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The evolution of patients hospitalized with coronavirus disease 2019 (COVID-19) is still hard to predict, even after several months of dealing with the pandemic.To develop and validate a score to predict outcomes in patients hospitalized with COVID-19.All consecutive adults hospitalized for COVID-19 from February to April 2020 were included in a nationwide observational study. Primary composite outcome was transfer to an intensive care unit from an emergency department or conventional ward, or in-hospital death. A score that estimates the risk of experiencing the primary outcome was constructed from a derivation cohort using stacked LASSO (Least Absolute Shrinkage and Selection Operator), and was tested in a validation cohort.Among 2873 patients analysed (57.9% men; 66.6±17.0 years), the primary outcome occurred in 838 (29.2%) patients: 551 (19.2%) were transferred to an intensive care unit; and 287 (10.0%) died in-hospital without transfer to an intensive care unit. Using stacked LASSO, we identified 11 variables independently associated with the primary outcome in multivariable analysis in the derivation cohort (n=2313), including demographics (sex), triage vitals (body temperature, dyspnoea, respiratory rate, fraction of inspired oxygen, blood oxygen saturation) and biological variables (pH, platelets, C-reactive protein, aspartate aminotransferase, estimated glomerular filtration rate). The Critical COVID-19 France (CCF) risk score was then developed, and displayed accurate calibration and discrimination in the derivation cohort, with C-statistics of 0.78 (95% confidence interval 0.75-0.80). The CCF risk score performed significantly better (i.e. higher C-statistics) than the usual critical care risk scores.The CCF risk score was built using data collected routinely at hospital admission to predict outcomes in patients with COVID-19. This score holds promise to improve early triage of patients and allocation of healthcare resources.

Purpose Growth hormone (GH) supplementation in association with in vitro fertilization (IVF) is worldwide again increasing, even though study outcomes have been discrepant. Since GH acts via insulin-like growth factor-1 (IGF-1), its utilization in IVF would only seem to make sense with low IGF-1. We, therefore, determined whether IGF-I levels affect IVF outcomes. Methods Retrospectively, 302 consecutive first fresh, non-donor IVF cycles were studied, excluding patients on GH supplementation. Patients were divided into 3 subgroups: IGF-1 in lower 25th percentile (group A, n = 64); 25th–75th percentile (B, 133–202 ng/mL, n = 164), and upper 25th percentile (C, > 202 ng/mL, n = 74). IGF-1 was tested immunochemiluminometric with normal range at 78–270 ng/mL. Because of the study patients’ adverse selection and low pregnancy chances, the main outcome measure for the study was cycle cancellation. Secondary outcomes were oocyte numbers, embryos transferred, pregnancies, and live births. Results Group A was significantly older than B and C (P = 0.019). IGF-1 decreased with increasing age per year by 2.2 ± 0.65 ng/mL (P = 0.0007). FSH was best in group B and worst in A (trend, P = 0.085); AMH was best in B and worst in A (N.S.). Cycle cancellations were lowest in C (11.6%) and highest in A (25.0%; P = 0.042). This significance further improved with age adjustment (P = 0.021). Oocytes, embryo numbers, pregnancies, and live birth rates did not differ, though oocyte numbers trended highest in B. Conclusions Here presented results support the hypothesis that IGF-1 levels affect IVF outcomes. GH treatments, therefore, may be effective only with low IGF-1.

OBJECTIVES The Doppler-based resistive index and semiquantitative evaluation of renal perfusion using color Doppler failed to discriminate renal recovery patterns in a recent study. The influence of operator experience on resistive index and semiquantitative evaluation of renal perfusion performances is however unknown. This study aimed at evaluating the performance of resistive index and semiquantitative evaluation of renal perfusion according to the operator experience to predict short-term renal prognosis in critically ill patients. DESIGN Preplanned ancillary analysis of a prospective multicenter cohort study. SETTING Seven ICUs. PATIENTS Unselected ICU patients. INTERVENTION Renal Doppler was performed at admission to the ICU. The diagnostic performance of resistive index and semiquantitative evaluation of renal perfusion to predict persistent acute kidney injury at day 3 was evaluated. MAIN RESULTS Overall, 371 patients were included, of whom 351 could be assessed for short-term renal recovery. Two thirds of the included patients had acute kidney injury (n = 233; 66.3%), of whom 136 had persistent acute kidney injury (58.4%). Overall performance in discriminating persistent acute kidney injury was however null with an area under the receiver operating characteristic curve less than 0.6 for both resistive index and semiquantitative evaluation of renal perfusion, and no difference across operator experience. A multivariate analysis using logistic regression with the center as a random effect adjusted on the operator experience showed no association between resistive index (odds ratio, 0.02 per international units (95% CI, 0.00-18.60 international units]) or semiquantitative evaluation of renal perfusion (odds ratio, 0.96 per international units [95% CI, 0.43-2.11 international units]) and persistent acute kidney injury. Similar results were obtained within subgroups of expert and nonexpert operators. CONCLUSIONS Doppler-based measurements performed by an expert or a nonexpert operator did not discriminate renal recovery patterns and neither modified the risk stratification of acute kidney injury persistence.

Objective To determine whether 4 cytoplasmic granulation patterns of human metaphase II oocytes have a predictive value for in vitro fertilization outcomes. Design A retrospective cohort study. Setting An academically affiliated private clinical infertility and research center. Patient(s) A total of 2,690 consecutive fresh autologous oocytes collected from women aged 41.2 ± 5.0 years between 2017 and 2019. Intervention(s) Determination of granulation pattern in every oocyte during intracytoplasmic sperm injection as fine, central, dispersed, and newly introduced uneven granulations. Main Outcome Measure(s) Fertilization outcomes (2 pronuclei [2PN], 2PN rates), pregnancy, and live birth rates for different granulation patterns at different ages. Result(s) Fine granulation produced the highest 2PN rate, followed by central, uneven, and dispersed granulation (91.8%, 83.9%, 77.9%, and 54.8%, respectively). Differences in fertilization were surprisingly relatively independent of age and other variables. Overall, compared with fine granulation, dispersed granulation resulted in lower pregnancy rates (4.6% vs. 10.7%) and known-outcome analysis (1.3% vs. 5.6%) as well as lower live birth rates (3.0% vs. 8.9%) and known-outcome analysis (0.6% vs. 5.6%). The known-outcome analysis demonstrated that uneven granulation had lower live birth rates than fine granulation (2.3% vs. 5.6%). Unexpectedly, the ooplasm granulation patterns were largely disassociated from embryo morphologic grades. Conclusion(s) We, for the first time, demonstrated that 4 distinct cytoplasmic granulation patterns in metaphase II oocytes had, largely independent of age and other variables, a predictive value for fertilization, pregnancy, and live birth outcomes in in vitro fertilization cycles of poor-prognosis patients. These data suggest that upstream ooplasm granulation patterns deserve closer attention in terms of embryo selection.

Left Bundle Branch Block (LBBB) is a frequently encountered electrical abnormality in patients with chronic (more than 3 months after myocardial infarction, or evidence of coronary artery disease with ischemia) coronary syndromes (CCS), but its prognostic significance remains unclear. We aimed to describe the prevalence, incidence and five-year outcomes of LBBB in outpatients with CCS using the CLARIFY registry. Main outcome was a composite of CV death, MI or stroke. Secondary outcomes included all cause death, hospitalization for heart failure (HF) and permanent pacemaker implantation. Among 23.544 patients with available information regarding LBBB status at baseline, 1.041 (4.4%) had LBBB at baseline and 1.015 (4.5%) patients developed a new LBBB during 5-year follow-up. In multivariate analysis, LBBB at baseline was not associated with the composite outcome of CV death, MI or stroke (HR 1.06, 95% CI [0.86 - 1.31], p = 0.67) or the risk of all-cause death (HR 1.07, 95% CI [0.87 - 1.32], p = 0.52) but was significantly associated with a higher risk of hospitalization for HF (HR 1.50, 95% CI [1.21 - 1.88], p0.001) and permanent pacemaker implantation (HR 2.11, 95% CI [1.45 - 3.07], p0.001). The main factors associated with new-onset LBBB were male sex (HR 0.8 [0.66-0.98], p = 0.028) history of atrial fibrillation (HR 1.29, 95% CI [1.01 - 1.64], p = 0.04), CABG (HR 1.27, [1.08 - 1.51], p = 0.004) and MI (HR 1.19, 95% CI [1.01 - 1.40], p = 0.034). In conclusion, in a contemporary registry of outpatients with CCS, the prevalence of LBBB was 4.4% and the additional 5-years incidence 6.2%. LBBB, in itself, was not associated with a higher risk of major adverse cardiovascular events or all cause mortality. It was however an independent predictor of risk of hospitalization for heart failure and permanent pacemaker implantation.

