Genome wide association study of Escherichia coli bloodstream infection isolates identifies genetic determinants for the portal of entry but not fatal outcome.

Escherichia coli is an important cause of bloodstream infections (BSI), which is of concern given its high mortality and increasing worldwide prevalence. Finding bacterial genetic variants that might contribute to patient death is of interest to better understand infection progression and implement diagnostic methods that specifically look for those factors. E. coli samples isolated from patients with BSI are an ideal dataset to systematically search for those variants, as long as the influence of host factors such as comorbidities are taken into account. Here we performed a genome-wide association study (GWAS) using data from 912 patients with E. coli BSI from hospitals in Paris, France. We looked for associations between bacterial genetic variants and three patient outcomes (death at 28 days, septic shock and admission to intensive care unit), as well as two portals of entry (urinary and digestive tract), using various clinical variables from each patient to account for host factors. We did not find any association between genetic variants and patient outcomes, potentially confirming the strong influence of host factors in influencing the course of BSI; we however found a strong association between the papGII operon and entrance of E. coli through the urinary tract, which demonstrates the power of bacterial GWAS when applied to actual clinical data. Despite the lack of associations between E. coli genetic variants and patient outcomes, we estimate that increasing the sample size by one order of magnitude could lead to the discovery of some putative causal variants. Given the wide adoption of bacterial genome sequencing of clinical isolates, such sample sizes may be soon available.

Clinical and Bacteriological Specificities of Escherichia coli Bloodstream Infections From Biliary Portal of Entries.

BACKGROUND: Escherichia coli is frequently responsible for bloodstream infections (BSIs). Among digestive BSIs, biliary infections appear to be less severe. Respective roles of host factors, bacterial determinants (phylogroups, virulence, and antibiotic resistance), and portal of entry on outcome are unknown. METHODS: Clinical characteristics and prognosis of 770 episodes of E coli BSI were analyzed and isolates sequenced (Illumina technology) comparing phylogroups, multilocus sequence type, virulence, and resistance gene content. BSI isolates were compared with 362 commensal E coli from healthy subjects. RESULTS: Among 770 episodes, 135 were biliary, 156 nonbiliary digestive, and 479 urinary. Compared to urinary infections, BSIs of digestive origin occurred significantly more in men, comorbid, and immunocompromised patients. Digestive portal of entry was significantly associated with septic shock and death. Among digestive infections, patients with biliary infections were less likely to die (P = .032), despite comparable initial severity. Biliary E coli resembled commensals (phylogroup distribution, sequence type, and few virulence-associated genes) whereas nonbiliary digestive and urinary strains carried many virulence-associated genes. CONCLUSIONS: Escherichia coli strains responsible for biliary infections exhibit commensal characteristics and are associated with lower mortality rates, despite similar initial severity, than other digestive BSIs. Biliary drainage in addition to antibiotics in the management of biliary infections may explain improved outcome.

Prospective head-to-head comparison of non-invasive scores for diagnosis of fibrotic MASH in patients with type 2 diabetes.

BACKGROUND & AIMS: Non-invasive scores have been proposed to identify patients with fibrotic, metabolic dysfunction-associated steatohepatitis (MASH), who are at the highest risk of progression to complications of cirrhosis and may benefit from pharmacologic treatments. However, data in patients with type 2 diabetes (T2DM) are lacking. The aim of this multicenter prospective study was to perform a head-to-head comparison of FAST (FibroScan-aspartate aminotransferase [AST]), MAST (MRI-AST), MEFIB (magnetic resonance elastography [MRE] plus FIB-4), and FNI (fibrotic NASH index) for detecting fibrotic MASH in patients with T2DM. METHODS: A total of 330 outpatients with T2DM and biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) from the QUID-NASH study (NCT03634098), who underwent FibroScan, MRI-proton density fat fraction and MRE at the time of liver biopsy were studied. The main outcome was fibrotic MASH, defined as NAS ≥4 (with at least one point for each parameter) and fibrosis stage ≥2 (centrally reviewed). RESULTS: All data for score comparisons were available for 245 patients (median age 59 years, 65% male, median BMI 31 kg/m2; fibrotic MASH in 39%). FAST and MAST had similar accuracy (AUROCs 0.81 vs. 0.79, p = 0.41) but outperformed FNI (0.74; p = 0.01) and MEFIB (0.68; p <0.0001). When using original cut-offs, MAST outperformed FAST, MEFIB and FNI when comparing the percentage of correctly classified patients, in whom liver biopsy would be avoided (69% vs. 48%, 46%, 39%, respectively; p <0.001). When using cut-offs specific to our population, FAST outperformed FNI and MAST (56% vs. 40%, and 38%, respectively; p <0.001). CONCLUSION: Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. IMPACT AND IMPLICATIONS: Among patients with type 2 diabetes (T2DM), identifying those with metabolic dysfunction-associated steatohepatitis and significant fibrosis, who are the most at risk of developing clinical liver-related outcomes and who may benefit from pharmacologic treatments, is an unmet need. In this prospective multicenter study, we compared four non-invasive scores, three based on imaging (MRI or ultrasound technologies) and one on laboratory blood tests, for this purpose, using original and study-specific cut-offs. Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. TRIAL REGISTRATION NUMBER: NCT03634098.

