatic severe aortic stenosis in elderly and comorbid population. Significant improvement in heart function has been observed in patients undergoing TAVI, but numerous patients are readmitted to hospital for heart failure (HF). Moreover, repeat HF hospitalization is strongly associated with an adverse prognosis and increases the financial burden of health care. Although studies have identified pre-existing and post-procedural factors that contribute to HF hospitalization after TAVI, there is a paucity of data regarding optimal post-procedural pharmacological treatments. This review aims to provide an overview of the current understanding of mechanisms, determinants, and potential treatments of HF following TAVI. We first review the pathophysiology of left ventricular (LV) remodelling, coronary microcirculation disorder, and endothelial dysfunction in patients with aortic stenosis and then examine the impact of TAVI on these conditions. We then present evidence of various factors and complications that may interplay with LV remodelling and contribute to HF events after TAVI. Next, we describe the triggers and predictors of early and late HF rehospitalizations following TAVI. Lastly, we discuss the potential of conventional pharmacological treatments, including renin-angiotensin blockers, beta-blockers, and diuretics in TAVI patients. The paper explores the potential of newer drugs, including sodium-glucose co-transporter 2 inhibitors, anti-inflammatory drugs, and ion supplementation. Comprehensive knowledge in this field may aid in recognizing successful existing therapies, developing effective new treatments, and establishing dedicated patient care strategies during follow-up after TAVI.

A best-evidence topic was written according to a structured protocol. The question addressed was the following: in patient undergoing lung transplantation, are lungs from donors of age &gt;60 years old (yo) associated with equivalent outcomes-including primary graft dysfunction, respiratory function and survival-than lungs from donors &lt; _60yo? Altogether, &gt;200 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journals, dates, country of publication, patients group studied, study type, relevant outcomes, and results of these papers were tabulated. Amongst the 12 papers reviewed, survival results were different depending on whether donor age was analysed raw or adjusted for recipients' age and initial diagnosis. Indeed, recipients with interstitial lung disease (ILD), pulmonary hypertension or cystic fibrosis (CF) had significantly inferior overall survival when receiving grafts from older donors. When older grafts are allocated to younger donors, a significant decrease in survival has been noticed in the case of single lung transplantation. In addition, 3 papers showed worse results regarding peak forced expiratory volume in 1 second (FEV1) in patients receiving older organs, and 4 showed comparable primary graft dysfunction incidence rates. We conclude that when carefully assessed and allocated to the recipient who could benefit most from the transplant (e.g., a patient with a diagnosis of chronic obstructive pulmonary disease (COPD), who would not require a prolonged cardiopulmonary bypass (CPB)), lung grafts from donors of &gt;60yo offer comparable results to younger donors.

No abstract available

Introduction: Central vision loss due to diabetic macular edema (DME) is related to the macular edema itself, but also in some cases to alterations of the foveal avascular zone (FAZ). The aim of this trial was to study changes in macular vessels in eyes with DME treated with aflibercept using optical coherence tomography angiography (OCTA). Methods: This was a longitudinal, prospective, non-controlled, single arm study. The primary objective was the quantitative assessment of macular vessels over time in patients with DME treated with intravitreal aflibercept during a 48-week follow-up using OCTA. Results: Twenty-six DME eyes from 26 patients were included (mean age, 64.6 years; women, 53.8%; prior anti-VEGF treatment, 46.1%). Each eye received a mean (SD) of 7.2 (2.2) injections. The parameters of the FAZ did not change during the 48-week follow-up: the mean (SD) FAZ area varied from 0.19 (0.19) mm2 at baseline (n=22) to 0.23 (0.20) mm2 at week 48 (n=15), boundary from 1.54 (1.21) to 2.04 (1.20) mm and circularity from 0.45 (0.33) % to 0.57 (0.20) %. There was no change in perfusion density and vessel density of the macula in the 3-mm circle. As expected, mean central retinal thickness, macular volume and visual acuity improved during follow-up. Discussion/Conclusion: No change in macular perfusion was observed in eyes with DME during a 48-week follow-up after intravitreal injections of aflibercept. Randomized controlled trials using OCT-angiography in large populations with extended observation periods are needed to assess changes in macular vessels after intravitreal anti-VEGF treatment.

Objective: This systematic review and meta-analysis evaluated the effect of the use of available drugs loaded gels used as adjunct to non-surgical periodontal therapy. Methods: Systematic research on PubMed/MEDLINE, Cochrane Central register of Controlled Trials, and Embase databases up to December 2021 was performed. Randomized clinical trials (RCT) which compared the outcomes of scaling and root planing (SRP) + local adjuvant administration (gel) versus SRP + placebo or SRP alone in Humans were included. The primary outcome measures were PPD and CAL changes at 3 months. Results: After articles screening, 77 articles were included and assessed for quality. Then, a metaanalysis was conducted in studies with at least 3 months of follow-up. Clinical improvements were found to be significant for tetracyclines (-0.51 [-0.71;-0.31] p &lt; 0.001), macrolides (-0.71 [-1.04;-0.38] p &lt; 0.001), statins (-0.84 [-0.98;-0.70] p &lt; 0.001), metformin (-1.47 [-1.66;-1.29] p &lt; 0.001) and hyaluronan (-1.61 [-2.28;-0.94] p &lt; 0.001) loaded gels, but non-significant for chlorhexidine (-0.48 [-1.10; 0.14] p = 0.13), metronidazole (-0.50 [-1.20; 0.20] p = 0.16) and bisphosphonates (-0.42 [-1.39; 0.54] p = 0.539) gels. Conclusion: Adjunctive use of drugs loaded gels to non-surgical periodondal treatment could improve PPD reduction at 3 months. However, huge disparities remain when comparing the outcomes of the differents drugs used. Future comparative studies should be considered to determine precisely short and long term benefits of such treatments.

<div><p>Inhibition of translation initiation prevents CLL growth in vitro and in vivo, through targeting the MYC oncogene.</p><p>• PHBs directly interact with the translation initiation machinery, filling a gap in the understanding of the crucial roles of these proteins.</p><p>Dysregulation of messenger RNA (mRNA) translation, including preferential translation of mRNA with complex 5′ untranslated regions such as the MYC oncogene, is recognized as an important mechanism in cancer. Here, we show that both human and murine chronic lymphocytic leukemia (CLL) cells display a high translation rate, which is inhibited by the synthetic flavagline FL3, a prohibitin (PHB)-binding drug. A multiomics analysis performed in samples from patients with CLL and cell lines treated with FL3 revealed the decreased translation of the MYC oncogene and of proteins involved in cell cycle and metabolism. Furthermore, inhibiting translation induced a proliferation arrest and a rewiring of MYCdriven metabolism. Interestingly, contrary to other models, the RAS-RAF-(PHBs)-MAPK pathway is neither impaired by FL3 nor implicated in translation regulation in CLL cells. Here, we rather show that PHBs are directly associated with the eukaryotic initiation factor (eIF)4F translation complex and are targeted by FL3. Knockdown of PHBs resembled FL3 treatment. Importantly, inhibition of translation controlled CLL development in vivo, either alone or combined with immunotherapy. Finally, high expression of translation initiation-related genes and PHBs genes correlated with poor survival and unfavorable clinical parameters in patients with CLL. Overall, we demonstrated that translation inhibition is a valuable strategy to control CLL development by blocking the translation of several oncogenic pathways including MYC. We also unraveled a new and direct role of PHBs in translation initiation, thus creating new therapeutic opportunities for patients with CLL. Treg CD4 + T CD8 + T CLL B Eμ-TCL1 splenocytes</p></div>

Introduction Surgical meniscal lesions are common and 80% of cases involve the medial meniscus of a stable knee. There is a lack of consensus regarding postoperative rehabilitation protocols and a wide variation between restrictive and accelerated rehabilitation protocols exists. The main objective of this study was to report the functional results and the failure rate of the various rehabilitation protocols of the retrospective series of the French Society of Arthroscopy (SFA) after suturing the medial meniscus of a stable knee, considering whether the tear is stable or unstable. Hypothesis Our hypothesis was that accelerated rehabilitation was not associated with an increased risk of failure. Materials and methods This retrospective, multicenter study was conducted across 10 centers (6 private hospitals and 4 public hospitals) including all patients tested for a medial meniscus suture in a stable knee between January 1, 2005 and November 31, 2017 for a minimum follow-up of 5 years. Demographic, imaging, suturing, rehabilitation protocol, and functional TEGNER and KOOS scores were collected. Failure was defined as performing a secondary meniscectomy. Results Three hundred and sixty-seven patients were analyzed with an average follow-up of 82 months. Immediate weight bearing was allowed in 85% of cases, the wearing of a brace was present in almost 74% of cases and flexion was limited in 97% of cases. Inter-group comparisons found a higher suture failure rate in the group with immediate weight bearing (35.6% vs. 20%, p = 0.011) and in the group with a brace (36.9% vs. 22.4%, p &lt; 0.001). There was no difference in the 90° flexion group. The TEGNER score was higher in the non-weight bearing group (6.5 vs. 5.4, p = 0.028) and the KOOS QOL score was higher in the group without a brace (82.2 vs. 66.8, p = 0.025). According to a multivariate analysis, immediate weight bearing (OR = 3.6, [1.62; 7.98], p = 0.0016) and wearing a brace (OR = 2.83, [1.54; 5.02], p &lt; 0.001) were associated with a higher failure rate. In the group of stable lesions, the use of a brace (OR = 3.73, [1.62; 8.56], p = 0.0019) was associated with a higher failure rate. Conclusion No consensus regarding rehabilitation protocols has been established to date and the results of this retrospective series of the SFA affirm the great variability of practices at a national level. Although accelerated rehabilitation protocols are presently favored, the resumption of immediate full weight bearing should be considered with caution, being associated with a higher risk of failure in this series. Deferring weight bearing for 1 month can be considered in the event of a large tear or in the event of damage to the circumferential fibers. Wearing a brace does not seem to have any influence, while limited flexion achieved a consensus. Level of evidence IV, retrospective study.

Radiation therapy and platinum-based chemotherapy are common treatments for lung cancer patients. Several factors are considered for the low overall survival rate of lung cancer, such as the patient's physical state and the complex heterogeneity of the tumor, which leads to resistance to the treatment. Consequently, precision medicines are needed for the patients to improve their survival and their quality of life. Until now, no patient-derived tumoroid model has been reported to predict the efficiency of radiation therapy in non-small-cell lung cancer. Using our patient-derived tumoroid model, we report that this model could be used to evaluate the efficiency of radiation therapy and cisplatin-based chemotherapy in non-small-cell lung cancer. In addition, these results can be correlated to clinical outcomes of patients, indicating that this patient-derived tumoroid model can predict the response to radiotherapy and chemotherapy in non-small-cell lung cancer.