Background There is a paucity of global data on cardiovascular disease (CVD) prevalence in people with type 2 diabetes (T2D). The primary objective of the CAPTURE study was to estimate the prevalence of established CVD and its management in adults with T2D across 13 countries from five continents. Additional objectives were to further characterize the study sample regarding demographics, clinical parameters and medication usage, with particular reference to blood glucose-lowering agents (GLAs: glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) with demonstrated cardiovascular benefit in randomized intervention trials. Methods Data were collected from adults with T2D managed in primary or specialist care in Australia, China, Japan, Czech Republic, France, Hungary, Italy, Argentina, Brazil, Mexico, Israel, Kingdom of Saudi Arabia, and Turkey in 2019, using standardized methodology. CVD prevalence, weighted by diabetes prevalence in each country, was estimated for the overall CAPTURE sample and participating countries. Country-specific odds ratios for CVD prevalence were further adjusted for relevant demographic and clinical parameters. Results The overall CAPTURE sample included 9823 adults with T2D (n = 4502 from primary care; n = 5321 from specialist care). The overall CAPTURE sample had median (interquartile range) diabetes duration 10.7 years (5.6–17.9 years) and glycated hemoglobin 7.3% (6.6–8.4%) [56 mmol/mol (49–68 mmol/mol)]. Overall weighted CVD and atherosclerotic CVD prevalence estimates were 34.8% (95% confidence interval [CI] 32.7–36.8) and 31.8% (95% CI 29.7–33.8%), respectively. Age, gender, and clinical parameters accounted for some of the between-country variation in CVD prevalence. GLAs with demonstrated cardiovascular benefit were used by 21.9% of participants, which was similar in participants with and without CVD: 21.5% and 22.2%, respectively. Conclusions In 2019, approximately one in three adults with T2D in CAPTURE had diagnosed CVD. The low use of GLAs with demonstrated cardiovascular benefit even in participants with established CVD suggested that most were not managed according to contemporary diabetes and cardiology guidelines. Study registration NCT03786406 (registered on December 20, 2018), NCT03811288 (registered on January 18, 2019).

Purpose Studies performed in spontaneously breathing patients with mild to moderate respiratory failure suggested that prone position (PP) in COVID-19 could be beneficial. Materials and methods Consecutive critically ill patients with COVID-19 were enrolled in four ICUs. PP sessions lasted at least 3 h each and were performed twice daily. A Cox proportional hazard model identified factors associated with the need of intubation. A propensity score overlap weighting analysis was performed to assess the association between spontaneous breathing PP (SBPP) and intubation. Results Among 379 patients, 40 underwent SBPP. Oxygenation was achieved by high flow nasal canula in all but three patients. Duration of proning was 2.5 [1.6;3.4] days. SBPP was well tolerated hemodynamically, increased PaO2/FiO2 (78 [68;96] versus 63 [53;77] mm Hg, p = 0.004) and PaCO2 (38 [34;43] versus 35 [32;38] mm Hg, p = 0.005). Neither day-28 survival (HR 0.51, 95% CI 0.16–1.16] nor risk of invasive ventilation [sHR 0.96; 95% CI 0.49;1.88] differed between patients who underwent PP and others. Conclusions SBPP in COVID-19 is feasible and well tolerated in severely hypoxemic patients. It did not induce any effect on risk of intubation and day-28 mortality.

Background: The coronavirus disease 2019 (COVID-19) pandemic has led to a public health crisis. Only limited data are available on the characteristics and outcomes of patients hospitalized for COVID-19 in France. Aims: To investigate the characteristics, cardiovascular complications and outcomes of patients hospitalized for COVID-19 in France. Methods: The Critical COVID-19 France (CCF) study is a French nationwide study including all consecutive adults with a diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection hospitalized in 24 centres between 26 February and 20 April 2020. Patients admitted directly to intensive care were excluded. Clinical, biological and imaging parameters were systematically collected at hospital admission. The primary outcome was in-hospital death. Results: Of 2878 patients included (mean ± SD age 66.6 ± 17.0 years, 57.8% men), 360 (12.5%) died in the hospital setting, of which 7 (20.7%) were transferred to intensive care before death. The majority of patients had at least one (72.6%) or two (41.6%) cardiovascular risk factors, mostly hypertension (50.8%), obesity (30.3%), dyslipidaemia (28.0%) and diabetes (23.7%). In multivariable analysis, older age (hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.03−1.06; P < 0.001), male sex (HR 1.69, 95% CI 1.11−2.57; P = 0.01), diabetes (HR 1.72, 95% CI 1.12−2.63; P = 0.01), chronic kidney failure (HR 1.57, 95% CI 1.02−2.41; P = 0.04), elevated troponin (HR 1.66, 95% CI 1.11−2.49; P = 0.01), elevated B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide (HR 1.69, 95% CI 1.0004−2.86; P = 0.049) and quick Sequential Organ Failure Assessment score ≥ 2 (HR 1.71, 95% CI 1.12−2.60; P = 0.01) were independently associated with in-hospital death. Conclusions: In this large nationwide cohort of patients hospitalized for COVID-19 in France, cardiovascular comorbidities and risk factors were associated with a substantial morbi-mortality burden.

OBJECTIVES To assess whether critically ill hematologic patients without diagnosis of hemophagocytic lymphohistiocytosis may have features mimicking hemophagocytic lymphohistiocytosis according to both diagnostic scores. DESIGN A retrospective case-control study. SETTING Hemophagocytic syndrome diagnosis was standardized and based on a consensual diagnosis by at least two experts of a university hospital which is a reference center for hemophagocytic syndrome. PATIENTS Cases (hemophagocytic syndrome+) consisted in a group of consecutive patients (n = 150) admitted in our ICU between 2007 and 2018. Control group (hemophagocytic syndrome-) consisted in patients included in a prospective multicenter cohort of hematologic patients in whom three independent experts ruled out the diagnosis of hemophagocytic syndrome (n = 1011). MEASUREMENTS AND MAIN RESULTS Overall, 1,161 patients were included. Hospital mortality was 45.8% in hemophagocytic syndrome- patients (n = 66) and 38.8% in control patients (n = 392; p = 0.126). Median HScore was 235 (205-262) in hemophagocytic syndrome+ and 42 (18-62) in hemophagocytic syndrome- patients (p < 0.001); number of hemophagocytic lymphohistiocytosis criteria was 4 (4-5) vs 1 (0-1), respectively (p < 0.001). Diagnostic performances of both scores were excellent with area under receiver operating characteristic curve of 0.99 (95% CI, 0.99-0.99) and 0.99 (95% CI, 0.99-0.99) for hemophagocytic lymphohistiocytosis and HScore, respectively. After propensity score matching (n = 144 × 2), the median HScore was 234 (205-262) in hemophagocytic syndrome+ patients versus 49 (18-71) in hemophagocytic syndrome- patients (p < 0.001). Median number of hemophagocytic lymphohistiocytosis criteria was 4 (4-5) in hemophagocytic syndrome+ and 1 (0-1) in hemophagocytic syndrome- patients (p < 0.001). Area under receiver operating characteristic curve was then of 0.98 (95% CI, 0.96-0.99) for hemophagocytic lymphohistiocytosis criteria and 0.99 (95% CI, 0.99-1) for HScore. CONCLUSIONS In ICU patients, several conditions share some similarities with hemophagocytic syndrome, explaining the poor predictive value of isolated biological markers such as ferritin level. Despite these potential confounding factors, our study suggests HScore and hemophagocytic lymphohistiocytosis criteria to be highly discriminant identifying hemophagocytic syndrome in critically ill patients.

Sea turtles are considered as bio-indicators for monitoring the efficiency of restoration measures to reduce marine litter impacts on health. However, the lack of extended and standardised empirical data has prevented the accurate analysis of the factors influencing litter ingestion and the relationships with individual health. Historic data collected from 1988 and standard data collected from 2016 were harmonised to enable such analyses on necropsied loggerhead turtles (Caretta caretta) in eight Mediterranean and North-East Atlantic countries. Litter was found in 69.24 % of the 1121 individuals, mostly single-use and fishing-related plastics. Spatial location, sex and life history stage explained a minor part of litter ingestion. While no relationships with health could be detected, indicating that all individuals can be integrated as bio-indicators, the mechanistic models published in literature suggest that the high proportion of plastics in the digestive contents (38.77 % per individual) could have long-term repercussions on population dynamics. © 2022

Summary Background Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care. Methods This international, multicentre, observational cohort study was done in 21 intensive care units in France, Spain, the USA, the UK, Russia, Canada, Germany, and Austria. Eligible patients were aged 18 years or older; had received CAR T-cell therapy in the past 30 days; and had been admitted to intensive care for any reason. Investigators retrospectively included patients admitted between Feb 1, 2018, and Feb 1, 2019, and prospectively included patients admitted between March 1, 2019, and Feb 1, 2020. Demographic, clinical, laboratory, treatment, and outcome data were extracted from medical records. The primary endpoint was 90-day mortality. Factors associated with mortality were identified using a Cox proportional hazard model. Findings 942 patients received CAR T-cell therapy, of whom 258 (27%) required admission to intensive care and 241 (26%) were included in the analysis. Admission to intensive care was needed within median 4·5 days (IQR 2·0–7·0) of CAR T-cell infusion. 90-day mortality was 22·4% (95% CI 17·1–27·7; 54 deaths). At initial evaluation on admission, isolated cytokine release syndrome was identified in 101 patients (42%), cytokine release syndrome and ICANS in 93 (39%), and isolated ICANS in seven (3%) patients. Grade 3–4 cytokine release syndrome within 1 day of admission to intensive care was found in 50 (25%) of 200 patients and grade 3–4 ICANS in 38 (35%) of 108 patients. Bacterial infection developed in 30 (12%) patients. Life-saving treatments were used in 75 (31%) patients within 24 h of admission to intensive care, primarily vasoactive drugs in 65 (27%) patients. Factors independently associated with 90-day mortality by multivariable analysis were frailty (hazard ratio 2·51 [95% CI 1·37–4·57]), bacterial infection (2·12 [1·11–4·08]), and lifesaving therapy within 24 h of admission (1·80 [1·05–3·10]). Interpretation Critical care management is an integral part of CAR T-cell therapy and should be standardised. Studies to improve infection prevention and treatment in these high-risk patients are warranted. Funding Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique.