Lupus activity and outcomes in lupus patients undergoing maintenance dialysis.

OBJECTIVES: Lupus activity has long been considered to decline after initiation of maintenance dialysis (MD). This assumption is based on limited historical data. We aimed to describe the natural history of lupus in patients undergoing MD. METHODS: We assembled a national retrospective cohort of lupus patients who started dialysis between 2008 and 2011, included in the REIN registry with a 5-year follow-up. We analysed healthcare consumption from the National Health Data System. We evaluated the proportion of patients 'off-treatment' (i.e. receiving 0-5 mg/d of corticosteroids, without any immunosuppressive therapy) after the start of MD. We describe the cumulative incidences of non-severe and severe lupus flares, cardiovascular events, severe infections, kidney transplantation and survival. RESULTS: We included 137 patients (121 females and 16 males), with a median age of 42 years. The proportion of patients 'off-treatment' at dialysis initiation was 67.7% (95% CI: 61.8, 73.8%), and increased to 76.0% (95% CI: 73.3, 78.8) at 1 year and 83.4% (95% CI: 81.0, 85.9%) at 3 years, with a lower proportion in younger patients. Lupus flares mainly occurred in the first year after MD initiation, and at 12 months 51.6% of patients had presented a non-severe lupus flare and 11.6% a severe lupus flare. In addition, 42.2% (95% CI: 32.9, 50.3%) and 23.7% (95% CI: 16.0, 30.7%) of patients at 12 months had been hospitalized for cardiovascular events or infections, respectively. CONCLUSION: The proportion of lupus patients off-treatment increases after MD initiation, but non-severe and severe lupus flares continue to occur, mainly during the first year. This calls for the continued follow-up of lupus patients by lupus specialists after dialysis initiation.

Modeling SARS-CoV-2 viral kinetics and association with mortality in hospitalized patients from the French COVID cohort.

The characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics in hospitalized patients and its association with mortality is unknown. We analyzed death and nasopharyngeal viral kinetics in 655 hospitalized patients from the prospective French COVID cohort. The model predicted a median peak viral load that coincided with symptom onset. Patients with age ≥65 y had a smaller loss rate of infected cells, leading to a delayed median time to viral clearance occurring 16 d after symptom onset as compared to 13 d in younger patients (P < 10-4). In multivariate analysis, the risk factors associated with mortality were age ≥65 y, male gender, and presence of chronic pulmonary disease (hazard ratio [HR] > 2.0). Using a joint model, viral dynamics after hospital admission was an independent predictor of mortality (HR = 1.31, P < 10-3). Finally, we used our model to simulate the effects of effective pharmacological interventions on time to viral clearance and mortality. A treatment able to reduce viral production by 90% upon hospital admission would shorten the time to viral clearance by 2.0 and 2.9 d in patients of age <65 y and ≥65 y, respectively. Assuming that the association between viral dynamics and mortality would remain similar to that observed in our population, this could translate into a reduction of mortality from 19 to 14% in patients of age ≥65 y with risk factors. Our results show that viral dynamics is associated with mortality in hospitalized patients. Strategies aiming to reduce viral load could have an effect on mortality rate in this population.

Neutrophil Activation and Immune Thrombosis Profiles Persist in Convalescent COVID-19.