Background: Hyperglycaemia is common in critically ill patients, but blood glucose and insulin management may differ widely among intensive care units (ICUs). We aimed to describe insulin use practices and the resulting glycaemic control in French ICUs. We conducted a multicentre 1-day observational study on November 23, 2021, in 69 French ICUs. Adult patients hospitalized for an acute organ failure, severe infection or post-operative care were included. Data were recorded from midnight to 11:59 p.m. the day of the study by 4-h periods. Results: Two ICUs declared to have no insulin protocol. There was a wide disparity in blood glucose targets between ICUs with 35 different target ranges recorded. In 893 included patients we collected 4823 blood glucose values whose distribution varied significantly across ICUs (P &lt; 0.0001). We observed 1135 hyperglycaemias (&gt; 1.8 g/L) in 402 (45.0%) patients, 35 hypoglycaemias (≤ 0.7 g/L) in 26 (2.9%) patients, and one instance of severe hypoglycaemia (≤ 0.4 g/L). Four hundred eight (45.7%) patients received either IV insulin (255 [62.5%]), subcutaneous (SC) insulin (126 [30.9%]), or both (27 [6.6%]). Among patients under protocolized intravenous (IV) insulin, 767/1681 (45.6%) of glycaemias were above the target range. Among patients receiving insulin, short-and long-acting SC insulin use were associated with higher counts of hyperglycaemias as assessed by multivariable negative binomial regression adjusted for the propensity to receive SC insulin: incidence rate ratio of 3.45 (95% confidence interval [CI] 2.97-4.00) (P &lt; 0.0001) and 3.58 (95% CI 2.84-4.52) (P &lt; 0.0001), respectively. Conclusions: Practices regarding blood glucose management varied widely among French ICUs. Administration of short or long-acting SC insulin was not unusual and associated with more frequent hyperglycaemia. The protocolized insulin algorithms used failed to prevent hyperglycaemic events.

Renal cell carcinoma (RCC) represents around 2% of cancer-related deaths worldwide per year. RCC is an immunogenic malignancy, and treatment of metastatic RCC (mRCC) has greatly improved since the advent of the new immunotherapy agents, including immune checkpoint inhibitors (ICIs). However, it should be stressed that a large proportion of patients does not respond to these therapies. There is thus an urgent need to identify predictive biomarkers of efficacy or resistance associated with ICIs or ICI/Tyrosine kinase inhibitor (TKI) combinations; this is a major challenge to achieve precision medicine for mRCC in routine practice. To identify potential biomarkers, it is necessary to improve our knowledge on the biology of immune checkpoints. A lot of efforts have been made over the last decade in the field of immuno-oncology. We summarize here the main data obtained in this field when considering mRCC. As for clinical biomarkers, clinician and scientific experts of the domain are facing difficulties in identifying such molecular entities, probably due to the complexity of immuno-oncology and the constant adaptation of tumor cells to their changing environment.

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Background Activation of the TREM-1 pathway is associated with outcome in life threatening COVID-19. Data suggest that modulation of this pathway with nangibotide, a TREM-1 modulator may improve survival in TREM-1 activated patients (identified using the biomarker sTREM-1). Methods Phase 2 double-blind randomized controlled trial assessing efficacy, safety, and optimum treatment population of nangibotide (1.0 mg/kg/h) compared to placebo. Patients aged 18–75 years were eligible within 7 days of SARS-CoV-2 documentation and within 48 h of the onset of invasive or non-invasive respiratory support because of COVID-19-related ARDS. Patients were included from September 2020 to April 2022, with a pause in recruitment between January and August 2021. Primary outcome was the improvement in clinical status defined by a seven-point ordinal scale in the overall population with a planned sensitivity analysis in the subgroup of patients with a sTREM-1 level above the median value at baseline (high sTREM-1 group). Secondary endpoints included safety and all-cause 28-day and day 60 mortality. The study was registered in EudraCT (2020-001504-42) and ClinicalTrials.gov (NCT04429334 ). Findings The study was stopped after 220 patients had been recruited. Of them, 219 were included in the mITT analysis. Nangibotide therapy was associated with an improved clinical status at day 28. Fifty-two (52.0%) of patients had improved in the placebo group compared to 77 (64.7%) of the nangibotide treated population, an odds ratio (95% CI) for improvement of 1.79 (1.02–3.14), p = 0.043. In the high sTREM-1 population, 18 (32.7%) of placebo patients had improved by day 28 compared to 26 (48.1%) of treated patients, an odds ratio (95% CI) of 2.17 (0.96–4.90), p = 0.063 was observed. In the overall population, 28 (28.0%) of placebo treated patients were not alive at the day 28 visit compared to 19 (16.0%) of nangibotide treated patients, an absolute improvement (95% CI) in all-cause mortality at day 28, adjusted for baseline clinical status of 12.1% (1.18–23.05). In the high sTREM-1 population (n = 109), 23 (41.8%) of patients in the placebo group and 12 (22.2%) of patients in the nangibotide group were not alive at day 28, an adjusted absolute reduction in mortality of 19.9% (2.78–36.98). The rate of treatment emergent adverse events was similar in both placebo and nangibotide treated patients. Interpretation Whilst the study was stopped early due to low recruitment rate, the ESSENTIAL study demonstrated that TREM-1 modulation with nangibotide is safe in COVID-19, and results in a consistent pattern of improved clinical status and mortality compared to placebo. The relationship between sTREM-1 and both risk of death and treatment response merits further evaluation of nangibotide using precision medicine approaches in life threatening viral pneumonitis.

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During the past few decades, thoracic surgery has been in constant evolution from open to more refined minimally invasive surgery techniques. Teaching and learning, in parallel with proficiency, competence and mastery are subject of debate nowadays. The aim of this paper is to describe the role of open surgery and video-assisted thoracic surgery (VATS) during training of the contemporary thoracic surgeon. The authors describe the learning process in different areas and phases throughout the paper. Open surgery, although less and less frequent, mainly for simple procedures, should not be under evaluated as it provides a unique source of learning opportunities. VATS, although globally adopted as the gold standard, must be part of any training program. Both open surgery and VATS provide complimentary learning methods and techniques and should happen simultaneously, not in a competitive way. Globally, despite the efforts from some institutions and experts, most countries do not present a unified and standardized approach to teaching new procedures. Introduction of standardized methods for quantification of training are recommended.<p>Simulators, dry and wet labs and step-by-step programs should be implemented. The authors recommend implementation of surgical learning programs that have a rationale in their core that involves gradual evolution, including both open surgery and VATS to complement each other, and to create a training that is simultaneous and not competitive.</p>

Abstract Aim To investigate sleep apnoea prevalence, factors influencing severity, and associations between sleep apnoea severity and micro‐/macrovascular complications in a large population of patients with type 1 diabetes. Materials and methods This French multicentre prospective cohort study was conducted between July 2016 and June 2020. Adults with type 1 diabetes using an insulin pump were eligible. Home care provider nurses collected demographic and clinical data and set up oximetry to determine the oxygen desaturation index (ODI). No, mild–moderate and severe sleep apnoea were defined as ODI &lt;15 events/h, 15 to &lt;30 events/h and ≥30 events/h, respectively. Univariate and multivariate analyses were performed to identify factors associated with sleep apnoea, and associations between sleep apnoea severity and micro‐/macrovascular complications were determined using logistic regression. Results Of 769 participants, 12.4% and 3.4% had mild‐to‐moderate or severe sleep apnoea, respectively. Factors significantly associated with sleep apnoea on multivariate analysis were age, sex, body mass index (BMI) and hypertension. After adjustment for age, sex and BMI, presence of severe sleep apnoea was significantly associated with macrovascular complications (odds ratio vs. no sleep apnoea: 3.96 [95% confidence interval 1.43‐11.11]; P &lt; 0.01), while mild‐to‐moderate sleep apnoea was significantly associated with presence of diabetic retinopathy (odds ratio 2.09 [95% confidence interval 1.10‐3.74]; P &lt; 0.01). Conclusion Sleep apnoea is a significant comorbidity in patients with type 1 diabetes, especially with respect to diabetic complications. This highlights the need for sleep apnoea screening and management in these individuals.

Abstract Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1 , HOXB9 and MITF and gain of MYC and NFE2L2 -associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.

Background: Despite the significant advances in the management of advanced prostate cancer (PCa), metastatic PCa is currently considered incurable. For further investigations in precision treatment, the development of preclinical models representing the complex prostate tumor heterogeneity are mandatory. Accordingly, we aimed to establish a resource of patient-derived xenograft (PDX) models that exemplify each phase of this multistage disease for accurate and rapid evaluation of candidate therapies. Methods: Fresh tumor samples along with normal corresponding tissues were obtained directly from patients at surgery. To ensure that the established models reproduce the main features of patient’s tumor, both PDX tumors at multiple passages and patient’s primary tumors, were processed for histological characteristics. STR profile analyses were also performed to confirm patient identity. Finally, the responses of the PDX models to androgen deprivation, PARP inhibitors and chemotherapy were also evaluated. Results: In this study, we described the development and characterization of 5 new PDX models of PCa. Within this collection, hormone-naïve, androgen-sensitive and castration-resistant (CRPC) primary tumors as well as prostate carcinoma with neuroendocrine differentiation (CRPC-NE) were represented. Interestingly, the comprehensive genomic characterization of the models identified recurrent cancer driver alterations in androgen signaling, DNA repair and PI3K, among others. Results were supported by expression patterns highlighting new potential targets among gene drivers and the metabolic pathway. In addition, in vivo results showed heterogeneity of response to androgen deprivation and chemotherapy, like the responses of patients to these treatments. Importantly, the neuroendocrine model has been shown to be responsive to PARP inhibitor. Conclusion: We have developed a biobank of 5 PDX models from hormone-naïve, androgen-sensitive to CRPC primary tumors and CRPC-NE. Increased copy-number alterations and accumulation of mutations within cancer driver genes as well as the metabolism shift are consistent with the increased resistance mechanisms to treatment. The pharmacological characterization suggested that the CRPC-NE could benefit from the PARP inhibitor treatment. Given the difficulties in developing such models, this relevant panel of PDX models of PCa will provide the scientific community with an additional resource for the further development of PDAC research.

BackgroundWhether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear.MethodsIn this phase 3, multicenter, double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days.ResultsA total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, −5.6 percentage points; 95% CI, −9.6 to −1.7; P=0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment.ConclusionsAmong patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489. opens in new tab.)