Previously anecdotally observed rebounds in follicle growth after interruption of exogenous gonadotropins in absolute non-responders were the impetus for here reported study. In a prospective cohort study, we investigated 49 consecutive patients, absolutely unresponsive to maximal exogenous gonadotropin stimulation, for a so-called rebound response to ovarian stimulation. A rebound response was defined as follicle growth following complete withdrawal of exogenous gonadotropin stimulation after complete failure to respond to maximal gonadotropin stimulation over up to 5–7 days. Median age of study patients was 40.5 ± 5.1 years (range 23–52). Women with and without rebound did not differ significantly (40.0 ± 6.0 vs. 41.0 ± 7.0 years, P = 0.41), with 24 (49.0%) recording a rebound and 25 (51.0%) not. Among the former, 21 (87.5%) reached retrieval of 1–3 oocytes and 15 (30.6%) reached embryo transfer. A successful rebound in almost half of prior non-responders was an unsuspected response rate, as was retrieval of 1–3 oocytes in over half of rebounding patients. Attempting rebounds may, thus, represent another incremental step in very poor prognosis patients before giving up on utilization of autologous oocytes. Here presented findings support further investigations into the underlying physiology leading to such an unexpectedly high rebound rate.

Background:\ud \ud The COMPASS trial showed a reduction of ischemic events with low-dose rivaroxaban and aspirin in chronic coronary syndromes (CCS) compared with aspirin alone, at the expense of increased bleeding.\ud \ud Hypothesis:\ud \ud The CHA DS VaSc Score, REACH Recurrent Ischemic (RIS), and REACH Bleeding Risk Score (BRS) could identify patients with a favorable trade-off between ischemic and bleeding events, among COMPASS-eligible patients.\ud \ud Methods\ud \ud We identified the COMPASS-eligible population within the CLARIFY registry (>30.000 patients with CCS). High-bleeding risk patients (REACH BRS > 10) were excluded, as in the COMPASS trial. Patients were categorized as low (0-1) or high (≥ 2) CHA DS VaSc; low (0-12) or intermediate (13-19) REACH RIS, and low (0-6) or intermediate (7-10) REACH BRS. Ischemic outcome was the composite of cardiovascular death, myocardial infarction or stroke. Bleeding was defined as serious bleeding (haemorrhagic stroke, hospitalization for bleeding, transfusion).\ud \ud Results:\ud \ud The COMPASS-eligible population comprised 5.142 patients with ischemic and bleeding outcome of 2.3 (2.1-2.5) and 0.5 (0.4-0.6) per 100 patient-years, respectively. Patients with intermediate REACH RIS (n = 1934 [37.6%]) had the higher ischemic risk (3.0 [2.6-3.4]) with similar bleeding risk (0.5 [0.4-0.7]) as the overall population. Patients with low CHA DS VaSc (n = 229 [4.4%]) had a very low ischemic risk (0.6 [0.3-1.3]) with similar bleeding risk (0.5 [0.2-1.1]).\ud \ud Conclusions:\ud \ud Intermediate REACH RIS identified potential optimal candidates for adjunction of low-dose rivaroxaban while patients with low CHA DS VaSc score .appears unlikely to benefit from the COMPASS regimen. None of the three risk scores predicted the occurrence of serious bleeding.

International audience; Reactive hemophagocytic lymphohistiocytosis (rHLH) management requires early recognition, trigger identification, and adequate treatment in order to reduce mortality. We assessed the diagnostic yield of tissue biopsies to identify trigger in severe rHLH. We included all consecutive patients presenting an rHLH diagnosis (HLH-2004 criteria) admitted to the intensive care unit (ICU) of a tertiary hospital. This retrospective diagnostic accuracy study was conducted according to the Standards for Reporting Diagnostic Accuracy Statement. Among the 134 included patients (median age 47 years [IQR 47-56]), an underlying immunodeficiency was previously known in 61.2%. rHLH trigger was identified in 127 patients (94.8%) (hematological disorder 75%, infection 16%, systemic disease 4%). Diagnostic yield of tissue biopsies was as follows: lymph node 75% (95% confidence interval [CI], 61-85), skin 50% (95% CI, 27-73), bone marrow 44% (95% CI, 34-55), liver 30% (95% CI, 15-49). Splenectomy (yield 77%; 95% CI, 46-95) was reserved to cases of diagnostic deadlock. Procedural severe adverse events included two cases of reversible hemorrhagic shock. Seventy-eight percent of patients received etoposide regarding to the rHLH severity, and 68% could receive trigger-specific treatment in the ICU. A comprehensive diagnostic workup led to an rHLH trigger identification in 95% of patients, allowing prompt initiation of appropriate therapy. Prospective studies to validate a standardized diagnostic approach are warranted.

Since the start of the coronavirus disease 2019 (COVID-19) pandemic, patients with diabetes were rapidly recognized as a high-risk population for severe disease. Indeed, a high prevalence of diabetes among patients with COVID-19 who required hospitalization has been consistently reported, reaching 33.8% in 5,700 people hospitalized for COVID-19 in the New York City area (1). In addition, diabetes was associated with more than a doubled risk of intensive care unit (ICU) admission and more than a tripled risk of death (2). However, precise data regarding the type of diabetes are scarce. We report here the clinical characteristics and early prognosis of patients with type 1 diabetes (T1D) hospitalized for COVID-19 in the nationwide multicenter observational CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study (3). The aim of the CORONADO study was to describe the phenotypic characteristics and prognosis of patients with diabetes admitted with COVID-19 between 10 March and 10 April 2020 in 68 French hospitals. The protocol (ClinicalTrials.gov reg. no. NCT04324736) obtained all regulatory approvals as recently described (3). Inclusion criteria were 1 ) hospitalization for biologically and/or clinically/radiologically attested COVID-19 and 2 ) personal history of diabetes or newly diagnosed diabetes on admission. The composite primary end point combined tracheal intubation for mechanical ventilation and/or death on day 7 (D7). Secondary outcomes included death, tracheal intubation, and discharge on D7. Classification of diabetes was recorded in the electronic case report form as noted in the medical file by the physician in charge of the patient. In the present subanalysis, patients in whom diabetes was diagnosed on admission were excluded since the etiological diagnosis had not been formally established. All cases noted as T1D were carefully reviewed by local investigators and the steering committee …

Objectives: Cancer affects up to 20% of critically ill patients, and sepsis is one of the leading reasons for ICU admission in this setting. Early signals suggested that survival might be increasing in this population. However, confirmation studies have been lacking. The goal of this study was to assess trends in survival rates over time in cancer patients admitted to the ICU for sepsis or septic shock over the last 2 decades. Data Source: Seven European ICUs. Study Selection: A hierarchical model taking into account the year of admission and the source dataset as random variables was used to identify risk factors for day 30 mortality. Data Extraction: Data from cancer patients admitted to ICUs for sepsis or septic shock were extracted from the Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique database (1994-2015). Data Synthesis: Overall, 2,062 patients (62% men, median [interquartile range] age 59 yr [48-67 yr]) were included in the study. Underlying malignancies were solid tumors (n = 362; 17.6%) or hematologic malignancies (n = 1,700; 82.4%), including acute leukemia (n = 591; 28.7%), non-Hodgkin lymphoma (n = 461; 22.3%), and myeloma (n = 244; 11.8%). Two-hundred fifty patients (12%) underwent allogeneic hematopoietic stem cell transplantation and 640 (31.0%) were neutropenic at ICU admission. Day 30 mortality was 39.9% (823 deaths). The year of ICU admission was associated with significant decrease in day 30 mortality over time (odds ratio, 0.96; 95% CI, 0.93-0.98; p = 0.001). Mechanical ventilation (odds ratio, 3.25; 95% CI, 2.52-4.19; p < 0.01) and vasopressors use (odds ratio, 1.42; 95% CI, 1.10-1.83; p < 0.01) were independently associated with day 30 mortality, whereas underlying malignancy, allogeneic hematopoietic stem cell transplantation, and neutropenia were not. Conclusions: Survival in critically ill oncology and hematology patients with sepsis improved significantly over time. As outcomes improve, clinicians should consider updating admission policies and goals of care in this population.