PURPOSE: Following a severe COVID-19 infection, a proportion of individuals develop prolonged symptoms. We investigated the immunological dysfunction that underlies the persistence of symptoms months after the resolution of acute COVID-19. METHODS: We analyzed cytokines, cell phenotypes, SARS-CoV-2 spike-specific and neutralizing antibodies, and whole blood gene expression profiles in convalescent severe COVID-19 patients 1, 3, and 6 months following hospital discharge. RESULTS: We observed persistent abnormalities until month 6 marked by (i) high serum levels of monocyte/macrophage and endothelial activation markers, chemotaxis, and hematopoietic cytokines; (ii) a high frequency of central memory CD4+ and effector CD8+ T cells; (iii) a decrease in anti-SARS-CoV-2 spike and neutralizing antibodies; and (iv) an upregulation of genes related to platelet, neutrophil activation, erythrocytes, myeloid cell differentiation, and RUNX1 signaling. We identified a "core gene signature" associated with a history of thrombotic events, with upregulation of a set of genes involved in neutrophil activation, platelet, hematopoiesis, and blood coagulation. CONCLUSION: The lack of restoration of gene expression to a normal profile after up to 6 months of follow-up, even in asymptomatic patients who experienced severe COVID-19, signals the need to carefully extend their clinical follow-up and propose preventive measures.

High sera levels of SARS-CoV-2 N antigen are associated with death in hospitalized COVID-19 patients.

The presence of free severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid-antigen in sera (N-antigenemia) has been shown in COVID-19 patients. However, the link between the quantitative levels of N-antigenemia and COVID-19 disease severity is not entirely understood. To assess the dynamics and clinical association of N-antigen sera levels with disease severity in COVID-19 patients, we analyzed data from patients included in the French COVID cohort, with at least one sera sample between January and September 2020. We assessed N-antigenemia levels and anti-N IgG titers, and patient outcomes was classified in two groups, survival or death. In samples collected within 8 days since symptom onset, we observed that deceased patients had a higher positivity rate (93% vs. 81%; p < 0.001) and higher median levels of predicted N-antigenemia (2500 vs. 1200 pg/mL; p < 0.001) than surviving patients. Predicted time to N-antigen clearance in sera was prolonged in deceased patients compared to survivors (23.3 vs 19.3 days; p < 0.0001). In a subset of patients with both sera and nasopharyngeal (NP) swabs, predicted time to N-antigen clearance in sera was prolonged in deceased patients (p < 0.001), whereas NP viral load clearance did not differ between the groups (p = 0.07). Our results demonstrate a strong relationship between N-antigenemia levels and COVID-19 severity on a prospective cohort.

Impact of corticosteroids use on midterm sequelae in survivors of COVID-19 admitted to hospital: A prospective cohort study.

An understanding of the midterm sequelae in COVID-19 and their association with corticosteroids use are needed. Between March and July 2020, we evaluated 1227 survivors of COVID-19, 3 months posthospitalization, of whom 213 had received corticosteroids within 7 days of admission. Main outcome was any midterm sequelae (oxygen therapy, shortness of breath, one major clinical sign, two minor clinical signs or three minor symptoms). Association between corticosteroids use and midterm sequelae was assessed using inverse propensity-score weighting models. Our sample included 753 (61%) male patients, and 512 (42%) were older than 65 years. We found a higher rate of sequelae among users than nonusers of corticosteroids (42% vs. 35%, odds ratio [OR] 1.40 [1.16-1.69]). Midterm sequelae were more frequent in users of low-dose corticosteroids than nonusers (64% vs. 51%, OR 1.60 [1.10-2.32]), whereas no association between higher doses (≥20 mg/day equivalent of dexamethasone) and sequelae was evidenced (OR 0.95 [0.56-1.61]). Higher risk of sequelae with corticosteroids use was observed among subjects with propensity score below the 90th percentile. Our study suggest that corticosteroids use during hospitalization for COVID-19 is associated with higher risk of midterm sequelae.

No increased prevalence of autoantibodies neutralizing type I IFNs in idiopathic pulmonary fibrosis patients.