Background: The International Society on Thrombosis and Haemostasis (ISTH) released overt disseminated intravascular coagulation (DIC) diagnostic criteria in 2001. Since then, DIC has been understood as the end-stage consumptive coagulopathy and not the therapeutic target. However, DIC is not merely a decompensated coagulation disorder, but also includes early stages with systemic activation in coagulation. Thus, the ISTH has recently released sepsis-induced coagulopathy (SIC) criteria that can diagnose compensated-phase of coagulopathy with readily available biomarkers. Main body: DIC is a laboratory-based diagnosis due to various critical conditions, although sepsis is the most common underlying disease. The pathophysiology of sepsis-associated DIC is multifactorial, and in addition to coagulation activation with suppressed fibrinolysis, multiple inflammatory responses are initiated by activated leukocytes, platelets, and vascular endothelial cells as part of thromboinflammation. Although overt DIC diagnostic criteria were established by ISTH to diagnose the advanced stage of DIC, additional criteria that can detect an earlier stage of DIC were needed for potential therapeutic considerations. Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to use and require only platelet count, prothrombin time-international normalized ratio, and Sequential Organ Failure Assessment Score. SIC score can be used to evaluate disease severity and determine the timing of potential therapeutic interventions. One of the major disadvantages in treating sepsis-associated DIC is the lack of availability of specific therapeutic approaches beyond treating the underlying infection. Clinical trials to date have failed because included patients who were not coagulopathic. Nevertheless, in addition to infection control, anticoagulant therapy will be the choice for sepsis-associated DIC. Therefore, the efficacy of heparin, antithrombin, and recombinant thrombomodulin has to be proven in future clinical studies. Conclusion: It is necessary to develop a novel therapeutic strategy against sepsis-associated DIC and improve the outcomes. Consequently, we recommend screening and monitoring DIC using SIC scoring system.

Background: Non-ST elevation acute coronary syndrome (NSTE-ACS) is one of the most frequent manifestations of coronary artery disease. The occurrence of serious heart rhythm disorders (SHRDs) in NSTE-ACS is not well documented. However, continuous heart rhythm monitoring is recommended during the initial management of NSTE-ACS. The targeted monitoring of patients at greater risk for SHRDs could facilitate patients' care in emergency departments (EDs) where the flow of patients is continuously increasing. Methods: This retrospective single-center study included 480 patients from emergency and cardiology departments within the Strasbourg University Hospital between 1 January 2019 and 31 December 2020. The objective was to estimate the frequency of the occurrence of SHRDs among patients with NSTE-ACS. The secondary objective was to highlight the factors associated with a higher risk of SHRDs. Results: The proportion of SHRDs during the first 48 h of hospital care was 2.3% (CI95%: 1.2-4.1%, n = 11). Two time periods were considered: before coronary angiography (1.0%), and during, or after coronary angiography (1.3%). In the first group, two patients required immediate treatment (0.4% of the patients) and no death occurred. In the univariate analysis, the variables significantly associated with SHRDs were age, anticoagulant medication, a decrease in glomerular filtration rate, plasmatic hemoglobin, and left ventricle ejection fraction (LVEF), and an increase in plasmatic troponin, BNP, and CRP levels. In the multivariable analysis, plasmatic hemoglobin &gt; 12 g/dL seemed to be a protective factor for SHRDs. Conclusions: In this study, SHRDs were rare and, most often, spontaneously resolved. These data challenge the relevance of systematic rhythm monitoring during the initial management of patients with NSTE-ACS.

Aortic stenosis (AS) affects more than 10% of the population over 80 years of age and constitutes a major risk factor for heart failure, thromboembolic stroke, and death. A better understanding of the disease, including its interaction with the haemostatic system, is a prerequisite to develop prophylactic treatments. AS pathogenesis is a dynamic process involving endothelial dysfunction, inflammation, fibrosis, and calcification. Several studies support the interplay between the components of the haemostatic system such as platelets, the coagulation system, von Willebrand factor, and extracellular micro-particles at each pathophysiological stage of AS. Previous reports have evidenced persistent biological activity of the native valve after transcatheter aortic valve replacement and the subsequent development of microthrombosis that may impact the function of the newly implanted valve. Here, we review the current evidence on the interplay between AS and prothrombotic activity, and we emphasize the clinical consequences of these interactions after aortic valve replacement.

In previous reports, it has been demonstrated that cyclometalated iron(II/III) complexes can be prepared by reacting iron(0) precursors and mercurated or brominated derivatives. However, in this report, the reaction between [Fe 3 (CO) 12 ] and mercurated 6-phenyl-2,2'-bipyridine or brominated 2,6-diphenyl-pyridine pincer derivatives led to compounds in which C(sp 2 )À C(sp 2 ) bonds have been formed between two ligands. A 16-electron iron(II) complex (1Cl) bearing a tetradentate ligand originating from the dimerization of 6-phenyl-2,2'-bipyridine was isolated, while a protonated 14-membered macrocycle with [FeBr 4 ] À as counterion (2) was obtained from 2,6-diphenylpyridine. Studies by X-ray diffraction crystallography, NMR, UVvis and cyclic voltammetry confirmed the structures. Additionally, the cytotoxicity of the new compounds toward gastric cancer cell lines was evaluated, and it was established that the presence of the iron(II) center was crucial for an elevated activity.

For a better understanding of the pathophysiology of spondyloarthropathy (SpA), a detailed anatomical description of the sacroiliac joint is required because sacroiliitis is the earliest and most common sign of SpA and an essential feature for the diagnosis of ankylosing spondylitis. Beyond the anatomy, the histopathology of sacroiliac entheses and immunological mechanisms involved in sacroiliitis are crucial for a better understanding of disease causation. In this narrative review, we discuss the core anatomical, histological, and immunohistological observations involved in the development of sacroiliitis, focusing particularly on imaging-based information associated with sacroiliitis. Finally, we try to answer the question of whether at the sacroiliac joint, enthesitis precedes synovitis and subchondral bone changes in SpA.

Cardiogenic shock is usually defined as primary cardiac dysfunction with low cardiac output leading to critical organ hypoperfusion, and tissue hypoxia, resulting in high mortality rate between 40% and 50% despite recent advances. Many studies have now evidenced that cardiogenic shock not only involves systemic macrocirculation, such as blood pressure, left ventricular ejection fraction, or cardiac output, but also involves significant systemic microcirculatory abnormalities which seem strongly associated with the outcome. Although microcirculation has been widely studied in the context of septic shock showing heterogeneous alterations with clear evidence of macro and microcirculation uncoupling, there is now a growing body of literature focusing on cardiogenic shock states. Even if there is currently no consensus regarding the treatment of microcirculatory disturbances in cardiogenic shock, some treatments seem to show a benefit. Furthermore, a better understanding of the underlying pathophysiology may provide hypotheses for future studies aiming to improve cardiogenic shock prognosis.

Biological rhythms are important regulators of immune functions. In intensive care unit (ICU), sepsis is known to be associated with rhythm disruption. Our objectives were to determine factors associated with rhythm disruption of the body temperature and to assess the relationship between temperature and mortality in septic shock patients; In a cohort of septic shock, we recorded body temperature over a 24-h period on day 2 after ICU admission. For each patient, the temperature rhythmicity was assessed by defining period and amplitude, and the adjusted average (mesor) of the temperature by sinusoidal regression and cosinor analysis. Analyses were performed to assess factors associated with the three temperature parameters (period, amplitude, and mesor) and mortality. 162 septic shocks were enrolled. The multivariate analysis demonstrates that the period of temperature was associated with gender (women, coefficient −2.2 h, p = 0.031) and acetaminophen use (coefficient −4.3 h, p = 0.002). The mesor was associated with SOFA score (coefficient −0.05 °C per SOFA point, p = 0.046), procalcitonin (coefficient 0.001 °C per ng/mL, p = 0.005), and hydrocortisone use (coefficient −0.5 °C, p = 0.002). The amplitude was associated with the dialysis (coefficient −0.5 °C, p = 0.002). Mortality at day 28 was associated with lower mesor (adjusted hazard ratio 0.50, 95% CI 0.28 to 0.90; p = 0.02), and higher amplitude (adjusted hazard ratio 5.48, 95% CI 1.66 to 18.12; p = 0.005) of temperature. Many factors, such as therapeutics, influence the body temperature during septic shock. Lower mesor and higher amplitude were associated with mortality and could be considered prognostic markers in ICU. In the age of artificial intelligence, the incorporation of such data in an automated scoring alert could compete with physicians to identify high-risk patients during septic shock.

The p53 protein, known as the 'guardian of the genome', plays an important role in cancer prevention. Unfortunately, p53 mutations result in compromised activity with over 50% of cancers resulting from point mutations to p53. There is considerable interest in mutant p53 reactivation, with the development of small-molecule reactivators showing promise. We have focused our efforts on the common p53 mutation Y220C, which causes protein unfolding, aggregation, and can result in the loss of a structural Zn from the DNA-binding domain. In addition, the Y220C mutant creates a surface pocket that can be stabilized using small molecules. We previously reported the bifunctional ligand L5 as a Zn metallochaperone and reactivator of the p53-Y220C mutant. Herein we report two new ligands L5-P and L5-O that are designed to act as Zn metallochaperones and non-covalent binders in the Y220C mutant pocket. For L5-P the distance between the Zn-binding di-(2-picolyl)amine function and the pocket-binding diiodophenol was extended in comparison to L5, while for L5-O we extended the pocket-binding moiety via attachment of an alkyne function. While both new ligands displayed similar Zn-binding affinity to L5, neither acted as efficient Zn-metallochaperones. However, the new ligands exhibited significant cytotoxicity in the NCI-60 cell line screen as well as in the NUGC3 Y220C mutant cell line. We identified that the primary mode of cytotoxicity is likely reactive oxygen species (ROS) generation for L5-P and L5-O, in comparison to mutant p53 reactivation for L5, demonstrating that subtle changes to the ligand scaffold can change the toxicity pathway.