The objective of this study was to compare the results of transcatheter arterial embolization (TAE) with surgery in terms of efficacy in the context of bleeding duodenal ulcer (BDU) refractory to endoscopic treatment. From January 2006 to December 2016, all patients treated for a BDU refractory to endoscopic treatment were included in this observational, comparative, retrospective, single-center study. Primary endpoint was the overall success of treatment of BDU requiring surgical and/or TAE. The secondary endpoints were pre-interventional data, recurrence rates, feasibility of secondary treatment, morbidity and mortality of surgical and radiological treatment, intensive care unit and length of stay. A systematic review of the literature was performed to compare results of surgery and TAE. 59 out of 396 patients (14.9%) treated for BDU required embolization and/or surgery: 15 patients underwent surgery (group S) including 7 patients after embolization failure and 44 patients underwent TAE (group TAE). The overall treatment success in intention to treat (85.7% vs 67.3%), per protocol (80% vs 79.5%) and bleeding recurrence rates (20% vs 15.9%) were also identical. Mortality (14.2% vs 15.3%) was similar between the two groups. Our study data were pooled with data from eight published studies and suggest that surgery have significant increased overall success (68.3% vs. 55.4%, p

Carcinogenic effects of tobacco smoke may affect breast tumorigenesis. To assess whether cigarette smoking is associated with breast cancer characteristics, we investigated the relationships between smoking, pathological characteristics, and outcomes in 2153 women diagnosed with breast cancer 2001–2016. Patients were classified as never, former, or current smokers at the time of diagnosis. Logistic regression and multivariable Cox proportional hazards analysis were performed to determine whether smoking was associated with tumor characteristics. Multivariable Cox proportional hazards analysis was conducted to compare former or current smokers to never smokers in survival with adjustment for the potential confounders. The majority of women (61.8%) never smoked, followed by former smokers (26.2%) and current smokers (12.0%). After adjustment for demographic variables, body mass index, and comorbidities, tumor characteristics were not significantly associated with smoking status or pack-years smoked. Ten-year overall survival was significantly lower for former and current smokers compared to never smokers (p = 0.0105). However, breast cancer specific survival did not differ significantly between groups (p = 0.1606). Although cigarette smoking did not alter the underlying biology of breast tumors or breast cancer-specific survival, overall survival was significantly worse in smokers, highlighting the importance of smoking cessation in the recently diagnosed breast cancer patient.

Background The field of mobile health (mHealth) is constantly expanding. Integrating mHealth apps and devices in clinical practice is a major and complex challenge. General practitioners (GPs) are an essential link in a patient’s care pathway. As they are patients’ preferred health care intermediaries, GPs play an important role in supporting patients’ transition to mHealth. Objective This study aims to identify the factors associated with the willingness of French GPs to prescribe mHealth apps and devices to their patients. Methods This study was part of the ApiAppS project whose overall objective was to help remove barriers GPs face when prescribing mHealth apps and devices by developing a custom-built platform to aid them. The study included GPs recruited from the general practice department of several medical faculties in France (Lyon, Nice, and Rouen) and mailing lists of academic GPs, health care professional associations, and social and professional networks. Participants were asked to complete a web-based questionnaire that collected data on various sociodemographic variables, indicators of their involvement in continued education programs and the amount of time they dedicated to promoting healthy behaviors during patient consultations, and indicators characterizing their patient population. Data on their perceptions of mHealth apps and devices were also collected. Finally, the questionnaire included items to measure GPs’ acceptability of prescribing mHealth apps and devices for several health-related dimensions. Results Of the 174 GPs, 129 (74.1%) declared their willingness to prescribe mHealth apps and devices to their patients. In multivariate analysis, involvement in continued education programs (odds ratio [OR] 6.17, 95% CI 1.52-28.72), a better patient base command of the French language (OR 1.45, 95% CI 1.13-1.88), GP-perceived benefits of mHealth apps and devices for both patients and their medical practice and GP-perceived drivers for mHealth apps and device implementation in their medical practice (OR 1.04, 95% CI 1.01-1.07), and validation of mHealth apps and devices through randomized clinical trials (OR 1.02, 95% CI 1.00-1.04) were all associated with GPs’ willingness to prescribe mHealth apps and devices. In contrast, older GPs (OR 0.95, 95% CI 0.91-0.98), female GPs (OR 0.26, 95% CI 0.09-0.69), and those who perceived risks for the patient or their medical practice (OR 0.96, 95% CI 0.94-0.99) were less inclined to prescribe mHealth apps and devices. Conclusions mHealth apps and devices were generally seen by GPs as useful in general medicine and were, for the most part, favorable to prescribing them. Their full integration in general medicine will be conditioned by the need for conclusive certification, transparency (reliable and precise data concerning mHealth app and device methods of construction and clinical validation), software aids to assist GPs prescribe them, and dedicated training programs.

Objective: Intensive Care Units (ICU) acquired Pneumonia (ICU-AP) is one of the most frequent nosocomial infections in critically ill patients. Our aim was to determine the effects of having an ICU-AP in immunosuppressed patients with acute hypoxemic respiratory failure. Design: Post-hoc analysis of a multinational, prospective cohort study in 16 countries. Settings: ICU. Patients: Immunosuppressed patients with acute hypoxemic respiratory failure. Intervention: None. Measurements and main results: The original cohort had 1611 and in this post-hoc analysis a total of 1512 patients with available data on hospital mortality and occurrence of ICU-AP were included. ICU-AP occurred in 158 patients (10.4%). Hospital mortality was higher in patients with ICU-AP (14.8% vs. 7.1% p < 0.001). After adjustment for confounders and centre effect, use of vasopressors (Odds Ratio (OR) 2.22; 95%CI 1.46-.39) and invasive me-chanical ventilation at day 1 (OR 2.12 vs. high flow oxygen; 95%CI 1.07-4.20) were associated with increased risk of ICU-AP while female gender (OR 0.63; 95%CI 0.43-94) and chronic kidney disease (OR 0.43; 95%CI 0.22-0.88) were associated with decreased risk of ICU-AP. After adjustment for confounders and centre effect, ICU-AP was independently associated with mortality (Hazard Ratio 1.48; 95%CI 14.-1.91; P = 0.003). Conclusions: The attributable mortality of ICU-AP has been repetitively questioned in immunosuppressed pa-tients with acute respiratory failure. This manuscript found that ICU-AP represents an independent risk factor for hospital mortality.(c) 2020 Elsevier Inc. All rights reserved.

Objectives The association between outcome and kidney injury detected at discharge from the ICU using different biomarkers remains unknown. The objective was to evaluate the association between 1-year survival and kidney injury at ICU discharge. Design Ancillary investigation of a prospective observational study. Setting Twenty-one ICUs with 1-year follow-up. Patients Critically ill patients receiving mechanical ventilation and/or hemodynamic support for at least 24 hours were included. Interventions Serum creatinine, plasma Cystatin C, plasma neutrophil gelatinase-associated lipocalin, urinary neutrophil gelatinase-associated lipocalin, plasma Proenkephalin A 119-159, and estimated glomerular filtration rate (on serum creatinine and plasma Cystatin C) were measured at ICU discharge among ICU survivors. Measurements and main results The association between kidney biomarkers at discharge and mortality was estimated using logistic model with and without adjustment for prognostic factors previously identified in this cohort. Subgroup analyses were performed in patients with discharge serum creatinine less than 1.5-fold baseline at ICU discharge. Among 1,207 ICU survivors included, 231 died during the year following ICU discharge (19.2%). Estimated glomerular filtration rate was significantly lower and kidney injury biomarkers higher at discharge in nonsurvivors. The association between biomarker levels or estimated glomerular filtration rate and mortality remained after adjustment to potential cofounding factors influencing outcome. In patients with low serum creatinine at ICU discharge, 25-47% of patients were classified as subclinical kidney injury depending on the biomarker. The association between kidney biomarkers and mortality remained and mortality was higher than patients without subclinical kidney injury. The majority of patients who developed acute kidney injury during ICU stay had elevated biomarkers of kidney injury at discharge even with apparent recovery based on serum creatinine (i.e., subclinical acute kidney disease). Conclusions Elevated kidney biomarkers measured at ICU discharge are associated with poor 1-year outcome, including in patients with low serum creatinine at ICU discharge.

Background Data on outcomes of critically ill patients requiring mechanical ventilation at the onset of stroke are limited. Objective To assess the hospital and long-term functional outcomes of patients with stroke who require mechanical ventilation. Methods This retrospective single-center cohort study performed from 1994 to 2008 involved adult patients within 7 days of stroke onset and who required intensive care unit admission and mechanical ventilation. Results A total of 274 patients requiring mechanical ventilation at the onset of stroke were analyzed. Indications for intubation included coma in 195 patients (71%). The median (interquartile range) score on the Glasgow Coma Scale at admission to the intensive care unit was 6 (3-9). Forty-four patients (16%) had sepsis at intensive care unit admission. The overall hospital mortality rate was 53%. After adjustment for confounders, severity of illness at admission as assessed by the Simplified Acute Physiology Score II (odds ratio, 1.07; 95% CI, 1.05-1.10), anisocoria (odds ratio, 5.26; 95% CI, 1.76-15.80), and sepsis at intensive care unit admission (odds ratio, 0.40; 95% CI, 0.19-0.85) were associated with outcome. At 1 year, median (interquartile range) modified Rankin Scale score was 6 (2-6). Only 89 patients (32%) exhibited mild to moderate neurologic impairment. Conclusion In this study, adult patients requiring mechanical ventilation at the onset of stroke experienced high 1-year mortality, with survivors having poor functional status.