SARS-CoV2 infection has a poor prognosis in patients affected of idiopathic pulmonary fibrosis (IPF). Autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) are found in the blood of at least 15% of patients with life-threatening COVID-19 pneumonia. Because of the elevated prevalence of some auto-Abs in IPF patients, we hypothesize that the prevalence of auto-Abs neutralizing type I IFNs might be increased in the IPF population and then explained specific poor outcome after COVID-19. We screened the plasma of 247 consecutive IPF patients for the presence of auto-Abs neutralizing type I IFNs. Three patients displayed auto-Abs neutralizing type I IFNs. Among them, the only patient with documented SARS-CoV-2 infection experienced life threatening COVID-19 pneumonia. The prevalence of auto-Abs neutralizing type I IFNs in this cohort of IPF patients was not significantly different from the one of the general population. Overall, this study did not suggest any association between auto-Abs neutralizing type I IFNs and IPF.

Clonal haematopoiesis of indeterminate potential and cardiovascular events in systemic lupus erythematosus (HEMATOPLUS study).

OBJECTIVE: The detection of somatic mutations among the genes of myeloid cells in asymptomatic patients-defining clonal haematopoiesis of indeterminate potential (CHIP)-is associated with a predisposition to cardiovascular events (CVEs) in the general population. We aimed to determine whether CHIP was associated with CVEs in SLE patients. METHODS: The study is an ancillary study of the randomized, double-blind, placebo-controlled, multicentre PLUS trial conducted from June 2007 through August 2010 at 37 centres in France, involving 573 SLE patients. The search for somatic mutations by high-throughput sequencing of 53 genes involved in clonal haematopoiesis was performed on genomic DNA collected at PLUS inclusion. CHIP prevalence was assessed in SLE and in a retrospective cohort of 479 patients free of haematological malignancy. The primary outcome was an incident CVE in SLE. RESULTS: Screening for CHIP was performed in 438 SLE patients [38 (29-47) years, 91.8% female]. Overall, 63 somatic mutations were identified in 47 patients, defining a CHIP prevalence of 10.7% in SLE. Most SLE patients (78.7%) carried a single mutation. Most variants (62.5%) were located in the DNMT3A gene. CHIP frequency was related to age and to age at SLE diagnosis, and was associated with a lower frequency of aPLs. CHIP occurred >20 years earlier (P < 0.00001) in SLE than in controls. The detection of CHIP at inclusion was not found to be associated with occurrence of CVEs during follow-up [HR = 0.42 (0.06-3.21), P = 0.406]. CONCLUSION: The prevalence of CHIP is relatively high in SLE for a given age, but was not found to be associated with incident CVEs. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05146414.

[Therapeutic alliance between sectorial psychiatry inpatients and nurses and aides: A prospective, observational and cross-sectional study]. / Alliance Thérapeutique Entre Les Patients Hospitalisés En Psychiatrie De Secteur Et Les Infirmier(e)s Et Aide-Soignant(e)s: Une Etude Prospective, Observationnelle Et Transversale.

BACKGROUND: Therapeutic alliance represents a rarely studied object when it relates to nurses and care provided by a nursing team in acute care hospitalization. OBJECTIVE: The objective was to study how factors might influence the therapeutic alliance built between nurses and aides and adult inpatients in an acute care unit of sectorial general psychiatry. METHOD: This is a prospective, observational and cross-sectional study using a therapeutic alliance measurement scale. Therapeutic alliance (TA) score was measured with a STAR-P scale in a sample of 240 patients. RESULTS: The median score found is 33.4 (±7.8) out of a maximum theoretical score of 48. The global score of TA in patients aged 60 years old or more is significantly higher than the score of patients between 18 and 29 years old (p=0.021). The lack of external follow-up in the three months after hospital release is not associated with TA global score (p=0.73). If inpatients, no matter what their diseases or types of care are, under legal obligation or not, consider their TA is rather good after their hospital stay. Only sociodemographic factors like age, housing conditions (insecure or sustainable), having a job or not, living alone or with a partner affect TA and follow-up. CONCLUSION: Results evoke concepts of anomie and attachment, that seem to play an important role in the lack of follow-up after hospital stay, and indicate the mandatory global approach to care and an involvement of health professionals as well as social beings, where empathy must find its place.

