Cardiac diastolic maladaptation is associated with the severity of exercise intolerance in sickle cell anemia patients.

This pilot study focusing on Sickle Cell Anemia (SCA) patients offers a comprehensive and integrative evaluation of respiratory, cardiovascular, hemodynamic, and metabolic variables during exercise. Knowing that diastolic dysfunction is frequent in this population, we hypothesize that a lack of cardiac adaptation through exercise might lead to premature increase in blood lactate concentrations in SCA patients, a potential trigger for acute disease complication. SCA patients were prospectively included in PHYSIO-EXDRE study and underwent a comprehensive stress test with a standardized incremental exercise protocol up to 4 mmol L-1 blood lactate concentration (BL4). Gas exchange, capillary lactate concentration and echocardiography were performed at baseline, during stress test (at ∼ 2 mmol L-1) and BL4. The population was divided into two groups and compared according to the median value of percentage of theoretical peak oxygen uptake (% V ˙ O 2 p e a k t h ) at BL4. Twenty-nine patients were included (42 ± 12 years old, 48% of women). Most patients reached BL4 at low-intensity exercise [median value of predicted power output (W) was 37%], which corresponds to daily life activities. The median value of % V ˙ O 2 p e a k t h at BL4 was 39%. Interestingly, diastolic maladaptation using echocardiography during stress test along with hemoglobin concentration were independently associated to early occurrence of BL4. As BL4 occurs for low-intensity exercises, SCA patients may be subject to acidosis-related complications even during their daily life activities. Beyond assessing physical capacities, our study underlines that diastolic maladaptation during exercise is associated with an early increase in blood lactate concentration.

14-day tailored PCR-guided triple therapy versus 14-day non-Bismuth concomitant quadruple therapy for Helicobacter pylori eradication: A multicenter, open-label randomized noninferiority controlled trial.

BACKGROUND: The systematic use of susceptibility testing and tailored first-line treatment for Helicobacter pylori eradication has yet to be established. AIM: To compare 14-day tailored PCR-guided triple therapy to 14-day non-Bismuth concomitant quadruple therapy for first-line Helicobacter pylori eradication. PATIENTS AND METHODS: We performed a multicenter, parallel-group, randomized noninferiority controlled trial. Naive adult patients with Helicobacter pylori infection were treated with 14-day tailored PCR-guided triple therapy (esomeprazole 40 mg and amoxicillin 1000 mg b.d. plus clarithromycin 500 mg or levofloxacin 500 mg b.d. according to clarithromycin susceptibility) or 14-day non-Bismuth concomitant quadruple therapy (esomeprazole 40 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and metronidazole 500 mg b.d.). The primary endpoint was H. pylori eradication. RESULTS: We screened 991 patients for eligibility and randomized 241 patients. The first-line eradication rate was 99.2% in the tailored PCR-guided group and 95.9% in the control group (ITT population; absolute difference of +3.30%, with a lower bound of CI at -0.68%). Both first-line therapies were well tolerated, with a formally significant difference in favor of the tailored PCR-guided group (61.4% vs. 41.2%, p = 0.003). Economic analyses revealed a lower cost of the tailored PCR-guided arm, with a 92% chance of being jointly more effective and less expensive than the control arm in the ITT population. CONCLUSION: In a country with a high level of clarithromycin resistance, the results of our study demonstrated the noninferiority of 14-day tailored PCR-guided triple therapy as a first-line H. pylori eradication therapy compared to 14-day non-Bismuth quadruple therapy (ClinicalTrials.gov NCT02576236).

COVID-19 associated pulmonary aspergillosis in critically-ill patients: a prospective multicenter study in the era of Delta and Omicron variants.

BACKGROUND: During the first COVID-19 pandemic wave, COVID-19-associated pulmonary aspergillosis (CAPA) has been reported in up to 11-28% of critically ill COVID-19 patients and associated with increased mortality. As new SARS-CoV-2 variants emerged, the characteristics of critically ill COVID-19 patients have evolved, particularly in the era of Omicron. The purpose of this study is to investigate the characteristics of CAPA in the era of new variants. METHODS: This is a prospective multicenter observational cohort study conducted in France in 36 participating intensive care units (ICU), between December 7th, 2021 and April 26th 2023. Diagnosis criteria of CAPA relied on European Confederation of Medical Mycology (ECMM)/International Society for Human & Animal Mycology (ISHAM) consensus criteria. RESULTS: 566 patients were included over the study period. The prevalence of CAPA was 5.1% [95% CI 3.4-7.3], and rose to 9.1% among patients who required invasive mechanical ventilation (IMV). Univariable analysis showed that CAPA patients were more frequently immunosuppressed and required more frequently IMV support, vasopressors and renal replacement therapy during ICU stay than non-CAPA patients. SAPS II score at ICU admission, immunosuppression, and a SARS-CoV-2 Delta variant were independently associated with CAPA in multivariable logistic regression analysis. Although CAPA was not significantly associated with day-28 mortality, patients with CAPA experienced a longer duration of mechanical ventilation and ICU stay. CONCLUSION: This study contributes valuable insights into the prevalence, characteristics, and outcomes of CAPA in the era of Delta and Omicron variants. We report a lower prevalence of CAPA (5.1%) among critically-ill COVID-19 patients than previously reported, mainly affecting intubated-patients. Duration of mechanical ventilation and ICU stay were significantly longer in CAPA patients.