The number of averted deaths due to therapeutic advances in oncology and hematology is substantial and increasing. Survival of critically ill cancer patients has also improved during the last 2 decades. However, these data stem predominantly from unadjusted analyses. The aim of this study was to assess the impact of ICU admission year on short-term survival of critically ill cancer patients, with special attention on those with neutropenia. Systematic review and meta-analysis of individual data according to the guidelines of meta-analysis of observational studies in epidemiology. Pubmed and Cochrane databases. Adult studies published in English between May 2005 and May 2015. Overall, 7354 patients were included among whom 1666 presented with neutropenia at ICU admission. Median ICU admission year was 2007 (IQR 2004–2010; range 1994–2012) and median number of admissions per year was 693 (IQR 450–1007). Overall mortality was 47.7%. ICU admission year was associated with a progressive decrease in hospital mortality (OR per year 0.94; 95% CI 0.93–0.95). After adjustment for confounders, year of ICU admission was independently associated with hospital mortality (OR for hospital mortality per year: 0.96; 95% CI 0.95–0.97). The association was also seen in patients with neutropenia but not in allogeneic stem cell transplant recipients. After adjustment for patient characteristics, severity of illness and clustering, hospital mortality decreased steadily over time in critically ill oncology and hematology patients except for allogeneic stem cell transplant recipients.

This study aimed at evaluating the performance of Doppler-based resistive index (RI) and semi-quantitative evaluation of renal perfusion using color-Doppler (SQP) to predict de novo AKI in the subgroup of critically ill patients without AKI at admission.This study is an ancillary analysis of a prospective multicenter cohort study. Consecutive ICU patients requiring mechanical ventilation were included. Renal Doppler was performed at ICU admission. The diagnostic performance of RI and SQP to predict de novo AKI at day 3 was evaluated.Among the 371 patients of the prospective cohort, 118 without AKI at study inclusion were included. Thirty-four patients (29%) developed an AKI. Neither RI (0.64 UI [0.57-0.70] vs 0.67 [0.62-0.70] in no AKI and de novo AKI group respectively, p = 0.177) nor SQP (2 [2, 3] vs 2 [1-3] in no AKI and de novo AKI group respectively, p = 0.061) were associated with AKI occurrence. Overall performance in predicting de novo AKI was null to poor with area under ROC curve of respectively 0.60 (95% CI 0.49-0.65) and 0.58 (95% CI 0.47-0.60) for RI and SQP. Similar results were obtained after adjustment for confounders.These results confirm the poor performance of Doppler-based indices in predicting renal prognosis of ICU patients.

The French food-based dietary guidelines recommend eating pulses at least twice a week and to reduce meat consumption. This study assessed the impact on the sustainability characteristics (nutrition, cost, environment) of individual diets of meeting the pulse guideline. Dietary data of 2028 adults from the Esteban survey were completed with the nutritional content (considering bioavailability on iron, zinc and protein), price and environmental impacts of foods. When the pulse guideline (i.e., 57 g/day) was not met, two substitution scenarios raised the quantity of pulses to the recommended level, in replacement of an equivalent portion of (i) starches or (ii) meat. Only 9.6% of the participants reached the pulse guideline. Diet sustainability characteristics improved with the meat scenario (nutritional indicators improved, diet cost, greenhouse gas emissions and acidification decreased), while several indicators deteriorated with the starches scenario. Zinc available for absorption slightly decreased in both scenarios while iron available for absorption decreased in the meat scenario only. Increasing pulse consumption to two portions/week could modestly improve the sustainability of diets when pulses replace meat but not starches. Cultural acceptability of that substitution still needs to be proven, and iron and zinc status of individuals at risk of deficiency should be monitored.

Aim and hypotheses The THEMIS randomized trial compared ticagrelor plus aspirin versus placebo plus aspirin for patients with stable coronary artery disease and type 2 diabetes mellitus (CAD-T2DM), and without prior myocardial infarction (MI) or stroke. The aim of the study was to quantify the size of the CAD-T2DM population without prior MI or stroke population in a real-world setting, and more specifically populations with similar THEMIS selection criteria (THEMIS-like and THEMIS-PCI-like populations), as well as their risk of major outcomes in current practice. Methods A 2-year follow-up cohort study included all CAD-T2DM without MI/stroke prevalent patients on January 1st, 2014 in the SNDS French nationwide claims database. The THEMIS-like population concerned those ≥ 50 years of age with similar THEMIS inclusion and exclusion criteria. Prevalence was standardized to the European population. The cumulative incidence function was used to estimate the incidence of clinical outcomes (MI, ischemic stroke, and major bleeding according to the TIMI classification) with death as competing risk, and the Kaplan–Meier estimate for all-cause death and a composite outcome of MI, stroke and all-cause death. Results From a population of about 50 million adults, the prevalence of CAD-T2DM without MI/stroke, THEMIS-like and THEMIS-PCI-like populations was respectively at 6.04, 1.50 and 0.27 per 1000 adults, with a mean age of 72.7, 72.3 and 70.9 years and less comorbidities and diabetic complications for the THEMIS-like and THEMIS-PCI-like population. The 2-year cumulative incidence was respectively 1.7%, 1.3% and 1.6% for MI, 1.7%, 1.5% and 1.4% for stroke, 4.8%, 3.1% and 2.9% for major bleeding, 13.6%, 9.7% and 6.8% for all-cause death, and 16.2%, 12.0% and 9.5% for the composite outcome. Conclusion THEMIS-like prevalence was estimated at 1.50 per 1,000 adults, representing about a quarter of CAD-T2DM without MI/stroke patients, and 0.27 per 1000 adults for the THEMIS-PCI-like populations. In current French practice, the median age of both these populations was about 5–6 years older than in the THEMIS trial, with a 2-year incidence of major outcomes between two or four time above the ones of the placebo arm of the THEMIS trial using very close definitions. Registration No. EUPAS27402 (http://www.ENCEPP.eu).

OBJECTIVES To describe short- and long-term neurologic prognosis of patients with thrombotic thrombocytopenic purpura and to identify clusters associated with evolution. DESIGN Prospective French cohort. SETTING ICU in a reference center. PATIENTS All consecutive patients with newly diagnosed thrombocytopenic purpura. INTERVENTION Comprehensive clinical, biological, and radiological evaluation at admission. Neurocognitive recovery was assessed using Glasgow Outcome Scale (range 1-5, with 1 representing death and 5 representing no or minimal neurologic deficit). MEASUREMENTS AND MAIN RESULTS Among the 130 newly diagnosed patients with thrombocytopenic purpura, 108 (83%; age 43 [30-52]; 73% women) presented with neurologic signs, including headaches (51%), limb weakness, paresthesia, and/or aphasia (49%), pyramidal syndrome (30%), decreased consciousness (20%), seizure (19%), cognitive impairment (34%), cerebellar syndrome (18%), and visual symptoms (20%). A hierarchical cluster analysis identified three distinct groups of patients. Cluster 1 included younger patients (37 [27-48], 41 [32-52], and 48 [35-54], in clusters 1, 2 and 3, respectively; p = 0.045), with a predominance of headaches (75%, 27%, and 36%; p < 0.0001). Cluster 2 patients had ataxic gait and cerebellar syndrome (77%, 0%, and 0%; p < 0.0001) and dizziness (50%, 0%, and 0%; p < 0.0001). Cluster 3 included patients with delirium (36%, 0%, and 9%; p < 0.0001), obtundation (58%, 0%, and 24%; p < 0.0001), and seizure (36%, 0%, and 14%; p < 0.0001). Acute kidney injury was 32%, 68%, and 77%, in clusters 1, 2, and 3, respectively (p < 0.0001). The three clusters did not differ for other biological or brain imaging. After a median follow-up of 34 months (12-71 mo), 100 patients (93%) were alive with full neurocognitive recovery (i.e., Glasgow Outcome Scale score 5) in 89 patients (89%). Patients from cluster 1 more frequently exhibited full recovery (Glasgow Outcome Scale score of 5) compared with clusters 2 and 3, (44 [98%], 13 [65%], and 21 [60%] at 3 mo; p < 0.0001), (44 [100%], 15 [68%], and 23 [69%] at 6 mo; p < 0.0001), and (40 [100%], 15 [79%], and 20 [57%] at 1 yr; p < 0.0001). CONCLUSIONS Initial clinical neurologic evaluation in thrombocytopenic purpura patients distinguishes three groups of patients with different clinical and functional outcomes.

Background Critically ill patients with coronavirus disease 2019 (COVID‐19) are prone to developing macrothrombosis and microthrombosis. COVID‐19 has been reported to be rarely associated with thrombotic microangiopathies. A disintegrin and metalloprotease with thrombospondin type I repeats, member 13 (ADAMTS13) severe deficiency, the hallmark of thrombotic thrombocytopenic purpura (TTP), induces the formation of platelet, unusually large von Willebrand factor (VWF) multimer microthrombi. In immune‐mediated TTP, ADAMTS13 adopts specifically an open conformation. The VWF/ADAMTS13 couple may contribute to the microthrombi formation in pulmonary alveolar capillaries in COVID‐19. Objective To investigate clinical features, hemostatic laboratory parameters, VWF/ADAMTS13 axis, and ADAMTS13 conformation in critically ill COVID‐19 patients at admission. Methods Fifty three critically ill COVID‐19 patients were enrolled between March 18 and May 9 2020 in a monocentric hospital. Results The median age was 59 years and the male‐to‐female ratio was 2.8/1. We reported seven pulmonary embolisms and 15 deaths. Biological investigations showed increased fibrinogen and factor V levels, and strongly increased D‐dimers correlated with mortality. No patient presented severe thrombocytopenia nor microangiopathic hemolytic anemia. An imbalance between high VWF antigen levels and normal or slightly decreased ADAMTS13 activity levels (strongly elevated VWF/ADAMTS13 ratio) was correlated with mortality. Three patients had a partial quantitative deficiency in ADAMTS13. We also reported a closed conformation of ADAMTS13 in all patients, reinforcing the specificity of an open conformation of ADAMTS13 as a hallmark of TTP. Conclusion We suggest that slightly decreased or normal ADAMTS13 activity and highly elevated VWF are rather biomarkers reflecting both the strong inflammation and the endothelial damage rather than drivers of the thrombotic process of COVID‐19.