CONTEXTE: L'alliance thérapeutique représente un objet très peu étudié quand il concerne les infirmiers et les soins prodigués par une équipe infirmière et dans le cadre de l'hospitalisation en soins aigus. OBJECTIF: L'objectif était d'étudier l'influence de facteurs sur l'alliance thérapeutique construite entre les infirmier(e)s et les aides-soignant(e)s et les patients adultes hospitalisés dans un service de soins aigus en psychiatrie générale de secteur. MÉTHODE: Il s'agit d'une étude prospective, observationnelle et transversale utilisant une échelle de mesure de l'alliance thérapeutique. Le score d'alliance thérapeutique (AT) a été mesuré à l'aide de l'échelle STAR-P sur un échantillon de 240 patients. RÉSULTATS: Le score moyen obtenu est de 33,4 (±7,8) sur un score maximum théorique de 48. Le score global d'AT des patients âgés de 60 ans ou plus, est significativement plus élevé que celui des patients ayant entre 18 et 29 ans (p = 0,021). L'absence de suivi ambulatoire au cours des trois mois suivant la sortie d'hospitalisation n'est pas associée au score global d'AT (p = 0,73). Si les patients hospitalisés, quelques soit leurs troubles et les différentes formes de soins, sous obligation légale ou non, jugent plutôt bonne l'AT à l'issue de leur hospitalisation. Seuls des facteurs sociaux-démographiques comme, l'âge, les conditions d'hébergement (précaire ou durable), avoir ou non un emploi, vivre seul ou avec un partenaire influent sur l'AT et le suivi. CONCLUSION: Les résultats convoquent les concepts d'anomie et d'attachement, qui semblent jouer un rôle important dans l'absence de suivi post-hospitalisation, ce qui indiquent la nécessaire approche globale des soins et une implication des professionnels de santé mais aussi du social où l'empathie doit trouver sa place.

Impact of Systematic Whole-body 18F-Fluorodeoxyglucose PET/CT on the Management of Patients Suspected of Infective Endocarditis: The Prospective Multicenter TEPvENDO Study.

BACKGROUND: Diagnostic and patients' management modifications induced by whole-body 18F-FDG-PET/CT had not been evaluated so far in prosthetic valve (PV) or native valve (NV) infective endocarditis (IE)-suspected patients. METHODS: In sum, 140 consecutive patients in 8 tertiary care hospitals underwent 18F-FDG-PET/CT. ESC-2015-modified Duke criteria and patients' management plan were established jointly by 2 experts before 18F-FDG-PET/CT. The same experts reestablished Duke classification and patients' management plan immediately after qualitative interpretation of 18F-FDG-PET/CT. A 6-month final Duke classification was established. RESULTS: Among the 70 PV and 70 NV patients, 34 and 46 were classified as definite IE before 18F-FDG-PET/CT. Abnormal perivalvular 18F-FDG uptake was recorded in 67.2% PV and 24.3% NV patients respectively (P < .001) and extracardiac uptake in 44.3% PV and 51.4% NV patients. IE classification was modified in 24.3% and 5.7% patients (P = .005) (net reclassification index 20% and 4.3%). Patients' managements were modified in 21.4% PV and 31.4% NV patients (P = .25). It was mainly due to perivalvular uptake in PV patients and to extra-cardiac uptake in NV patients and consisted in surgery plan modifications in 7 patients, antibiotic plan modifications in 22 patients and both in 5 patients. Altogether, 18F-FDG-PET/CT modified classification and/or care in 40% of the patients (95% confidence interval: 32-48), which was most likely to occur in those with a noncontributing echocardiography (P < .001) or IE classified as possible at baseline (P = .04), while there was no difference between NV and PV. CONCLUSIONS: Systematic 18F-FDG-PET/CT did significantly and appropriately impact diagnostic classification and/or IE management in PV and NV-IE suspected patients. CLINICAL TRIALS REGISTRATION: NCT02287792.

Pregnancy Outcomes after ZIKV Infection in French Territories in the Americas.