Respiratory outcomes and survival after unplanned extubation in the NICU: a prospective cohort study from the SEPREVEN trial.

OBJECTIVE: To compare reintubation rates after planned extubation and unplanned extubation (UE) in patients in neonatal intensive care units (NICUs), to analyse risk factors for reintubation after UE and to compare outcomes in patients with and without UE. DESIGN: Prospective, observational study nested in a randomised controlled trial (SEPREVEN/Study on Epidemiology and PRevention of adverse EVEnts in Neonates). Outcomes were expected to be independent of the intervention tested. SETTING: 12 NICUs in France with a 20-month follow-up, starting November 2015. PATIENTS: n=2280 patients with a NICU stay >2 days, postmenstrual age ≤42 weeks on admission. INTERVENTIONS/EXPOSURE: Characteristics of UE (context, timing, sedative administration in the preceding 6 hours, weaning from ventilation at time of UE) and patients. MAIN OUTCOME MEASURES: Healthcare professional-reported UE rates, reintubation/timing after extubation, duration of mechanical ventilation, mortality and bronchopulmonary dysplasia (BPD). RESULTS: There were 162 episodes of UE (139 patients, median gestational age (IQR) 27.3 (25.6-31.7) weeks). Cumulative reintubation rates within 24 hours and 7 days of UE were, respectively, 50.0% and 57.5%, compared with 5.5% and 12.3% after a planned extubation. Independent risk factors for reintubation within 7 days included absence of weaning at the time of UE (HR, 95% CI) and sedatives in the preceding 6 hours (HR 1.93, 95% CI 1.04 to 3.60). Mortality at discharge did not differ between patients with planned extubation or UE. UE was associated with a higher risk of BPD. CONCLUSION: In the SEPREVEN trial, reintubation followed UE in 58% of the cases, compared with 12% after planned extubation. TRIAL REGISTRATION NUMBER: NCT02598609.

Study protocol for FASTRAK: a randomised controlled trial evaluating the cost impact and effectiveness of FAST-MRI for HCC suRveillance in pAtients with high risK of liver cancer.

INTRODUCTION: The surveillance of hepatocellular carcinoma (HCC) using semi-annual liver ultrasound (US) is justified in patients with cirrhosis. In this context, US has a low sensitivity (<30%) for the detection of HCC at the very early stage (ie, Barcelona clinic liver cancer (BCLC) 0, uninodular tumour <2 cm). The sensitivity of abbreviated liver MRI (AMRI) is reported to exceed 80%, but its use is hampered by costs and availability. Our hypothesis is that AMRI used as a screening examination in patients at high risk of HCC (>3% per year) could increase the rates of patients with a tumour detected at an early stage accessible to curative-intent treatment, and demonstrate its cost-effectiveness in this population. METHODS AND ANALYSIS: The FASTRAK trial is a multicentre, randomised controlled trial with two parallel arms, aiming for superiority and conducted on patients at high risk for HCC (yearly HCC incidence >3%). Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial, each patient will be randomly assigned to the experimental group (semi-annual US and AMRI) or the control group (semi-annual US alone). The main objective is to assess the cost/quality-adjusted life year and cost/patient detected with a BCLC 0 HCC in both arms. A total of 944 patients will be recruited in 37 tertiary French centres during a 36-month period and will be followed-up during 36 months. ETHICS AND DISSEMINATION: The FASTRAK trial received ethical approval on 4 April 2022. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. TRIAL REGISTRATION NUMBER: Clinical trial number (ClinicaTrials.gov) NCT05095714.

The clinical and financial burden of nonhepatocellular carcinoma focal lesions detected during the surveillance of patients with cirrhosis.