Summary Background Although cardiovascular comorbidities seem to be strongly associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19), data regarding patients with preexisting heart failure are limited. Aims To investigate the incidence, characteristics and clinical outcomes of patients with COVID-19 with a history of heart failure with preserved or reduced ejection fraction. Methods We performed an observational multicentre study including all patients hospitalized for COVID-19 across 24 centres in France from 26 February to 20 April 2020. The primary endpoint was a composite of in-hospital death or need for orotracheal intubation. Results Overall, 2809 patients (mean age 66.4 ± 16.9 years) were included. Three hundred and seventeen patients (11.2%) had a history of heart failure; among them, 49.2% had heart failure with reduced ejection fraction and 50.8% had heart failure with preserved ejection fraction. COVID-19 severity at admission, defined by a quick sequential organ failure assessment score > 1, was similar in patients with versus without a history of heart failure. Before and after adjustment for age, male sex, cardiovascular comorbidities and quick sequential organ failure assessment score, history of heart failure was associated with the primary endpoint (hazard ratio [HR]: 1.41, 95% confidence interval [CI]: 1.06–1.90; P = 0.02). This result seemed to be mainly driven by a history of heart failure with preserved ejection fraction (HR: 1.61, 95% CI: 1.13–2.27; P = 0.01) rather than heart failure with reduced ejection fraction (HR: 1.19, 95% CI: 0.79–1.81; P = 0.41). Conclusions History of heart failure in patients with COVID-19 was associated with a higher risk of in-hospital death or orotracheal intubation. These findings suggest that patients with a history of heart failure, particularly heart failure with preserved ejection fraction, should be considered at high risk of clinical deterioration.

OBJECTIVES Acute kidney injury, acute kidney injury severity, and acute kidney injury duration are associated with both short- and long-term outcomes. Despite recent definitions, only few studies assessed pattern of renal recovery and time-dependent competing risks are usually disregarded. Our objective was to describe pattern of acute kidney injury recovery, change of transition probability over time and their risk factors. DESIGN Monocenter retrospective cohort study. Acute kidney injury was defined according to Kidney Disease Improving Global Outcomes definition. Renal recovery was defined as normalization of both serum creatinine and urine output criteria. Competing risk analysis, time-inhomogeneous Markov model, and group-based trajectory modeling were performed. SETTING Monocenter study. PATIENTS Consecutive patients admitted in ICU from July 2018 to December 2018 were included. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Three-hundred fifty patients were included. Acute kidney injury occurred in 166 patients at ICU admission, including 64 patients (38.6%) classified as acute kidney disease according to Acute Disease Quality Initiative definition and 44 patients (26.5%) who could not be classified. Cumulative incidence of recovery was 25 % at day 2 (95% CI, 18-32%) and 35% at day 7 (95% CI, 28-42%). After adjustment, need for mechanical ventilation (subdistribution hazard ratio, 0.42; 95% CI, 0.23-0.74) and severity of the acute kidney injury (stage 3 vs stage 1 subdistribution hazard ratio, 0.11; 95% CI, 0.03-0.35) were associated with lack of recovery. Group-based trajectory modeling identified three clusters of temporal changes in this setting, associated with both acute kidney injury recovery and patients' outcomes. CONCLUSIONS In this study, we demonstrate Acute Disease Quality Initiative to allow recovery pattern classification in 75% of critically ill patients. Our study underlines the need to take into account competing risk factors when assessing recovery pattern in critically ill patients.

Aims/hypothesis This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19). Methods The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days. Results We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th–75th percentile) 28.4 (25.0–32.4) kg/m2. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5–14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors. Conclusions/interpretation In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period. Trial registration Clinicaltrials.gov identifier: NCT04324736 Graphical abstract

The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality.In this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model.Three distinct phenotypes were derived in the derivation cohort (n=2667)-phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])-and reproduced in the internal validation cohort (n=1368)-phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4-4·3) for patients with phenotype A, 30·5% (28·5-32·6) for patients with phenotype B, and 60·7% (53·7-67·2) for patients with phenotype C (log-rank test p0·0001). The predicted phenotypes in the internal validation cohort and external validation cohort showed similar mortality rates to the assigned phenotypes (internal validation cohort: 5·3% [95% CI 3·4-8·1] for phenotype A, 31·3% [28·5-34·2] for phenotype B, and 59·5% [48·8-69·3] for phenotype C; external validation cohort: 3·7% [2·0-6·4] for phenotype A, 23·7% [21·8-25·7] for phenotype B, and 51·4% [41·9-60·7] for phenotype C).Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated.Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.

Objective.To assess the prevalence of axial articular manifestations (AAMs) in patients with primary Sjögren syndrome (pSS), to investigate whether these symptoms reveal an associated spondyloarthritis (SpA), and to assess their therapeutic management.Methods.Among 148 consecutive patients with pSS fulfilling European League Against Rheumatism (EULAR)/American College of Rheumatology 2019 classification criteria followed between 2010 and 2018, we selected those who presented with AAMs. The association with SpA was retained when patients fulfilled Assessment of SpA international Society criteria.Results.A total of 29 patients (20%, 28 women) with a median age of 43 years (range 15–65 yrs), were identified. The main extraglandular features were peripheral arthralgia and arthritis in 93% and 90% of patients, respectively. Positive anti-Ro/SSA (anti-SSA) antibody was reported in 62%. AAMs were inaugural in 7%, delayed from the diagnostic of pSS in 7%, and occurred concomitantly in 86% of patients. AAMs were not associated to multisystemic involvement of pSS. Radiographic sacroiliitis was mentioned in 65%, and HLA-B27 was positive in 13%. The diagnosis of SpA was retained in 23/29 patients (79%), among which 74% and 26% fulfilled psoriatic arthritis and ankylosing spondylitis criteria, respectively. There was no phenotypic difference according to the anti-SSA antibody status. With a median follow-up of 60 months (range: 5–96), 61% of patients with associated SpA required biotherapies, mainly of anti–tumor necrosis factor-α or anti–interleukin 17A molecules with a good clinical outcome in 64% and no effect on pSS.Conclusion.AAMs are not uncommon in patients with pSS and may reveal an associated SpA. Treatment of AAMs, especially when clearly associated with SpA, may necessitate biologics, following SpA-management therapeutic guidelines.

Early thrombotic thrombocytopenic purpura (TTP) recognition is critical as this disease is almost always lethal if not treated promptly with therapeutic plasma exchanges. Currently, as ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity is not widely available in emergency, scores have been developed to help differentiating TTP from other thrombotic microangiopathies (TMAs). The aim of this work was to study the accuracy of these diagnostic scores in the intensive care unit (ICU) setting. Performance of both Coppo and PLASMIC scores was studied in a cohort of adult TMA patients requiring admission to one university hospital ICU from 2006 to 2017. Receiver operating characteristic (ROC) curves were established, and confidence intervals of the area under the curve (AUC) were determined. Multivariate logistic regression analysis was performed to identify parameters specifically associated with TTP, to compare diagnostic scores and to elaborate more accurate diagnostic models. During the study period, 154 TMA patients required ICU admission, including 99 (64.2%) TTP and 55 (35.7%) non-TTP patients. AUC under the ROC curve in predicting TTP was 0.86 (95% confidence interval [CI]: 0.81–0.92) for the Coppo score, 0.67 (95% CI: 0.58–0.76) for the PLASMIC score, and 0.86 (95% CI: 0.81–0.92) for platelet count alone. Platelet count ≤20 G/L, determined as the best cut-off rate for thrombocytopenia, performed similarly to the Coppo score and better than the PLASMIC score to differentiate TTP from non-TTP patients, both using AUC ROC curve and logistic regression. In a monocentric cohort of TMA patients requiring ICU admission, the PLASMIC score had limited performance for the diagnosis of TTP. The performance of the Coppo score was good but similar to a single highly discriminant item: platelet count ≤20 G/L at admission.

Background Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causes direct lung damage, overwhelming endothelial activation, and inflammatory reaction, leading to acute respiratory failure and multi-organ dysfunction. Ongoing clinical trials are evaluating targeted therapies to hinder this exaggerated inflammatory response. Critically ill coronavirus disease 2019 (COVID-19) patients have shown heterogeneous severity trajectories, suggesting that response to therapies is likely to vary across patients. Research Question Are critically ill COVID-19 patients biologically and immunologically dissociable based on profiling of currently evaluated therapeutic targets? Study Design and Methods We did a single-center, prospective study in an ICU department in France. Ninety-six critically ill adult patients admitted with a documented SARS-CoV-2 infection were enrolled. We conducted principal components analysis and hierarchical clustering on a vast array of immunologic variables measured on the day of ICU admission. Results We found that patients were distributed in three clusters bearing distinct immunologic features and associated with different ICU outcomes. Cluster 1 had a “humoral immunodeficiency” phenotype with predominant B-lymphocyte defect, relative hypogammaglobulinemia, and moderate inflammation. Cluster 2 had a “hyperinflammatory” phenotype, with high cytokine levels (IL-6, IL-1β, IL-8, tumor necrosis factor-alpha [TNF⍺]) associated with CD4+ and CD8+ T-lymphocyte defects. Cluster 3 had a “complement-dependent” phenotype with terminal complement activation markers (elevated C3 and sC5b-9). Interpretation Patients with severe COVID-19 exhibiting cytokine release marks, complement activation, or B-lymphocyte defects are distinct from each other. Such immunologic variability argues in favor of targeting different mediators in different groups of patients and could serve as a basis for patient identification and clinical trial eligibility.