BACKGROUND: The risk of congenital neurologic defects related to Zika virus (ZIKV) infection has ranged from 6 to 42% in various reports. The aim of this study was to estimate this risk among pregnant women with symptomatic ZIKV infection in French territories in the Americas. METHODS: From March 2016 through November 2016, we enrolled in this prospective cohort study pregnant women with symptomatic ZIKV infection that was confirmed by polymerase-chain-reaction (PCR) assay. The analysis included all data collected up to April 27, 2017, the date of the last delivery in the cohort. RESULTS: Among the 555 fetuses and infants in the 546 pregnancies included in the analysis, 28 (5.0%) were not carried to term or were stillborn, and 527 were born alive. Neurologic and ocular defects possibly associated with ZIKV infection were seen in 39 fetuses and infants (7.0%; 95% confidence interval, 5.0 to 9.5); of these, 10 were not carried to term because of termination of pregnancy for medical reasons, 1 was stillborn, and 28 were live-born. Microcephaly (defined as head circumference more than 2 SD below the mean for sex and gestational age) was detected in 32 fetuses and infants (5.8%), of whom 9 (1.6%) had severe microcephaly (more than 3 SD below the mean). Neurologic and ocular defects were more common when ZIKV infection occurred during the first trimester (24 of 189 fetuses and infants [12.7%]) than when it occurred during the second trimester (9 of 252 [3.6%]) or third trimester (6 of 114 [5.3%]) (P=0.001). CONCLUSIONS: Among pregnant women with symptomatic, PCR-confirmed ZIKV infection, birth defects possibly associated with ZIKV infection were present in 7% of fetuses and infants. Defects occurred more frequently in fetuses and infants whose mothers had been infected early in pregnancy. Longer-term follow-up of infants is required to assess any manifestations not detected at birth. (Funded by the French Ministry of Health and others; ClinicalTrials.gov number, NCT02916732 .).

Highly sensitive serum cardiac troponin T and cardiovascular events in patients with systemic lupus erythematosus (TROPOPLUS study).

OBJECTIVE: Identification of biological markers able to better stratify cardiovascular risks in SLE patients is needed. We aimed to determine whether serum cardiac troponin T (cTnT) levels measured with a highly sensitive assay [high sensitivity cTnT (HS-cTnT)] may predict cardiovascular events (CVEs) in SLE. METHOD: All SLE patients included between 2007 and 2010 in the randomized, double-blind, placebo-controlled, multicentre PLUS trial were screened. Patients with no past history of CVE at inclusion and a follow-up period of >20 months were analysed. HS-cTnT concentration was measured using the electrochemiluminescence method on serum collected at PLUS inclusion. The primary outcome was the incident CVE. Factors associated with the primary outcome were identified and multivariate analysis was performed. RESULTS: Overall, 442 SLE patients (of the 573 included in the PLUS study) were analysed for the primary outcome with a median follow up of 110 (interquartile range: 99-120) months. Among them, 29 (6.6%) experienced at least one CVE that occurred at a median of 67 (interquartile range: 31-91) months after inclusion. Six out of 29 patients had more than one CVE. In the multivariate analysis, dyslipidaemia, age and HS-cTnT were associated with the occurrence of CVE. Kaplan-Meier analysis showed that a concentration of HS-cTnT > 4.27 ng/l at inclusion increased by 2.7 [hazard ratio 2.7 (95% CI: 1.3, 5.6), P =0.0083] the risk of CVE in SLE. CONCLUSION: HS-cTnT measured in serum is the first identified biomarker independently associated with incident CVE in SLE patients.

CD62L on blood basophils: a first pre-treatment predictor of remission in severe lupus nephritis.

BACKGROUND: Basophils were recently shown to contribute to lupus nephritis (LN). This study assessed blood basophil activation markers (BAMs) for the diagnosis of LN severity and as pre-treatment prognostic markers of the response to treatment in patients with severe LN. METHOD: The diagnostic study included all the patients of a monocentric prospective observational cohort built with consecutive patients diagnosed with LN on the basis of a renal biopsy. The prognostic study selected patients of this cohort according to the following inclusion criteria: ≥18 years old, Class III or IV A ± C ± Class V or pure Class V LN at the time of inclusion and treated with an induction treatment for LN. Clinical data and BAMs were obtained at the time of the kidney biopsy. LN remission status was recorded 12 months after induction therapy initiation. Associations between baseline data and histological severity of LN or LN remission were assessed using logistic regression. RESULTS: No significant association was found between BAMs and the histological severity of LN in 101 patients. Among the 83 patients included in the prognostic study, 64 reached renal remission. CD62L expression on blood basophils at baseline was independently negatively associated with remission at 12 months [odds ratio = 0.26, 95% confidence interval 0.08-0.82, P = 0.02 for quantitative CD62L expression >105 (geometric fluorescent intensity) gMFI]. CD62L <105 gMFI was associated with a probability of 0.87 of LN remission in the next 12 months after the start of induction therapy. CONCLUSION: Pre-treatment CD62L expression on blood basophils could be a first predictive biomarker of renal response to induction therapy at 12 months in patients with severe LN.