BACKGROUND AND AIMS: HCC surveillance is challenged by the detection of hepatic focal lesions (HFLs) of other types. This study aimed to describe the incidence, characteristics, outcomes, and costs of non-HCC HFL detected during surveillance. APPROACH AND RESULTS: We retrospectively analyzed nonstandardized workup performed in French patients included in HCC surveillance programs recruited in 57 French tertiary centers (ANRS CirVir and CIRRAL cohorts, HCC 2000 trial). The overall cost of workup was evaluated, with an estimation of an average cost per patient for the entire population and per lesion detected. A total of 3295 patients were followed up for 59.8 months, 391 (11.9%) patients developed HCCs (5-year incidence: 12.1%), and 633 (19.2%) developed non-HCC HFLs (5-year incidence: 21.8%). Characterization of non-HCC HFL required a median additional of 0.7 exams per year. A total of 11.8% of non-HCC HFLs were not confirmed on recall procedures, and 19.6% of non-HCC HFLs remained undetermined. A definite diagnosis of benign liver lesions was made in 65.1%, and malignant tumors were diagnosed in 3.5%. The survival of patients with benign or undetermined non-HCC HFL was similar to that of patients who never developed any HFL (5-year survival 92% vs. 88%, p = 0.07). The average cost of the diagnostic workup was 1087€ for non-HCC HFL and €1572 for HCC. CONCLUSIONS: Non-HCC HFLs are frequently detected in patients with cirrhosis, and do not impact prognosis, but trigger substantial costs. This burden must be considered in cost-effectiveness analyses of future personalized surveillance strategies.

Left atrial appendage closure in very elderly patients in the French National Registry.

OBJECTIVE: Left atrial appendage closure (LAAC) is recommended to decrease the stroke risk in patients with atrial fibrillation and contraindications to anticoagulation. However, age-stratified data are scarce. The aim of this study was to provide information on the safety and efficacy of LAAC, with emphasis on the oldest patients. METHODS: A nationwide, prospective, multicentre, observational registry was established by 53 French cardiology centres in 2018-2021. The composite primary endpoint included ischaemic stroke, systemic embolism, and unexplained or cardiovascular death. Separate analyses were done in the groups <80 years and ≥80 years. RESULTS: Among the 1053 patients included, median age was 79.7 (73.6-84.3) years; 512 patients (48.6%) were aged ≥80 years. Procedure-related serious adverse events were non-significantly more common in octogenarians (7.0% vs 4.4% in patients aged <80 years, respectively; p=0.07). Despite a higher mean CHA2DS2-VASc score in octogenarians, the rate of thromboembolic events during the study was similar in both groups (3.0 vs 3.1/100 patient-years; p=0.85). By contrast, all-cause mortality was significantly higher in octogenarians (15.3 vs 10.1/100 patient-years, p<0.015), due to a higher rate of non-cardiovascular deaths (8.2 vs 4.9/100 patient-years, p=0.034). The rate of the primary endpoint was 8.1/100 patient-years overall with no statistically significant difference between age groups (9.4 and 7.0/100 patient-years; p=0.19). CONCLUSION: Despite a higher mean CHA2DS2-VASc score in octogenarians, the rate of thromboembolic events after LAAC in this age group was similar to that in patients aged <80 years. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03434015).

Combined effects of smoking and HIV infection on the occurrence of aging-related manifestations.

Both HIV-1 infection and smoking may contribute to the development of ageing-related manifestations affecting the prognosis of people living with HIV, but it is unclear whether HIV and smoking exert their effects independently or interact by potentiating each other. We conducted a cross-sectional study in 192 people living with HIV aged- and gender-matched with 192 HIV-uninfected controls, assessing the relative effect of HIV-1/smoking status on lung function (FEV1), bone mineral density (BMD), appendicular skeletal muscle mass index (ASMI), aortic pulse-wave velocity (PWV), insulin resistance (HOMA-IR) and renal function. In both unadjusted and adjusted analyses, FEV1, BMD and ASMI significantly differed according to smoking/HIV status, with the worst parameters found in HIV-1 infected patients currently smoking, and BMD and ASMI decreased to a lesser extent in HIV-1 infected patients formerly smoking (> 10 pack-years). Values in people living with HIV with < 10 pack-years exposure were of similar magnitude to those from controls. Regarding PWV, HOMA-R and eGFR, no significant differences were found, with the exception of eGFR values which were globally lower in HIV-1 infected patients. In conclusion HIV infection and smoking acted synergistically and were associated with a wasting phenotype combining muscle mass and bone mineral reduction.Clinical Trial Registration (registrar, website, and registration number), where applicable: CPP 10-023, 09-027, 10-034.

Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling.