Background: Many questions remain about the appropriate use of intrauterine balloon devices in postpartum hemorrhage after vaginal delivery refractory to first-line uterotonics. Available data suggest that early use of intrauterine balloon tamponade might be beneficial. Objective: This study aimed to compare the effect of intrauterine balloon tamponade used in combination with second-line uterotonics vs intrauterine balloon tamponade used after the failure of second-line uterotonic treatment on the rate of severe postpartum hemorrhage in women with postpartum hemorrhage after vaginal delivery refractory to first-line uterotonics. Study design: This multicenter, randomized, controlled, parallel-group, nonblinded trial was conducted at 18 hospitals and enrolled 403 women who had just given birth vaginally at 35 to 42 weeks of gestation. The inclusion criteria were a postpartum hemorrhage refractory to first-line uterotonics (oxytocin) and requiring a second-line uterotonic treatment with sulprostone (E1 prostaglandin). In the study group, the sulprostone infusion was combined with intrauterine tamponade by an ebb balloon performed within 15 minutes of randomization. In the control group, the sulprostone infusion was started alone within 15 minutes of randomization, and if bleeding persisted 30 minutes after the start of sulprostone infusion, intrauterine tamponade using the ebb balloon was performed. In both groups, if the bleeding persisted 30 minutes after the insertion of the balloon, an emergency radiological or surgical invasive procedure was performed. The primary outcome was the proportion of women who either received ≥3 units of packed red blood cells or had a calculated peripartum blood loss of &gt;1000 mL. The prespecified secondary outcomes were the proportions of women who had a calculated blood loss of ≥1500 mL, any transfusion, an invasive procedure and women who were transferred to the intensive care unit. The analysis of the primary outcome with the triangular test was performed sequentially throughout the trial period. Results: At the eighth interim analysis, the independent data monitoring committee concluded that the incidence of the primary outcome did not differ between the 2 groups and stopped inclusions. After 11 women were excluded because they met an exclusion criterion or withdrew their consent, 199 and 193 women remained in the study and control groups, respectively, for the intention-to-treat analysis. The women's baseline characteristics were similar in both groups. Peripartum hematocrit level change, which was needed for the calculation of the primary outcome, was missing for 4 women in the study group and 2 women in the control group. The primary outcome occurred in 131 of 195 women (67.2%) in the study group and 142 of 191 women (74.3%) in the control group (risk ratio, 0.90; 95% confidence interval, 0.79-1.03). The groups did not differ substantially for rates of calculated peripartum blood loss pf ≥1500 mL, any transfusion, invasive procedure, and admission to an intensive care unit. Endometritis occurred in 5 women (2.7%) in the study group and none in the control group (P=.06). Conclusion: The early use of intrauterine balloon tamponade did not reduce the incidence of severe postpartum hemorrhage compared with its use after the failure of second-line uterotonic treatment and before recourse to invasive procedures. Keywords: intrauterine balloon tamponade; postpartum hemorrhage; randomized controlled trial; transfusion; uterotonics; vaginal delivery.

Background: In recent years, an increasing prevalence of obesity in inflammatory bowel disease (IBD) has been observed. However, only a few studies have focused on the impact of overweight and obesity on IBD-related disability.Aims: To identify the factors associated with obese and overweight patients with IBD, including IBD-related disability.Patients and methods: In this cross-sectional study, we included 1704 consecutive patients with IBD in 42 centres affiliated with the Groupe d'Etude Therapeutique des Affections Inflammatoires du tube Digestif (GETAID) using a 4-page questionnaire. Factors associated with obesity and overweight were assessed using univariate and multivariate analyses (odds ratios (ORs) are provided with 95% confidence intervals).Results: The prevalence rates of overweight and obesity were 24.1% and 12.2%, respectively. Multivariable analyses were stratified by age, sex, type of IBD, clinical remission and age at diagnosis of IBD. Overweight was significantly associated with male sex (OR = 0.52, 95% CI [0.39-0.68], p &lt; 0.001), age (OR = 1.02, 95% CI [1.01-1.03], p &lt; 0.001) and body image subscore (OR = 1.15, 95% CI [1.10-1.20], p &lt; 0.001) (Table 2). Obesity was significantly associated with age (OR = 1.03, 95% CI [1.02-1.04], p &lt; 0.001), joint pain subscore (OR = 1.08, 95% CI [1.02-1.14], p &lt; 0.001) and body image subscore (OR = 1.25, 95% CI [1.19-1.32], p &lt; 0.001) (Table 3).Conclusion: The increasing prevalence of overweight and obesity in patients with IBD is associated with age and poorer body image. A holistic approach to IBD patient care should be encouraged to improve IBD-related disability and to prevent rheumatological and cardiovascular complications.

Human cytomegalovirus (HCMV) infection is common and often severe in lung transplant recipients (LTRs), and it is a risk factor associated with chronic lung allograft dysfunction (CLAD). The complex interplay between HCMV and allograft rejection is still unclear. Currently, no treatment is available to reverse CLAD after diagnosis, and the identification of reliable biomarkers that can predict the early development of CLAD is needed. This study investigated the HCMV immunity in LTRs who will develop CLAD. Methods This study quantified and phenotyped conventional (HLA-A2pp65) and HLA-E-restricted (HLA-EUL40) anti-HCMV CD8 + T (CD8 T) cell responses induced by infection in LTRs developing CLAD or maintaining a stable allograft. The homeostasis of immune subsets (B, CD4T, CD8 T, NK, and γδT cells) post-primary infection associated with CLAD was also investigated. Results At M18 post-transplantation, HLA-EUL40 CD8 T responses were less frequently found in HCMV + LTRs (21.7%) developing CLAD (CLAD) than in LTRs (55%) keeping a functional graft (STABLE). In contrast, HLA-A2pp65 CD8 T was equally detected in 45% of STABLE and 47.8% of CLAD LTRs. The frequency of HLA-EUL40 and HLA-A2pp65 CD8 T among blood CD8 T cells shows lower median values in CLAD LTRs. Immunophenotype reveals an altered expression profile for HLA-EUL40 CD8 T in CLAD patients with a decreased expression for CD56 and the acquisition of PD-1. In STABLE LTRs, HCMV primary infection causes a decrease in B cells and inflation of CD8 T, CD57 + /NKG2C + NK, and δ2 − γδT cells. In CLAD LTRs, the regulation of B, total CD8 T, and δ2 + γδT cells is maintained, but total NK, CD57 + /NKG2C + NK, and δ2 − γδT subsets are markedly reduced, while CD57 is overexpressed across T lymphocytes. Conclusions CLAD is associated with significant changes in anti-HCMV immune cell responses. Our findings propose that the presence of dysfunctional HCMV-specific HLA-E-restricted CD8 T cells together with post-infection changes in the immune cell distribution affecting NK and γδT cells defines an early immune signature for CLAD in HCMV + LTRs. Such a signature may be of interest for the monitoring of LTRs and may allow an early stratification of LTRs at risk of CLAD.

Nano plastics (NPs) have been a significant threat to human health and are known to cause premature endothelial senescence. Endothelial senescence is considered one of the primary risk factors contributing to numerous cardiovascular disorders. Recent studies have suggested that inhibition of sodium glucose co-transporter (SGLT2) ameliorates endothelial senescence and dysfunction. Therefore, our study intends to explore the role of SGLT2 in NPs-induced endothelial senescence and dysfunction. Porcine coronary artery and its endothelial cells were treated with NPs in the presence or absence of Enavogliflozin (ENA), a SGLT2 inhibitor and then SGLTs expression, senescence markers and vascular function were evaluated. NPs significantly up-regulated SGLT2 and ENA significantly decreased NPs-induced senescence-associated-β-gal activity, cell-cycle arrest, and senescence markers p53 and p21 suggesting that inhibition of SGLT2 prevents NPs-induced endothelial senescence. In addition, ENA decreased the formation of reactive oxygen species with the downregulation of Nox2, and p22phox. Furthermore, SGLT2 inhibition also up regulated the endothelial nitric oxide synthase expression along with improving vascular function. In conclusion, premature endothelial senescence by NPs is, at least in part, associated with SGLT2 and it could be a potential therapeutic target for preventing and/or treating environmental pollutants-induced cardiovascular disorders mediated by endothelial senescence and dysfunction.

Background: Patients with atrial fibrillation (AF) are likely to have a poor prognosis including bleedings following transcatheter aortic valve replacement (TAVR). Closure time of adenosine diphosphate (CT-ADP) is a primary hemostasis point-of-care test and is a predictor of bleeding events following TAVR. We aimed to evaluate the impact of ongoing primary hemostatic disorders on bleeding events in TAVR patients with AF. Methods: We enrolled 878 patients from our prospective registry. The primary endpoint was VARC-2 major/life-threatening bleeding complications (MLBCs) at 1 year after TAVR and secondary endpoint was major adverse cardiac and cerebrovascular events (MACCEs) at 1 year, defined as a composite of all-cause death, myocardial infarction, stroke, and heart failure hospitalization. Ongoing primary hemostatic disorder was defined by a postprocedural CT-ADP &gt;180 seconds. Results: Patients with AF had a higher incidence of MLBCs (20 vs. 12%, p = 0.002), MACCE (29 vs. 20%, p = 0.002), and all-cause mortality (15 vs. 8%, p = 0.002) within 1 year compared to non-AF patients. When the cohort was split into four subgroups according to AF and CT-ADP &gt;180 seconds, patients with AF and CT-ADP &gt;180 seconds had the highest risk of MLBCs and MACCE. Multivariate Cox regression analysis confirmed that the patients with AF and CT-ADP &gt;180 seconds had 3.9-fold higher risk of MLBCs, whereas those patients were no longer associated with MACCE after the adjustment. Conclusion: In TAVR patients, AF with postprocedural CT-ADP &gt;180 seconds was strongly associated with MLBCs following TAVR. Our study suggests that persistent primary hemostatic disorders contribute to a higher risk of bleeding events particularly in AF patients.

PURPOSE: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. EXPERIMENTAL DESIGN: We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib. RESULTS: A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial-mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort. CONCLUSIONS: We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients' treatments. See related commentary by Zhou and Kim, p. 1170.

Aim: To investigate the impact of teleconsultation on glycemic control in patients with diabetes during the COVID-19 pandemic. Methods: In this observational prospective study, the main outcome was the comparison of glycated hemoglobin (HbA1c) between patients with or without teleconsultation at 6-month follow-up. Results: From March 17 to May 31, 2020, 610 patients were included, 456 were followed-up using Teleconsultation présent (TC+) and 154 not using No Teleconsultation (TC−). Patients of TC+ Group were younger, 57 ± 17 versus 65 ± 15.5 years (p &lt; 0.001), with a lower body mass index, 28 ± 6.2 kg/m2 versus 30 ± 5.8 kg/m2, compared to those of TC− Group (p &lt; 0.001). HbA1c were comparable between the two groups: 7.35 ± 0.27% for TC+ versus 7.48 ± 0.22% for TC− Group. At 6-month follow-up, HbA1c was lower in TC+ versus TC− Group: 7.21 ± 0.15% versus 7.6 ± 0.18% (p = 0.004). Conclusion: Our findings point toward the feasibility and usefulness of teleconsultation for the follow-up of patients with diabetes in such exceptional circumstances.