Evaluation by simulation of clinical trial designs for evaluation of treatment during a viral haemorrhagic fever outbreak.

BACKGROUND: Viral haemorrhagic fevers are characterized by irregular outbreaks with high mortality rate. Difficulties arise when implementing therapeutic trials in this context. The outbreak duration is hard to predict and can be short compared to delays of trial launch and number of subject needed (NSN) recruitment. Our objectives were to compare, using clinical trial simulation, different trial designs for experimental treatment evaluation in various outbreak scenarios. METHODS: Four type of designs were compared: fixed or group-sequential, each being single- or two-arm. The primary outcome was 14-day survival rate. For single-arm designs, results were compared to a pre-trial historical survival rate pH. Treatments efficacy was evaluated by one-sided tests of proportion (fixed designs) and Whitehead triangular tests (group-sequential designs) with type-I-error = 0.025. Both survival rates in the control arm pC and survival rate differences Δ (including 0) varied. Three specific cases were considered: "standard" (fixed pC, reaching NSN for fixed designs and maximum sample size NMax for group-sequential designs); "changing with time" (increased pC over time); "stopping of recruitment" (epidemic ends). We calculated the proportion of simulated trials showing treatment efficacy, with K = 93,639 simulated trials to get a type-I-error PI95% of [0.024;0.026]. RESULTS: Under H0 (Δ = 0), for the "standard" case, the type-I-error was maintained regardless of trial designs. For "changing with time" case, when pC > pH, type-I-error was inflated, and when pC < pH it decreased. Wrong conclusions were more often observed for single-arm designs due to an increase of Δ over time. Under H1 (Δ = + 0.2), for the "standard" case, the power was similar between single- and two-arm designs when pC = pH. For "stopping of recruitment" case, single-arm performed better than two-arm designs, and fixed designs reported higher power than group-sequential designs. A web R-Shiny application was developed. CONCLUSIONS: At an outbreak beginning, group-sequential two-arm trials should be preferred, as the infected cases number increases allowing to conduct a strong randomized control trial. Group-sequential designs allow early termination of trials in cases of harmful experimental treatment. After the epidemic peak, fixed single-arm design should be preferred, as the cases number decreases but this assumes a high level of confidence on the pre-trial historical survival rate.

Chikungunya, a Risk Factor for Guillain-Barré Syndrome.

In a matched case-control study where 24 cases developed Guillain-Barré syndrome (GBS) during the 2014 chikungunya outbreak in the French West Indies and 72 controls were blood donors during the same period, chikungunya infection was a risk factor for GBS (odds ratio, 8.3; 95% confidence interval, 2.3-29.7; P = .001).

Impact of cardiac function, refractory ascites and beta blockers on the outcome of patients with cirrhosis listed for liver transplantation.

BACKGROUND & AIMS: Whether non-selective beta blockers (NSBBs) are deleterious in patients with end-stage cirrhosis and refractory ascites has been widely debated. We hypothesized that only the subset of patients on the liver transplant waiting list who had impaired cardiac performance would be at increased risk of mortality if receiving NSBBs. METHODS: This study included 584 consecutive patients with cirrhosis evaluated for transplantation between 1999 and 2014. All patients had right heart catheterization with hemodynamic measurements at evaluation. Fifty percent received NSBBs. Refractory ascites was present in 33%. Cardiac performance was assessed by left ventricular stroke work index (LVSWI). Waiting list mortality without liver transplantation was explored using competing risk analysis. RESULTS: LVSWI was significantly lower in patients with refractory ascites. In multivariate analysis using competing risk, refractory ascites, NSBBs and LVSWI were associated with waiting list mortality in the whole population, with a statistically significant interaction between NSBBs and LVSWI. The most discriminant value of LVSWI was 64.1 g-m/m2. In the final model, refractory ascites (subdistribution hazard ratio 1.52; 95% CI1.01-2.28; p = 0.0083) and treatment by NSBBs with LVSWI <64.1 g-m/m2 (subdistribution hazard ratio 1.96; 95% CI 1.32-2.90; p = 0.0009) were significantly associated with waiting list mortality, taking into account serum sodium and the model for end-stage liver disease score. CONCLUSIONS: This study suggests that compromised cardiac performance is more common in patients with refractory ascites and that NSBBs are deleterious in cirrhotic patients with compromised cardiac performance. These results highlight the prognostic value of cardiac function in patients with end-stage cirrhosis. LAY SUMMARY: There are still controversies concerning the impact of non-selective beta blockers on outcomes in patients with decompensated cirrhosis, especially in those with refractory ascites. In this study of 584 cirrhotic patients evaluated for liver transplantation, who underwent right heart catheterization, we have shown that global cardiac performance measured by left ventricular stroke work index is lower in patients with refractory ascites. Administration of non-selective beta blockers in patients with compromised cardiac performance may increase waiting list mortality. These results highlight the prognostic value of global cardiac performance in patients with end-stage cirrhosis.