International audience; Rationale: Frontline healthcare providers (HCPs) during the coronavirus disease (COVID-19) pandemic are at high risk of mental morbidity.Objectives: To assess the prevalence of symptoms of anxiety, depression, and peritraumatic dissociation in HCPs.Methods: This was a cross-sectional study in 21 ICUs in France between April 20, 2020, and May 21, 2020. The Hospital Anxiety and Depression Scale and the Peritraumatic Dissociative Experience Questionnaire were used. Factors independently associated with reported symptoms of mental health disorders were identified.Measurements and Main Results: The response rate was 67%, with 1,058 respondents (median age 33 yr; 71% women; 68% nursing staff). The prevalence of symptoms of anxiety, depression, and peritraumatic dissociation was 50.4%, 30.4%, and 32%, respectively, with the highest rates in nurses. By multivariable analysis, male sex was independently associated with lower prevalence of symptoms of anxiety, depression, and peritraumatic dissociation (odds ratio of 0.58 [95% confidence interval, 0.42–0.79], 0.57 [95% confidence interval, 0.39–0.82], and 0.49 [95% confidence interval, 0.34–0.72], respectively). HCPs working in non–university-affiliated hospitals and nursing assistants were at high risk of symptoms of anxiety and peritraumatic dissociation. Importantly, we identified the following six modifiable determinants of symptoms of mental health disorders: fear of being infected, inability to rest, inability to care for family, struggling with difficult emotions, regret about the restrictions in visitation policies, and witnessing hasty end-of-life decisions.Conclusions: HCPs experience high levels of psychological burden during the COVID-19 pandemic. Hospitals, ICU directors, and ICU staff must devise strategies to overcome the modifiable determinants of adverse mental illness symptoms.

BACKGROUND: In view of the high mortality rate of immunocompromised patients with ARDS, it is important to identify targets for improvement. RESEARCH QUESTION: This study investigated factors associated with mortality in this specific ARDS population, including factors related to respiratory mechanics (plateau pressure [Pplat,rs], compliance [Crs], and driving pressure [Delta Prs]). STUDY DESIGN AND METHODS: This study consisted of a predefined secondary analysis of the EFRAIM data. Overall, 789 of 1,611 patients met the Berlin criteria for ARDS, and Pplat,rs, Delta Prs, and Crs were available for 494 patients. A hierarchical model was used to assess factors at ARDS onset independently associated with hospital mortality. RESULTS: Hospital mortality was 56.3%. After adjustment, variables independently associated with hospital mortality included ARDS of undetermined etiology (OR, 1.66; 95% CI, 1.012.72), need for vasopressors (OR, 1.91; 95% CI, 1.27-2.88), and need for renal replacement therapy (OR, 2.02; 95% CI, 1.37-2.97). ARDS severity according to the Berlin definition, neutropenia on admission, and the type of underlying disease were not significantly associated with mortality. Before adjustment, higher Pplat,rs, higher Delta Prs, and lower Crs were associated with higher mortality. Addition of each of these individual variables to the final hierarchical model revealed a significant association with mortality: Delta Prs (OR, 1.08; 95% CI, 1.05-1.12), Pplat,rs (OR, 1.07; 95% CI, 1.04-1.11), and Crs (OR, 0.97; 95% CI, 0.95-0.98). Tidal volume was not associated with mortality. INTERPRETATION: In immunocompromised patients with ARDS, respiratory mechanics provide additional prognostic information to predictors of hospital mortality. Studies designed to define lung-protective ventilation guided by these physiological variables may be warranted in this specific population.

Background Following the publication of the COMPASS trial, the European Medicines Agency has approved a regimen of combination of rivaroxaban 2.5 mg twice daily and a daily dose of 75–100 mg acetylsalicylic acid (ASA) for patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischemic events. However, the applicability of such a therapeutic strategy in France is currently unknown. Aims To describe the proportion of patients eligible to COMPASS in France, their baseline clinical characteristics and the rate of major adverse cardiovascular events, using the REACH registry. Methods From the the REduction of Atherothrombosis for Continued Health (REACH) registry database, a large international registry of patients with, or at risk, of atherothrombosis, we analyzed patients included in France with either established CAD and/or PAD and fulfilling the inclusion and exclusion criteria of the COMPASS trial. The ischemic outcome was a composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke, and serious bleeding were defined as haemorrhagic stroke or bleeding leading to hospitalization or transfusion. Results Among more than 65000 patients enrolled in REACH, 2.012 patients were evaluable and enrolled in France. Among them, 1194 patients (59.3%) were eligible to COMPASS. The main reasons for exclusion of the COMPASS trial, were high bleeding risk (59.1%), anticoagulant use (43.4%), requirement for dual antiplatelet therapy within 1 year of an ACS or PCI (24.7%). In the “COMPASS eligible population”, the rate of MACE (CV, MI and stroke) at 4 years follow-up was 13.4% [11.3–15.8], and serious bleeding was 2.5% at 4 years [1.6–3.4]. Patients with polyvascular disease (n = 219) had the highest rate of MACE, compared with patients with CAD only and PAD only (19.1% [13.9–26.1] vs. 11.6% [9.1–14.8] vs 13.2% [9.2–18.8], P Conclusion The COMPASS therapeutic strategy in France appears to be applicable to more than half of CAD or PAD patients. This population appears at high residual risk of atherothrombotic events, and patients with polyvascular disease experienced the highest rate of events.

International audience; Altered function of serotonin receptor 1A (5-HT1AR) has been consistently implicated in anxiety, major depressive disorder and resistance to antidepressants. Mechanisms by which the function of 5-HT1AR (expressed as an autoreceptor in serotonergic raphe neurons and as a heteroreceptor in serotonin [5-HT] projection areas) is altered include regulation of its expression, but 5-HT1AR traffick-ing may also be involved. Methods: We investigated the consequences of the lack of Yif1B (the 5-HT1AR trafficking protein) on 5-HT neurotransmission in mice, and whether Yif1B expression might be affected under conditions known to alter 5-HT neurotransmission, such as anxious or depressive states or following treatment with fluoxetine (a selective serotonin reuptake inhibitor) in humans, monkeys and mice. Results: Compared with wild-type mice, Yif1B-knockout mice showed a significant decrease in the forebrain density of 5-HT projection fibres and a hypofunctionality of 5-HT1A autoreceptors expressed on raphe 5-HT neurons. In addition, social interaction was less in Yif1B-knockout mice, which did not respond to the antidepressant-like effect of acute fluoxetine injection. In wild-type mice, social defeat was associated with downregulated Yif1B mRNA in the prefrontal cortex, and chronic fluoxetine treatment increased Yif1B expression. The expression of Yif1B was also downregulated in the postmortem prefrontal cortex of people with major depressive dis-order and upregulated after chronic treatment with a selective serotonin reuptake inhibitor in monkeys. Limitations: We found sex differ-ences in Yif1B expression in humans and monkeys, but not in mice under the tested conditions. Conclusion: These data support the concept that Yif1B plays a critical role in 5-HT1AR functioning and brain 5-HT homeostasis. The opposite changes in its expression observed in anxious or depressive states and after therapeutic fluoxetine treatment suggest that Yif1B might be involved in vulnerability to anxiety and depression, and fluoxetine efficacy

Purpose Coronavirus disease 2019 (COVID-19) is creating an unprecedented healthcare crisis. Understanding the determinants of mortality is crucial to optimise intensive care unit (ICU) resource use and to identify targets for improving survival. Methods In a multicentre retrospective study, we included 379 COVID-19 patients admitted to four ICUs between 20 February and 24 April 2020 and categorised according to time from disease onset to ICU admission. A Cox proportional-hazards model identified factors associated with 28-day mortality. Results Median age was 66 years (53–68) and 292 (77%) were men. The main comorbidities included obesity and overweight (67%), hypertension (49.6%) and diabetes (30.1%). Median time from disease onset (i.e., viral symptoms) to ICU admission was 8 (6–11) days (missing for three); 161 (42.5%) patients were admitted within a week of disease onset, 173 (45.6%) between 8 and 14 days, and 42 (11.1%) > 14 days after disease onset; day 28 mortality was 26.4% (22–31) and decreased as time from disease onset to ICU admission increased, from 37 to 21% and 12%, respectively. Patients admitted within the first week had higher SOFA scores, more often had thrombocytopenia or acute kidney injury, had more limited radiographic involvement, and had significantly higher blood IL-6 levels. Age, COPD, immunocompromised status, time from disease onset, troponin concentration, and acute kidney injury were independently associated with mortality. Conclusion The excess mortality in patients admitted within a week of disease onset reflected greater non-respiratory severity. Therapeutic interventions against SARS-CoV-2 might impact different clinical endpoints according to time since disease onset. Electronic supplementary material The online version of this article (10.1007/s00134-020-06202-3) contains supplementary material, which is available to authorized users.