Background: Identifying the 30% of adhesive small bowel obstructions (aSBO) for which conservative management will require surgery is essential. The association between the previously described radiological score and failure of the conservative management of aSBO remains to be confirmed in a large prospective multicentric cohort. Our aim was to assess the risk factors of failure of the conservative management of aSBO considering the radiological score.Material and methods: This prospective observational study took place in 15 French centers over 3 months. Consecutive patients experiencing aSBO with no early surgery were included. The six radiological features from the Angers radiological computed tomography (CT) score were noted (beak sign, closed loop, focal or diffuse intraperitoneal liquid, focal or diffuse mesenteric haziness, focal or diffuse mesenteric liquid, and diameter of the most dilated small bowel loop &gt; 40 mm).Results: Two hundred and seventy nine patients with aSBO were screened. Sixty patients (21.5%) underwent early surgery, and 219 (78.5%) had primary conservative management. In the end, 218 patients were included in the analysis of the risk factors for conservative treatment failure. Among them, 162 (74.3%) had had successful management while for 56 (25.7%) management had failed. In multivariate analysis, a history of surgery was not a significant risk factor for the failure of conservative treatment (OR = 0.11; 95%CI = 0-1.23). A previous episode of aSBO was protective against the failure of conservative treatment (OR = 0.36; 95%CI = 0.15-0.85) and an Angers CT score ≥ 5 as the only individual risk factor (OR = 2.39; 95%CI = 1.01-5.69).Conclusion: The radiological score of aSBO is a promising tool in improving the management of aSBO patients. A first episode of aSBO and/or a radiological score ≥5 should lead physicians to consider early surgical management.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease mainly characterized by the hepatic accumulation of lipid inducing a deregulation of β-oxidation. Its advanced form is non-alcoholic steatohepatitis (NASH), which, in addition to lipid accumulation, induces hepatocellular damage, oxidative stress and fibrosis that can progress to cirrhosis and to its final stage: hepatocellular carcinoma (HCC). To date, no specific therapeutic treatment exists. The implications of organ crosstalk have been highlighted in many metabolic disorders, such as diabetes, metabolic-associated liver diseases and obesity. Skeletal muscle, in addition to its role as a reservoir and consumer of energy and carbohydrate metabolism, is involved in this inter-organs’ communication through different secreted products: myokines, exosomes and enzymes, for example. Interestingly, resistance exercise has been shown to have a beneficial impact on different metabolic pathways, such as lipid oxidation in different organs through their secreted products. In this review, we will mainly focus on myokines and their effects on non-alcoholic fatty liver disease, and their complication: non-alcoholic steatohepatitis and HCC.

Background: Fatigue is commonly reported by patients with inflammatory bowel disease [IBD], but the determinants of IBD-related fatigue have yet to be determined. Aims: To identify the factors associated with fatigue in a large population of patients with IBD. Patients and methods: Fatigue and nine other IBD-related disability dimensions were assessed in a cohort of 1704 consecutive patients with IBD using the IBD-disk questionnaire in a cross-sectional survey of 42 French and Belgian centres. Fatigue and severe fatigue were defined as energy subscores &gt;5 and &gt;7, respectively. Determinants of fatigue were assessed using univariate and multivariate analyses (odds ratios [ORs] are provided with 95% confidence intervals). Results: The prevalence rates of fatigue and severe fatigue were 54.1% and 37.1%, respectively. Both fatigue and severe fatigue were significantly higher in patients with active disease than in patients with inactive disease [64.9% vs 44.7% and 47.4% vs 28.6%, respectively; p &lt; 0.001 for both comparisons]. In the multivariate analysis stratified by age, sex, type of IBD and IBD activity, fatigue was associated with age &gt;40 years (OR = 0.71 [0.54-0.93]), female sex (OR = 1.48 [1.13-1.93]) and IBD-related sick leave (OR = 1.61 [1.19-2.16]), and joint pain (OR = 1.60 [1.17-2.18]), abdominal pain (OR = 1.78 [1.29-2.45]), regulating defecation (OR = 1.67 [1.20-2.32]), education and work (OR = 1.96 [1.40-2.75]), body image (OR = 1.38 [1.02-1.86]), sleep (OR = 3.60 [2.66-4.88]) and emotions (OR = 3.60 [2.66-4.88]) subscores &gt;5. Conclusion: Determinants of fatigue are not restricted to IBD-related factors but also include social factors, sleep and emotional disturbances, thus supporting a holistic approach to IBD patient care.

Health care systems worldwide have been battling the ongoing COVID-19 pandemic. Since the beginning of the COVID-19 pandemic, Lymphocytes and CRP have been reported as markers of interest. We chose to investigate the prognostic value of the LCR ratio as a marker of severity and mortality in COVID-19 infection. Between 1 March and 30 April 2020, we conducted a multicenter, retrospective cohort study of patients with moderate and severe coronavirus disease 19 (COVID-19), all of whom were hospitalized after being admitted to the Emergency Department (ED). We conducted our study in six major hospitals of northeast France, one of the outbreak's epicenters in Europe. A total of 1035 patients with COVID-19 were included in our study. Around three-quarters of them (76.2%) presented a moderate form of the disease, while the remaining quarter (23.8%) presented a severe form requiring admission to the ICU. At ED admission, the median LCR was significantly lower in the group presenting severe disease compared to that with moderate disease (versus 6.24 (3.24-12) versus 12.63 ((6.05-31.67)), p &lt; 0.001). However, LCR was neither associated with disease severity (OR: 0.99, CI 95% (0.99-1)), p = 0.476) nor mortality (OR: 0.99, CI 95% (0.99-1)). In the ED, LCR, although modest, with a threshold of 12.63, was a predictive marker for severe forms of COVID-19.

Background: Limitations of life-sustaining therapies (LST) practices are frequent and vary among intensive care units (ICUs). However, scarce data were available during the COVID-19 pandemic when ICUs were under intense pressure. We aimed to investigate the prevalence, cumulative incidence, timing, modalities, and factors associated with LST decisions in critically ill COVID-19 patients. Methods: We did an ancillary analysis of the European multicentre COVID-ICU study, which collected data from 163 ICUs in France, Belgium and Switzerland. ICU load, a parameter reflecting stress on ICU capacities, was calculated at the patient level using daily ICU bed occupancy data from official country epidemiological reports. Mixed effects logistic regression was used to assess the association of variables with LST limitation decisions. Results: Among 4671 severe COVID-19 patients admitted from February 25 to May 4, 2020, the prevalence of in-ICU LST limitations was 14.5%, with a nearly six-fold variability between centres. Overall 28-day cumulative incidence of LST limitations was 12.4%, which occurred at a median of 8 days (3-21). Median ICU load at the patient level was 126%. Age, clinical frailty scale score, and respiratory severity were associated with LST limitations, while ICU load was not. In-ICU death occurred in 74% and 95% of patients, respectively, after LST withholding and withdrawal, while median survival time was 3 days (1-11) after LST limitations. Conclusions: In this study, LST limitations frequently preceded death, with a major impact on time of death. In contrast to ICU load, older age, frailty, and the severity of respiratory failure during the first 24 h were the main factors associated with decisions of LST limitations.

Background : Chronic lung allograft dysfunction (CLAD) is the leading cause of poor long-term survival after lung transplantation (LT). Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) aimed to predict CLAD. Methods : To predict CLAD, we investigated the clinicome of patients with LT; the exposome through assessment of airway microbiota in bronchoalveolar lavage cells and air pollution studies; the immunome with works on activation of dendritic cells, the role of T cells to promote the secretion of matrix metalloproteinase-9, and subpopulations of T and B cells; genome polymorphisms; blood transcriptome; plasma proteome studies and assessment of MSK1 expression. Results : Clinicome: the best multivariate logistic regression analysis model for early-onset CLAD in 422 LT eligible patients generated a ROC curve with an area under the curve of 0.77. Exposome: chronic exposure to air pollutants appears deleterious on lung function levels in LT recipients (LTRs), might be modified by macrolides, and increases mortality. Our findings established a link between the lung microbial ecosystem, human lung function, and clinical stability post-transplant. Immunome: a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and associated with a higher level of interleukin 17A; Immune cells support airway remodeling through the production of plasma MMP-9 levels, a potential predictive biomarker of CLAD. Blood CD9-expressing B cells appear to favor the maintenance of long-term stable graft function and are a potential new predictive biomarker of BOS-free survival. An early increase of blood CD4 + CD57 + ILT2+ T cells after LT may be associated with CLAD onset. Genome: Donor Club cell secretory protein G38A polymorphism is associated with a decreased risk of severe primary graft dysfunction after LT. Transcriptome: blood POU class 2 associating factor 1, T-cell leukemia/lymphoma domain, and B cell lymphocytes, were validated as predictive biomarkers of CLAD phenotypes more than 6 months before diagnosis. Proteome: blood A2MG is an independent predictor of CLAD, and MSK1 kinase overexpression is either a marker or a potential therapeutic target in CLAD. Conclusion : Systems prediction of Chronic Lung Allograft Dysfunction generated multiple fingerprints that enabled the development of predictors of CLAD. These results open the way to the integration of these fingerprints into a predictive handprint.

Background Prognostic assessment in patients undergoing cancer treatments is of paramount importance to plan subsequent management. In resectable lung cancer availability of an easy-to use nomogram to predict long-term outcome would be extremely useful to identify high-risk patients in the era of perioperative targeted and immune therapies. Methods We retrieved clinical, surgical and pathological data of all consecutive patients included in Epithor, the database of French Society of Thoracic and Cardiovascular Surgery, and operated on between 2003 and 2020 for non-small cell lung cancer in a curative intent. The primary endpoint was overall survival up to 5 years. We assessed prognostic significance of available variables using Cox modelling, in the whole dataset, and in men and in women separately, and performed temporal validation. Finally, we constructed two sex-specific nomograms. Survivals by fifths of score were assessed in the development and temporal validation sets. Findings The study included 62,633 patients (43,551 men and 19,082 women). Median survival time was 9.2 years. Nine factors had strong prognostic impact and were used to construct nomograms. The optimism-corrected c statistic for the prognostic score was 0.689 in the development sample, and 0.726 (95% CI 0.718–0.735) in the temporal validation sample. All differences between adjacent fifths of score were significant (P < 0.0001). Figures of 3-year OS by fifths of score were 92.2%, 83.0%, 74.3%, 64.0%, and 43.4%, respectively, in the development set and 93.3%, 88.4%, 81.0%, 73.7%, 55.7% in the temporal validation set. Performance of score was maintained when stratifying by stage of diseases. Interpretation In the present work, we report evidence that long-term overall survival after resection of NSCLC can be predicted by an easy to construct and use composite score taking into account both host and tumour related factors. Funding Epithor is funded by FSTCVS.

Introduction: Both non-contrast Computed Tomography (CT) and ultrasound (US) are used for the diagnosis of renal colic in the emergency department (ED). Although US reduces radiation exposure, its diagnostic accuracy is inferior to that of CT. In this context, data regarding the cost and organizational impact of these strategies represent essential elements in the choice of imaging; however, they remain poorly documented. Aim of the study The aim of this study was to compare the costs and effectiveness of diagnostic workup by US and CT for patients consulting with renal colic in the ED. Methods: We conducted a monocentric real-life retrospective study of patients consulting for a renal colic in an ED between 1 July 2018 and 31 December 2018. We estimated length of stay (LOS), total hospital costs at 60 days including ED, and initial and repeat admissions. Patients with initial US in the ED were compared to patients with initial CT using inverse probability weighting of the propensity score calculated from demographic variables, vital parameters, and clinical presentation. We calculated the incremental cost effectiveness ratio as the difference in costs by the difference in LOS. The variability of the results was assessed using non-parametric bootstrapping. Results: In this study, of the 273 patients included, 67 were patients assessed with US and 206 with CT. The average costs were €1159 (SD 1987) and €956 (SD 1462) for US and CT, respectively, and the ED LOS was 8.9 [CI 95% 8.1; 9.4] and 8.7 [CI 95% 7.9; 9.9] hours for US and CT, respectively. CT was associated with a decreased LOS by 0.139 [CI 95% -1.1; 1.5] hours and was cost-saving, with a €199 [CI 95% -745; 285] reduction per patient. Conclusion: When imaging is required in the ED for suspected renal colic as recommended, there is real-life evidence that CT is a cost-effective strategy compared to US, reducing costs and LOS in the ED.