Pharmacokinetics of lopinavir/ritonavir oral solution to treat COVID-19 in mechanically ventilated ICU patients.

BACKGROUND: The combination lopinavir/ritonavir is recommended to treat HIV-infected patients at the dose regimen of 400/100 mg q12h, oral route. The usual lopinavir trough plasma concentrations are 3000-8000 ng/mL. A trend towards a 28 day mortality reduction was observed in COVID-19-infected patients treated with lopinavir/ritonavir. OBJECTIVES: To assess the plasma concentrations of lopinavir and ritonavir in patients with severe COVID-19 infection and receiving lopinavir/ritonavir. PATIENTS AND METHODS: Mechanically ventilated patients with COVID-19 infection included in the French COVID-19 cohort and treated with lopinavir/ritonavir were included. Lopinavir/ritonavir combination was administered using the usual adult HIV dose regimen (400/100 mg q12h, oral solution through a nasogastric tube). A half-dose reduction to 400/100 mg q24h was proposed if lopinavir Ctrough was >8000 ng/mL, the upper limit considered as toxic and reported in HIV-infected patients. Lopinavir and ritonavir pharmacokinetic parameters were determined after an intensive pharmacokinetic analysis. Biological markers of inflammation and liver/kidney function were monitored. RESULTS: Plasma concentrations of lopinavir and ritonavir were first assessed in eight patients treated with lopinavir/ritonavir. Median (IQR) lopinavir Ctrough reached 27 908 ng/mL (15 928-32 627). After the dose reduction to 400/100 mg q24h, lopinavir/ritonavir pharmacokinetic parameters were assessed in nine patients. Lopinavir Ctrough decreased to 22 974 ng/mL (21 394-32 735). CONCLUSIONS: In mechanically ventilated patients with severe COVID-19 infections, the oral administration of lopinavir/ritonavir elicited plasma exposure of lopinavir more than 6-fold the upper usual expected range. However, it remains difficult to safely recommend its dose reduction without compromising the benefit of the antiviral strategy, and careful pharmacokinetic and toxicity monitoring are needed.

Head-to-head comparison of the diagnostic performances of Rubidium-PET and SPECT with CZT camera for the detection of myocardial ischemia in a population of women and overweight individuals.

BACKGROUND: The aim of this study was to compare the diagnostic performances for the detection of myocardial ischemia of 82-Rb-PET-MPS and 99m-Tc-SPECT-MPS in overweight individuals and women. METHODS AND RESULTS: Men with BMI ≥ 25 and women referred for MPS were considered for inclusion. All individuals underwent 99m-Tc-SPECT-MPS with CZT cameras and 82-Rb-PET-MPS in 3D-mode. Individuals with at least one positive MPS were referred for coronary angiography (CA) with FFR measurements. A criterion for positivity was a composite endpoint including significant stenosis on CA or, in the absence of CA, the occurrence of acute coronary event during the following year. 313 patients (46% women) with mean BMI of 31.8 ± 6.5 were included. Sensitivity for the detection of myocardial ischemia was higher with 82-Rb-PET-MPS compared with 99m-Tc-SPECT-MPS (85% vs. 57%, P < .05); specificity was equally high with both imaging techniques (93% vs. 94%, P > .05). 82-Rb-PET allowed for a more accurate detection of patients with a high-risk coronary artery disease (HR-CAD) than 99m-Tc-SPECT-MPS (AUC = 0.86 vs. 0.75, respectively; P = .04). CONCLUSIONS: In women and overweight individuals, 82-Rb-PET-MPS provides higher sensitivity for the detection of myocardial ischemia than 99m-Tc-SPECT-MPS thanks to a better image quality and an improved detection of HR-CAD.