Background Despite an increasing number of studies highlighting the health benefits of community gardening, the literature is limited by cross-sectional designs. The “JArDinS” quasi-experimental study aimed to assess the impact of community garden participation on the adoption of more sustainable lifestyles among French adults. Methods Individuals entering a community garden in Montpellier (France) in 2018 (n = 66) were compared with pairwise matched individuals with no experience in community gardening (n = 66). Nutritional quality, environmental impact and cost of monthly household food supplies, level of physical activity measured by accelerometers, as well as mental and social well-being, sensitivity to food waste, and connection with nature were evaluated at baseline (t0) and 12 months later (t1) to explore sustainability of lifestyles in social/health, environmental and economic dimensions. Linear mixed models were used to determine the independent effect of community gardening on investigated lifestyles components. In-depth interviews were conducted at t1 with 15 gardeners to better understand changes that may have occurred in gardeners’ lives during the first year of gardening. Results At t0, gardeners had lower education level, lower BMI and their household reported lower percentage of meals consumed outside of the home compared to non-gardeners (p

International audience; Rationale: Subclinical acute kidney injury (sub-AKI) refers to patients with low serum creatinine but elevated alternative biomarkers of AKI. Its incidence and outcome in critically ill patients remain, however, largely unknown. Plasma proenkephalin A 119–159 (penKid) has been proposed as a sensitive biomarker of glomerular function.Objectives: In this ancillary study of two cohorts, we explored the incidence and outcome of sub-AKI based on penKid.Methods: A prospective observational study in ICUs was conducted. FROG-ICU (French and European Outcome Registry in ICUs) enrolled 2,087 critically ill patients, and AdrenOSS-1 (Adrenomedullin and Outcome in Severe Sepsis and Septic Shock-1) enrolled 583 septic patients. The primary endpoint was 28-day mortality after ICU admission. Sub-AKI was defined by an admission penKid concentration above the normal range (i.e., >80 pmol/L) in patients not meeting the definition of AKI. A sensitivity analysis was performed among patients with estimated glomerular filtration rate above 60 ml/min/1.73 m2 at ICU admission.Measurements and Main Results: In total, 6.1% (122/2,004) and 6.7% (39/583) of patients from the FROG-ICU and AdrenOSS-1 cohorts met the definition of sub-AKI (11.6% and 17.5% of patients without AKI). In patients without AKI or with high estimated glomerular filtration rate, penKid was associated with higher mortality (adjusted standardized hazard ratio [HR], 1.4 [95% confidence interval, 1.1–1.8]; P = 0.010; and HR, 1.6 [95% confidence interval, 1.3–1.8]; P

We read with interest the correspondence from Montagud‐Marrahi et al. putting forward that solid organ transplant (SOT) recipients are not at higher risk of severe COVID‐19 infection despite their immunosuppression and the mild or atypical nature of their symptoms in their Spanish cohort. In the recent literature, this population achieves a mortality rate between 20% and 52% when they become critically ill. Moreover, as innate immunity is altered by the infection, decreased doses of immunosuppressive drugs should be considered.

International audience; Objectives: This study hypothesized that the association of D-dimer blood level and several clinical items in a new risk score could predict the absence of atrial thrombus.Background: Symptomatic and drug resistant atrial fibrillation (AF) can be treated by catheter ablation. The procedure-related risk of thromboembolism is limited by the pre-operative use of transesophageal echocardiography (TEE) to detect atrial thrombi.Methods: Patients admitted for catheter ablation of AF (n = 2,494) were prospectively included in a multicenter study. TEE was systematically performed before the procedure to search for atrial thrombus (primary endpoint). D-dimer level, CHADS2 score, left ventricular ejection fraction, pre-operative anticoagulation regimen, and medical history were collected. A logistic regression model was used to identify factors associated with the presence of atrial thrombus (hypertension, history of stroke, heart failure, D-dimer level >270 ng/ml). These factors were aggregated in a new score called atrial thrombus exclusion (ATE).Results: The incidence of atrial thrombus was 1.92%. CHADS2 score and D-dimer level were significantly associated with atrial thrombus (p < 0.0001 and p < 0.0001, respectively). A zero CHADS2 score failed to exclude all atrial thrombi (5 false negatives; sensitivity: 89.58%, specificity: 52.2%). No false negative was found with a zero ATE score, which had a specificity of 37% and a higher sensitivity (100%) than the CHADS2 score (p < 0.031) to predict the absence of intra-atrial thrombi on TEE. Conversely, the positive predictive value was poor, and the ATE score should not be used to conclude a positive diagnosis of thrombus.Conclusions: An ATE score of zero was strongly associated with the absence of atrial thrombus. This new score could be useful to rule out a diagnosis of atrial thrombus before catheter ablation of AF.

Ping Zhang,* Audrey Darmon,* Julie Marill, Naeemunnisa Mohamed Anesary, Sébastien Paris Nanobiotix, Paris, France*These authors contributed equally to this workCorrespondence: Sébastien Paris Email sebastien.paris@nanobiotix.comPurpose: Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumor-specific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare.Methods: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model.Results: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells.Conclusion: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.Keywords: CD8+ T cells, antitumor immune response, TILs, NBTXR3, radioenhancer

Mediated via the androgen receptor on granulosa cells, models of small growing follicle stages demonstrate dependence on testosterone. Androgen deficiency reduces ovarian response to follicle stimulation hormone (FSH), granulosa cell mass and estradiol (E2) production falls and FSH, therefore, rises. Though potentially of adrenal and/or ovarian origin, androgen deficiency in association with female infertility is almost universally primarily of adrenal origin, raising the possibility that women with presumptive diagnosis of primary ovarian insufficiency (POI), also called primary ovarian failure (POF) may actually suffer from secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism that leads to follicular arrest at small-growing follicle stages.This retrospective cohort study was performed in a private, academically affiliated infertility center in New York City. We searched the center's anonymized electronic research data bank for consecutive patients who presented with a diagnosis of POI, defined by age41 year, FSH 40.0 mIU/mL, amenorrhea for at least 6 month, and low testosterone (T), defined as total T (TT) in the lowest age-specific quartile of normal range. This study did not include patients with oophoritis. Since dehydroepiandrosterone sulfate (DHEAS) is the only androgen almost exclusively produce by adrenals, adrenal hypoandrogenism was defined by DHEAS 100ug/dL. Thirteen of 78 presumed POI women (16.67%) qualified and represented the original study population. POI patients are usually treated with third-party egg donation; 6/13, however, rejected egg donation for personal or religious reasons and insisted on undergoing at least one last IVF cycle attempt (final study population). In preparation, they were supplemented with DHEA 25 mg TID and CoQ10 333 mg TID for at least 6 weeks prior to ovarian stimulation for IVF with FSH and human menopausal gonadotropins (hMG). Since POI patients are expected to be resistant to ovarian stimulation, primary outcome for the study was ovarian response, while secondary outcome was pregnancy/delivery.Though POI/POF patients usually are completely unresponsive to ovarian stimulation, to our surprise, 5/6 (83.3%) patients demonstrated an objective follicle response. In addition, 2/6 (33.3%) conceived spontaneously between IVF cycles, while on DHEA and CoQ10 supplementation and delivered healthy offspring. One of those is currently in treatment for a second child.This preliminary report suggests that a surprising portion of young women below age 41, tagged with a diagnosis of POI/POF, due to adrenal hypoandrogenism actually suffer from a form of SOI, at least in some cases amenable to treatment by androgen supplementation. Since true POI/POF usually requires third-party egg donation, correct differentiation between POI and SOI in such women appears of great importance and may warrant a trial stimulation after androgen pre-supplementation for at least 6 weeks.

Sjögren's syndrome (SS) and ANCA-associated vasculitis (AAV) have distinct clinical presentation and evolution, with paucity of reports on overlap syndrome. We aimed to better characterize this entity.We report four additional cases from the Montpellier university hospital. We also performed a systematic literature review, according to PRISMA guidelines, in Medline, Embase, Web of science, Cochrane Library, and grey literature. Demographic, clinical, and paraclinical data on SS and AAV were analysed.A total of 3133 articles was identified in databases, with 2695 articles screened for eligibility. After exclusion, we had 30 articles on 40 patients to analyse, in addition to 4 patients from our local recruitment (44 patients overall). Patients were female in 81.8%, with median age at AAV onset of 63.5 years. All patients but one presented with SS before, or concomitantly to the diagnosis of AAV, with a median delay of 12 months between both diagnoses. AAV predominantly had renal involvement (35/44 patients, 79.5%), anti-MPO antibodies being the most frequent (35 patients), even in patients presenting with granulomatosis with polyangiitis. We observed significantly more Raynaud phenomenon and associated auto-immune diseases in the group of non-granulomatous AAV (10 patients versus 1, p = 0.015 and 8 patients versus 0, p = 0.013, respectively).This is the largest descriptive study on the association between SS and AAV, providing information on this challenging diagnosis and interplay between these two diseases. Particular attention should be paid in the first months after diagnosis, given the specific complications and outcomes of each disease.