The fundamental purpose of this study was to develop a stable lyophilised finasteride nanosystem (FNS-NS) for topical delivery. The FNS-NS was fabricated using an ultrasonication technique. The impact of two different cryoprotectants on the physicochemical characteristics of FNS-NS before and after lyophilisation was thoroughly investigated. The lyophilised FNS-NS had spherical shape with particle size lied between 188.6 nm ± 4.4 and 298.7 nm ± 4.7, low PDI values (0.26 ± 0.02 to 0.32 ± 0.02) and zeta potential ranging from −38.3 to +53.3 mV. The confocal laser microscopy depicted a comparatively higher cellular internalisation achieved for undecorated FNS-NS with respect to its chitosan-decorated counterpart. The lyophilised FNS-NS was stable for 90 days at proper storage conditions. The FNS-NS with 15% trehalose had appropriate physicochemical attributes that could be a promising carrier for topical delivery to treat androgenic alopecia.

Aim: The aim of this in vivo study was to compare the clinical trueness of primary mucostatic impressions obtained either by a classical alginate technique or by an optical intraoral scanner of fully maxilla edentulous patients. Materials and methods: 30 patients with fully edentulous maxilla were included and underwent conventional impressions as well as intraoral optical impressions (TRIOS 3®, 3Shape®). The conventional impressions were casted and the resulting stone models were digitized using a desktop scanner (Iscan D104i®, Imetric®). These digitized impressions were superimposed over the optical impressions to compare differences between the two datasets. Statistical analyses were performed to identify relevant deviations. Result: For the 30 intraoral impressions, 80.88% of the surface areas were below the tolerance threshold of 25 μm and thus considered similar to the area scanned with the desktop scanner from the reference stone model. Interestingly, the differences (19.12% of the surfaces) were localized in depressible areas like vestibule, soft palate, incisal papilla and flabby ridge. These locations were coherent with the positive mean of differences of +22.8μm, indicating deformation or less compression using the intraoral scanner. Conclusion: Digital primary impression of the fully edentulous maxilla can be considered as similar to the conventional alginate impression, except in the depressible areas. Considering the mucostatic objective of such a primary impression, one may consider optical impression as more accurate than the conventional one. Keywords: clinical trial; conventional impression; digital impression; edentulous patients; intraoral scanner; maxilla.

Background: In critically ill patients, positive fluid balance is associated with excessive mortality. The POINCARE-2 trial aimed to assess the effectiveness of a fluid balance control strategy on mortality in critically ill patients. Methods: POINCARE-2 was a stepped wedge cluster open-label randomized controlled trial. We recruited critically ill patients in twelve volunteering intensive care units from nine French hospitals. Eligible patients were ≥ 18 years old, under mechanical ventilation, admitted to one of the 12 recruiting units for &gt; 48 and ≤ 72 h, and had an expected length of stay after inclusion &gt; 24 h. Recruitment started on May 2016 and ended on May 2019. Of 10,272 patients screened, 1361 met the inclusion criteria and 1353 completed follow-up. The POINCARE-2 strategy consisted of a daily weight-driven restriction of fluid intake, diuretics administration, and ultrafiltration in case of renal replacement therapy between Day 2 and Day 14 after admission. The primary outcome was 60-day all-cause mortality. We considered intention-to-treat analyses in cluster-randomized analyses (CRA) and in randomized before-and-after analyses (RBAA). Results: A total of 433 (643) patients in the strategy group and 472 (718) in the control group were included in the CRA (RBAA). In the CRA, mean (SD) age was 63.7 (14.1) versus 65.7 (14.3) years, and mean (SD) weight at admission was 78.5 (20.0) versus 79.4 (23.5) kg. A total of 129 (160) patients died in the strategy (control) group. Sixty-day mortality did not differ between groups [30.5%, 95% confidence interval (CI) 26.2-34.8 vs. 33.9%, 95% CI 29.6-38.2, p = 0.26]. Among safety outcomes, only hypernatremia was more frequent in the strategy group (5.3% vs. 2.3%, p = 0.01). The RBAA led to similar results. Conclusion: The POINCARE-2 conservative strategy did not reduce mortality in critically ill patients. However, due to open-label and stepped wedge design, intention-to-treat analyses might not reflect actual exposure to this strategy, and further analyses might be required before completely discarding it. Trial registration POINCARE-2 trial was registered at ClinicalTrials.gov (NCT02765009). Registered 29 April 2016.

No abstract available

The identity and role of environmental factors in the etiology of sporadic amyotrophic lateral sclerosis (sALS) is poorly understood outside of three former high-incidence foci of Western Pacific ALS and a hotspot of sALS in the French Alps. In both instances, there is a strong association with exposure to DNA-damaging (genotoxic) chemicals years or decades prior to clinical onset of motor neuron disease. In light of this recent understanding, we discuss published geographic clusters of ALS, conjugal cases, single-affected twins, and young-onset cases in relation to their demographic, geographic and environmental associations but also whether, in theory, there was the possibility of exposure to genotoxic chemicals of natural or synthetic origin. Special opportunities to test for such exposures in sALS exist in southeast France, northwest Italy, Finland, the U.S. East North Central States, and in the U.S. Air Force and Space Force. Given the degree and timing of exposure to an environmental trigger of ALS may be related to the age at which the disease is expressed, research should focus on the lifetime exposome (from conception to clinical onset) of young sALS cases. Multidisciplinary research of this type may lead to the identification of ALS causation, mechanism, and primary prevention, as well as to early detection of impending ALS and pre-clinical treatment to slow development of this fatal neurological disease.

Aim: To evaluate (1) whether periodontitis has an influence on the prevalence/ incidence of respiratory diseases (chronic obstructive pulmonary disease [COPD], asthma, community-acquired pneumonia [CAP], obstructive sleep apnoea [OSA] and COVID-19), and ( 2) what is the impact of periodontal therapy on the onset or progression of respiratory diseases.<p>Materials and Methods: An electronic search was performed on Pubmed, Cochrane Library and Scopus databases up to October 2021, to identify studies answering the PECOS and PICOS questions.</p><p>Results: Seventy-five articles were selected. Meta-analyses identified statistically significant associations of periodontitis with COPD (n studies = 12, odds ratio [OR] = 1.28, 95% confidence interval [CI] [1.16; 1.42], p &lt; .001), and OSA (n s = 6, OR = 1.65, 95% CI [1.21; 2.25], p = .001), but not for asthma (n s = 9, OR = 1.53, 95% CI [0.82; 2.86], p = .181). For acute conditions, two studies were found for CAP, while for COVID-19, significant associations were found for the need of assisted ventilation (n s = 2, OR = 6.24, 95% CI [2.78; 13.99], p &lt; .001) and COVID-related mortality (n s = 3, OR = 2.26, 95% CI [1.36, 3.77], p = .002). Only four intervention studies were found, showing positive effects of periodontal treatment on COPD, asthma and CAP.</p><p>Conclusions: A positive association between periodontitis and COPD, OSA and COVID-19 complications has been found, while there is a lack of intervention studies.</p>

BACKGROUND: Several studies have reported an increased risk of thrombotic events in COVID-19 patients, but the pathophysiology of this procoagulant phenotype remains poorly understood. We hypothesized that corticosteroids may attenuate this procoagulant state through their anti-inflammatory effects. The aim of this study was to evaluate the impact of dexamethasone (DXM) on the coagulation profile of severely ill COVID-19 patients. METHODS: We conducted a retrospective, observational before/after bi-centric cohort study among ICU patients hospitalized for severe COVID-19 and receiving therapeutic anticoagulation by unfractionated heparin (UFH). Before and after the standardized use of DXM, we compared inflammatory and coagulation profiles, as well as the kinetics of heparin requirement, adjusted for weight and anti-Xa activity. RESULTS: Eighty-six patients were included, 35 in the no-DXM group, and 51 in the DXM group. At admission, CRP and fibrinogen levels were not different between groups, neither were UFH infusion rates. At day 3 after ICU admission, CRP (178±94 mg/L vs. 99±68 mg/L, P&lt;0.001) and fibrinogen (7.2±1.4 g/L vs. 6.1±1.4 g/L, P=0.001) significantly decreased in the DXM group, but not in the no-DXM group. Over time, UFH infusion rates were lower in the DXM group (P&lt;0.001) without any significant difference in plasma anti-Xa activity. CRP variations correlated with heparin dose variations between Day 0 and Day 3 (r=0.39, P=0.009). Finally, the incidence of venous thromboembolic events during in-ICU stay was significantly reduced in the DXM group (4 vs. 43%, P&lt;0.0001). CONCLUSIONS: In critically ill COVID-19 patients, dexamethasone use was associated with a decrease in both pro-inflammatory and procoagulant profile.

Microvesicles (MVs) are key markers in human body fluids that reflect cellular activation related to diseases as thrombosis. These MVs display phosphatidylserine at the outer leaflet of their plasma membrane as specific recognition moieties. The work reported in this manuscript focuses on the development of an original method where MVs are captured by bimetallic zinc complexes. A set of ligands have been synthetized based on a phenol spacer bearing in para position an amine group appended to a short or a longer alkyl chain (for grafting on surface) and bis(dipicolylamine) arms in ortho position (for zinc coordination). The corresponding dibridged zinc phenoxido and hydroxido complexes have been prepared in acetronitrile in presence of triethylamine and characterized by several spectroscopic techniques. The pH-driven interconversion studies for both complexes in H2O:DMSO (70:30) evidence that at physiologic pH the main species are mono-bridged by the phenoxido spacer. An X-Ray structure obtained from complex 2 (based on the ligand with the amine group on the short chain) in aqueous medium confirms the presence of a mono-bridged complex. Then, the complexes have been used for interaction studies with short-chain phospholipids. Both have established the selective recognition of the anionic phosphatidylserine model versus zwitterionic phospholipids (in solution by 31P NMR and after immobilization on solid support by surface plasmon resonance (SPR)). Moreover, both complexes have also demonstrated their ability to capture MVs isolated from human plasma. These complexes are thus promising candidates for MVs probing by a new approach based on coordination chemistry.

No abstract available

Renal-cell carcinoma (RCC) accounts for 2% of cancer diagnoses and deaths worldwide. Clear-cell RCCs represent the vast majority (85%) of kidney cancers and are considered morphologically and genetically as immunogenic tumors. Indeed, the RCC tumoral microenvironment comprises T cells and myeloid cells in an immunosuppressive state, providing an opportunity to restore their activity through immunotherapy. Standard first-line systemic treatment for metastatic patients includes immune-checkpoint inhibitors (ICIs) targeting PD1, in combination with either another ICI or with antiangiogenic targeted therapy. During the past few years, several combinations have been approved with an overall survival benefit and overall response rate that depend on the combination. Interestingly, some patients achieve prolonged complete responses, raising the question of whether these metastatic RCC patients can be cured. This review will focus on recent therapeutic advances in RCC and the clinical and biological aspects underpinning the potential for healing.

Question addressed by the study: Do three coronavirus disease 2019 (COVID-19) vaccine doses induce a serological response in lung transplant recipients? Methods: We retrospectively included 1071 adults (551 (52%) males) at nine transplant centres in France. Each had received three COVID-19 vaccine doses in 2021, after lung transplantation. An anti-spike protein IgG response, defined as a titre &gt;264 BAU·mL −1 after the third dose (median (interquartile range (IQR)) 3.0 (1.7–4.1) months), was the primary outcome and adverse events were the secondary outcomes. Median (IQR) age at the first vaccine dose was 54 (40–63) years and median (IQR) time from transplantation to the first dose was 64 (30–110) months. Results: Median (IQR) follow-up after the first dose was 8.3 (6.7–9.3) months. A vaccine response developed in 173 (16%) patients. Factors independently associated with a response were younger age at vaccination, longer time from transplantation to vaccination and absence of corticosteroid or mycophenolate therapy. After vaccination, 51 (5%) patients (47 non-responders (47/898 (5%)) and four (4/173 (2%)) responders) experienced COVID-19, at a median (IQR) of 6.6 (5.1–7.3) months after the third dose. No responders had severe COVID-19 compared with 15 non-responders, including six who died of the disease. Conclusions Few lung transplant recipients achieved a serological response to three COVID-19 vaccine doses, indicating a need for other protective measures. Older age and use of mycophenolate or corticosteroids were associated with absence of a response. The low incidence of COVID-19 might reflect vaccine protection via cellular immunity and/or good adherence to shielding measures.

Background and objectives: Venous thromboembolism (VTE) represents a health and economic burden with consequent healthcare resource utilization. Direct oral anticoagulants (DOACs) have emerged as the mainstay option for VTE treatment but few data exist on their cost-effectiveness as compared to the standard therapy (vitamin K antagonists (VKAs)). This study aimed to assess the cost-effectiveness of rivaroxaban compared to VKAs in VTE treatment by calculating the incremental cost effectiveness ratio (ICER). Materials and methods: We conducted a prospective observational study based on the REMOTEV registry, including patients hospitalized for VTE from 23 October 2013 to 31 July 2015, to evaluate the impact of the anticoagulant treatment (DOACs versus VKAs) on 6-month complications: major or clinically relevant non-major bleeding, VTE recurrence and all-cause death. Rivaroxaban was the only DOAC prescribed in this study. The ICER was calculated as the difference in costs divided by the difference in effectiveness. Results: Among the 373 patients included, 279 were treated with rivaroxaban (63.1 ± 17.9 years old; 49% men) and 94 with VKAs (71.3 ± 16.6 years old; 46% men). The mean cost was EUR 5662 [95% CI 6606; 9060] for rivaroxaban and EUR 7721 [95% CI 5130; 6304] for VKAs, while effectiveness was 0.0586 95% CI [0.0114; 0.126] for DOACs and 0.0638 [95% CI 0.0208; 0.109] for VKAs. The rivaroxaban treatment strategy was dominant with costs per patient EUR 2059 lower [95% CI −3582; −817] and a higher effectiveness of 0.00527 [95% CI −0.0606; 0.0761] compared to VKAs. Conclusions: This study provides real-world evidence that rivaroxaban is not only an efficient and safe alternative to VKAs for eligible VTE patients, but also cost-saving.

Invasive fungal infections caused by Candida species remain a significant public health problem worldwide. The increasing prevalence of drug-resistant infections and a limited arsenal of antifungal drugs underscore the need for novel interventions. Here, we screened several classes of pharmacologically active compounds against mammalian diseases for antifungal activity. We found that the synthetic triazine-based compound melanogenin (Mel) 56 is fungicidal in Candida albicans laboratory and clinical strains with minimal inhibitory concentrations of 8-16 µg/mL. Furthermore, Mel56 has general antifungal activity in several non-albicans&amp;nbsp;Candida species and the non-pathogenic yeast Saccharomyces cerevisiae. Surprisingly, Mel56 inhibited the yeast-to-hyphae transition at sublethal concentrations, revealing a new role for triazine-based compounds in fungi. In human cancer cell lines, Mel56 targets the inner mitochondrial integral membrane prohibitin proteins, PHB1 and PHB2. However, Mel56 treatment did not impact C. albicans mitochondrial activity, and antifungal activity was similar in prohibitin single, double, and triple homozygous mutant strains compared to the wild-type parental strain. These results suggests that Mel56 has a novel mechanism-of-action in C. albicans. Therefore, Mel56 is a promising antifungal candidate warranting further analyses.

Background: Timely management of acute myocardial infarction (AMI) and acute stroke has undergone impressive progress during the last decade. However, it is currently unknown whether both sexes have profited equally from improved strategies. We sought to analyze sex-specific temporal trends in intensive care unit (ICU) admission and mortality in younger patients presenting with AMI or stroke in Switzerland. Methods: Retrospective analysis of temporal trends in 16,954 younger patients aged 18 to ≤ 52 years with AMI or acute stroke admitted to Swiss ICUs between 01/2008 and 12/2019. Results: Over a period of 12 years, ICU admissions for AMI decreased more in women than in men (− 6.4% in women versus − 4.5% in men, p &lt; 0.001), while ICU mortality for AMI significantly increased in women (OR 1.2 [1.10–1.30], p = 0.032), but remained unchanged in men (OR 0.99 [0.94–1.03], p = 0.71). In stroke patients, ICU admission rates increased between 3.6 and 4.1% per year in both sexes, while ICU mortality tended to decrease only in women (OR 0.91 [0.85–0.95, p = 0.057], but remained essentially unaltered in men (OR 0.99 [0.94–1.03], p = 0.75). Interventions aimed at restoring tissue perfusion were more often performed in men with AMI, while no sex difference was noted in neurovascular interventions. Conclusion: Sex and gender disparities in disease management and outcomes persist in the era of modern interventional neurology and cardiology with opposite trends observed in younger stroke and AMI patients admitted to intensive care. Although our study has several limitations, our data suggest that management and selection criteria for ICU admission, particularly in younger women with AMI, should be carefully reassessed.

PURPOSE Universal cancer peptide–based vaccine (UCPVax) is a therapeutic vaccine composed of two highly selected helper peptides to induce CD4+ T helper-1 response directed against telomerase. This phase Ib/IIa trial was designed to test the safety, immunogenicity, and efficacy of a three-dose schedule in patients with metastatic non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with refractory NSCLC were assigned to receive three vaccination doses of UCPVax (0.25 mg, 0.5 mg, and 1 mg) using a Bayesian-based phase Ib followed by phase IIa de-escalating design. The primary end points were dose-limiting toxicity and immune response after three first doses of vaccine. Secondary end points were overall survival (OS) and progression-free survival at 1 year. RESULTS A total of 59 patients received UCPVax; 95% had three prior lines of systemic therapy. No dose-limiting toxicity was observed in 15 patients treated in phase Ib. The maximum tolerated dose was 1 mg. Fifty-one patients were eligible for phase IIa. The third and sixth dose of UCPVax induced specific CD4+ T helper 1 response in 56% and 87.2% of patients, respectively, with no difference between three dose levels. Twenty-one (39%) patients achieved disease control (stable disease, n = 20; complete response, n = 1). The 1-year OS was 34.1% (95% CI, 23.1 to 50.4), and the median OS was 9.7 months, with no significant difference between dose levels. The 1-year progression-free survival and the median OS were 17.2% (95% CI, 7.8 to 38.3) and 11.6 months (95% CI, 9.7 to 16.7) in immune responders ( P = .015) and 4.5% (95% CI, 0.7 to 30.8) and 5.6 months (95% CI, 2.5 to 10) in nonresponders ( P = .005), respectively. CONCLUSION UCPVax was highly immunogenic and safe and provide interesting 1-year OS rate in heavily pretreated advanced NSCLC.

Background: The number of heatstroke victims hit record numbers in 2022 as global warming continues. In heat-induced injuries, circulatory shock is the most severe and deadly complication. This review aims to examine the mechanisms and potential approaches to heat-induced shock and the life-threatening complications of heatstroke. Methods: A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning heatstroke, shock, inflammation, coagulopathy, endothelial cell, cell death, and heat shock proteins. Results: Dehydration and heat-induced cardiomyopathy were reported as the major causes of heat-induced shock, although other heat-induced injuries are also involved in the pathogenesis of circulatory shock. In addition to dehydration, the blood volume decreases considerably due to the increased vascular permeability as a consequence of endothelial damage. Systemic inflammation is induced by factors that include elevated cytokine and chemokine levels, dysregulated coagulation/fibrinolytic responses, and the release of damage-associated molecular patterns (DAMPs) from necrotic cell death that cause distributive shock. The cytoprotective heat shock proteins can also facilitate circulatory disturbance under excess heat stress. Conclusions: Multiple mechanisms are involved in the pathogenesis of heat-induced shock. In addition to dehydration, heat stress-induced cardiomyopathy due to the thermal damage of mitochondria, upregulated inflammation via damage-associated molecular patterns released from oncotic cells, unbalanced coagulation/fibrinolysis, and endothelial damage are the major factors that are related to circulatory shock.

Introduction: Primary Failure of Eruption (PFE) is a rare condition affecting posterior teeth eruption resulting in a posterior open bite malocclusion. Differential diagnosis like ankylosis or mechanical eruption failure should be considered. For non-syndromic forms, mutations in PTH1R, and recently in KMT2C genes are the known etiologies. The aim of this work was to describe the variability of clinical presentations of PFE associated with pathogenic variants of PTHR1. Material and methods: Diagnosis of non-syndromic PFE has been suggested for three members of a single family. Clinical and radiological features were collected, and genetic analyses were performed. Results: The clinical phenotype (type and number of involved teeth, depth of bone inclusions, functional consequences) is variable within the family. Severe tooth resorptions were detected. A heterozygous substitution in PTH1R (NM_000316.3): c.899T > C was identified as a class 4 likely pathogenic variant. The multidisciplinary management is described involving oral biology, pediatric dentistry, orthodontics, oral surgery, and prosthodontics. Conclusion: In this study, we report a new PTH1R variant involved in a familial form of PFE with variable expressivity. Therapeutic care is complex and difficult to systematize, hence the lack of evidence-based recommendations and clinical guidelines.

Purpose:: Occult lymph node involvement is a major issue in the management of non-small cell lung carcinoma (NSCLC), with an estimated prevalence of approximately 2.9–21.6% in 18F-FDG PET/CT series. The aim of the study is to construct a PET model to improve lymph node assessment. Methods:: Patients with a non-metastatic cT1 NSCLC were retrospectively included from two centers, one used to constitute the training set, the other for the validation set. The best multivariate model based on Akaike’s information criterion was selected, considering age, sex, visual assessment of lymph node (cN0 status), lymph node SUVmax, primary tumor location, tumor size, and tumoral SUVmax (T_SUVmax). A threshold minimizing false pN0 prediction was chosen. This model was then applied to the validation set. Results:: In total, 162 patients were included (training set: 44, validation set: 118). A model combining cN0 status and T_SUVmax was selected (AUC 0.907, specificity at threshold: 88.2%). In the validation cohort, this model resulted in an AUC of 0.832 and a specificity of 92.3% versus 65.4% for visual interpretation alone (p = 0.02). A total of two false N0 predictions were noted (1 pN1 and 1 pN2). Conclusion:: Primary tumor SUVmax improves N status prediction and could allow a better selection of patients who are candidates for minimally invasive approaches.

During hemorrhagic shock, blood loss causes a fall in blood pressure, decreases cardiac output, and, consequently, O2 transport. The current guidelines recommend the administration of vasopressors in addition to fluids to maintain arterial pressure when life-threatening hypotension occurs in order to prevent the risk of organ failure, especially acute kidney injury. However, different vasopressors exert variable effects on the kidney, depending on the nature and dose of the substance chosen as follows: Norepinephrine increases mean arterial pressure both via its α-1-mediated vasoconstriction leading to increased systemic vascular resistance and its β1-related increase in cardiac output. Vasopressin, through activation of V1-a receptors, induces vasoconstriction, thus increasing mean arterial pressure. In addition, these vasopressors have the following different effects on renal hemodynamics: Norepinephrine constricts both the afferent and efferent arterioles, whereas vasopressin exerts its vasoconstrictor properties mainly on the efferent arteriole. Therefore, this narrative review discusses the current knowledge of the renal hemodynamic effects of norepinephrine and vasopressin during hemorrhagic shock.

Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely due to the downfall of peripheral arterial resistance through direct or indirect effects on adrenergic signaling. TTX is a high-affinity blocker of voltage-gated Na+ (NaV) channels. In arteries, NaV channels are expressed in sympathetic nerve endings, both in the intima and media. In this present work, we aimed to decipher the role of NaV channels in vascular tone using TTX. We first characterized the expression of NaV channels in the aorta, a model of conduction arteries, and in mesenteric arteries (MA), a model of resistance arteries, in C57Bl/6J mice, by Western blot, immunochemistry, and absolute RT-qPCR. Our data showed that these channels are expressed in both endothelium and media of aorta and MA, in which scn2a and scn1b were the most abundant transcripts, suggesting that murine vascular NaV channels consist of NaV1.2 channel subtype with NaVβ1 auxiliary subunit. Using myography, we showed that TTX (1 µM) induced complete vasorelaxation in MA in the presence of veratridine and cocktails of antagonists (prazosin and atropine with or without suramin) that suppressed the effects of neurotransmitter release. In addition, TTX (1 µM) strongly potentiated the flow-mediated dilation response of isolated MA. Altogether, our data showed that TTX blocks NaV channels in resistance arteries and consecutively decreases vascular tone. This could explain the drop in total peripheral resistance observed during mammal tetrodotoxications.

Within the life-cycle assessment of health technologies, real-world data (RWD) have until now been of secondary importance to clinical trial data. The availability of massive, better quality RWD, particularly with the emergence of connected devices, the improvement of methods for characterizing populations, make it possible to have a better insight into the effects of treatment, sometimes on a national scale the importance of RWD is likely to progress in the eyes of health technology assessors, going from being traditionally complementary to possibly replacing clinical trial data. This is the fundamental question that the round table, involving experts from the academic and/or hospital, institutional, and industrial worlds, set out to answer. This work served first to establish the current role of RWD in health technology assessment, by distinguishing the main purposes of RWD, the timing of the evaluation in relation to the life cycle of the technology, and then according to the party commissioning or receiving the outcomes of RWD-based studies. Secondly, the round table proposed six general recommendations for more intensive and decisive use of RWD in the assessment and decision-making process.

The efficacy of immune checkpoint inhibitors varies in clear-cell renal cell carcinoma (ccRCC), with notable primary resistance among patients. Here, we integrate epigenetic (DNA methylation) and transcriptome data to identify a ccRCC subtype characterized by cancer-specific promoter hypermethylation and epigenetic silencing of Polycomb targets. We develop and validate an index of methylation-based epigenetic silencing (iMES) that predicts primary resistance to immune checkpoint inhibition (ICI) in the BIONIKK trial. High iMES is associated with VEGF pathway silencing, endothelial cell depletion, immune activation/suppression, EZH2 activation, BAP1/SETD2 deficiency, and resistance to ICI. Combination therapy with hypomethylating agents or tyrosine kinase inhibitors may benefit patients with high iMES. Intriguingly, tumors with low iMES exhibit increased endothelial cells and improved ICI response, suggesting the importance of angiogenesis in ICI treatment. We also develop a transcriptome-based analogous system for extended applicability of iMES. Our study underscores the interplay between epigenetic alterations and tumor microenvironment in determining immunotherapy response.

Background: The atrioventricular reentrant tachycardia (AVRT) is the most common tachycardia associated with accessory pathways (APs). Although sporadic Wolff-Parkinson-White (WPW) syndrome has been well-described, AP occurrence in identical twins with WPW syndrome remains rarely reported. Case presentation: We report a case of 14-year-old monozygotic twin brothers referred for an electrophysiology (EP) study. Twin A presented with recurrent symptomatic narrow complex tachycardia after exercise, noted for 3 years. His 12-lead surface electrocardiogram (ECG) did not show ventricular pre-excitation. However, an orthodromic AVRT utilizing a concealed right posteroseptal AP was found and successfully ablated. AVRT did not recur 12 months after the procedure. Twin B was asymptomatic. During his medical examination for firefighter volunteerism, his 12-lead ECG showed a spontaneous ventricular pre-excitation. EP study revealed a short anterograde right midseptal AP, which was then successfully eliminated by catheter ablation. His 12-lead ECG showed no ventricular pre-excitation recurrence 12 months after the procedure. Conclusions: These identical twin brothers had a right-side AP in almost the same place but showed completely different phenotypes. This case clearly illustrates the difficulty in understanding genetic contribution in the origin of atrioventricular APs. Environmental exposure could play a role in their clinical presentations and AP electrophysiological properties.

A number of stressors and inflammatory mediators (cytokines, proteases, oxidative stress mediators) released during inflammation or ischemia stimulate and activate cells in blood, the vessel wall or tissues. The most well-known functional and phenotypic responses of activated cells are (1) the immediate expression and/or release of stored or newly synthesized bioactive molecules, and (2) membrane blebbing followed by release of microvesicles. An ultimate response, namely the formation of extracellular traps by neutrophils (NETs), is outside the scope of this work. The main objective of this article is to provide an overview on the mechanism of plasminogen reception and activation at the surface of cell-derived microvesicles, new actors in fibrinolysis and proteolysis. The role of microvesicle-bound plasmin in pathological settings involving inflammation, atherosclerosis, angiogenesis, and tumour growth, remains to be investigated. Further studies are necessary to determine if profibrinolytic microvesicles are involved in a finely regulated equilibrium with pro-coagulant microvesicles, which ensures a balanced haemostasis, leading to the maintenance of vascular patency.

Background and purpose: Cerebral hypoperfusion has been reported in patients with COVID-19 and neurological manifestations in small cohorts. We aimed to systematically assess changes in cerebral perfusion in a cohort of 59 of these patients, with or without abnormalities on morphological MRI sequences.Methods: Patients with biologically-confirmed COVID-19 and neurological manifestations undergoing a brain MRI with technically adequate arterial spin labeling (ASL) perfusion were included in this retrospective multicenter study. ASL maps were jointly reviewed by two readers blinded to clinical data. They assessed abnormal perfusion in four regions of interest in each brain hemisphere: frontal lobe, parietal lobe, posterior temporal lobe, and temporal pole extended to the amygdalo-hippocampal complex.Results: Fifty-nine patients (44 men (75%), mean age 61.2 years) were included. Most patients had a severe COVID-19, 57 (97%) needed oxygen therapy and 43 (73%) were hospitalized in intensive care unit at the time of MRI. Morphological brain MRI was abnormal in 44 (75%) patients. ASL perfusion was abnormal in 53 (90%) patients, and particularly in all patients with normal morphological MRI. Hypoperfusion occurred in 48 (81%) patients, mostly in temporal poles (52 (44%)) and frontal lobes (40 (34%)). Hyperperfusion occurred in 9 (15%) patients and was closely associated with post-contrast FLAIR leptomeningeal enhancement (100% [66.4%-100%] of hyperperfusion with enhancement versus 28.6% [16.6%-43.2%] without, p=0.002). Studied clinical parameters (especially sedation) and other morphological MRI anomalies had no significant impact on perfusion anomalies.Conclusion: Brain ASL perfusion showed hypoperfusion in more than 80% of patients with severe COVID-19, with or without visible lesion on conventional MRI abnormalities.

Introduction: Corticosteroids affect variably survival in sepsis trials, suggesting heterogeneity in patients’ response to corticosteroids. The RECORDS (Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis) trial aimed at defining endotypes associated with adults with sepsis responsiveness to corticosteroids. Methods and analysis: RECORDS, a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial, will randomly assign to a biomarker stratum 1800 adults with community-acquired pneumonia, vasopressor-dependent sepsis, septic shock or acute respiratory distress syndrome. In each stratum, patients will be randomly assigned to receive a 7-day course of hydrocortisone and fludrocortisone or their placebos. Patients with COVID-19 will be treated with a 10-day standard course of dexamethasone and randomised to fludrocortisone or its placebo. Primary outcome will be 90-day death or persistent organ dysfunction. Large simulation study will be performed across a range of plausible scenarios to foresee power to detect a 5%–10% absolute difference with corticosteroids. We will assess subset-by-treatment interaction by estimating in a Bayesian framework two quantities: (1) measure of influence, relying on the value of the estimation of corticosteroids’ effect in each subset, and (2) measure of interaction. Ethics and dissemination: The protocol was approved by the Ethics Committee ( Comité de Protection des Personnes, Dijon, France), on 6 April 2020. Trial results will be disseminated at scientific conferences and results will be published in peer-reviewed journals. Trial registration number ClinicalTrials.gov Registry ( NCT04280497 ).