We previously reported initial clinical results of post-transcriptional gene silencing of BCL11A expression (NCT03282656) reversing the fetal to adult hemoglobin switch. A goal of this approach is to increase fetal hemoglobin (HbF) expression while coordinately reducing sickle hemoglobin (HbS) expression. The resulting combinatorial effect should prove effective in inhibiting HbS polymerization at lower physiologic oxygen values thereby mitigating disease complications. Here we report results of exploratory single-cell analysis of patients in which BCL11A is targeted molecularly and compare results with cells of patients treated with hydroxyurea (HU), the current standard of care. We use single-cell assays to assess HbF, HbS, oxygen saturation, and hemoglobin polymer content in RBCs for nine gene therapy trial subjects (BCLshmiR, median HbF% = 27.9) and compare them to 10 HU-treated subjects demonstrating high and comparable levels of HbF (HU High Responders, median HbF% = 27.0). All BCL11A patients achieved the primary endpoint for NCT03282656, which was defined by an absolute neutrophil count greater than or equal to 0.5 × 109 cells/L for three consecutive days, achieved within 7 weeks following infusion. Flow cytometric assessment of single-RBC HbF and HbS shows fewer RBCs with high HbS% that would be most susceptible to sickling in BCLshmiR vs. HU High Responders: median 42% of RBCs with HbS%>70% in BCLshmiR vs. 61% in HU High Responders (p = 0.004). BCLshmiR subjects also demonstrate more RBCs resistant to HbS polymerization at lower physiologic oxygen tension: median 32% vs. 25% in HU High Responders (p = 0.006). Gene therapy-induced BCL11A down-regulation reverses the fetal-to-adult hemoglobin switch and induces RBCs with higher HbF%, lower HbS%, and greater resistance to deoxygenation-induced polymerization in clinical trial subjects compared with a cohort of highly responsive hydroxyurea-treated subjects.

ERS: A simple scoring system to predict early recurrence after surgical resection for hepatocellular carcinoma.

BACKGROUND: Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant setting, but standardised risk stratification tools of HCC recurrence are lacking. OBJECTIVES: To develop and validate a simple scoring system to predict 2-year recurrence after SR for HCC. METHODS: 2359 treatment-naïve patients who underwent SR for HCC in 17 centres in Europe and Asia between 2004 and 2017 were divided into a development (DS; n = 1558) and validation set (VS; n = 801) by random sampling of participating centres. The Early Recurrence Score (ERS) was generated using variables associated with 2-year recurrence in the DS and validated in the VS. RESULTS: Variables associated with 2-year recurrence in the DS were (with associated points) alpha-fetoprotein (<10 ng/mL:0; 10-100: 2; >100: 3), size of largest nodule (≥40 mm: 1), multifocality (yes: 2), satellite nodules (yes: 2), vascular invasion (yes: 1) and surgical margin (positive R1: 2). The sum of points provided a score ranging from 0 to 11, allowing stratification into four levels of 2-year recurrence risk (Wolbers' C-indices 66.8% DS and 68.4% VS), with excellent calibration according to risk categories. Wolber's and Harrell's C-indices apparent values were systematically higher for ERS when compared to Early Recurrence After Surgery for Liver tumour post-operative model to predict time to early recurrence or recurrence-free survival. CONCLUSIONS: ERS is a user-friendly staging system identifying four levels of early recurrence risk after SR and a robust tool to design personalised surveillance strategies and adjuvant therapy trials.

Clinical phenotypes and outcomes associated with SARS-CoV-2 Omicron variants BA.2, BA.5 and BQ.1.1 in critically ill patients with COVID-19: a prospective, multicenter cohort study.

BACKGROUND: Despite current broad natural and vaccine-induced protection, a substantial number of patients infected with emerging SARS-CoV-2 variants (e.g., BF.7 and BQ.1.1) still experience severe COVID-19. Real-life studies investigating the impact of these variants on clinical outcomes of severe cases are currently not available. We performed a prospective multicenter observational cohort study. Adult patients with acute respiratory failure admitted between December 7, 2021 and December 15, 2022, in one of the 20 participating intensive care units (17 from the Greater Paris area and 3 from the North of France) were eligible for inclusion if they had SARS-CoV-2 infection confirmed by a positive reverse transcriptase-polymerase chain reaction (RT-PCR). Full-length SARS-CoV-2 genomes from all included patients were sequenced by means of next-generation sequencing. The primary endpoint of the study was day-28 mortality. RESULTS: The study included 158 patients infected with three groups of Omicron sublineages, including (i) BA.2 variants and their early sublineages referred as "BA.2" (n = 50), (ii) early BA.4 and BA.5 sublineages (including BA.5.1 and BA.5.2, n = 61) referred as "BA.4/BA.5", and (iii) recent emerging BA.5 sublineages (including BQ.1, BQ.1.1, BF.7, BE.1 and CE.1, n = 47) referred as "BQ.1.1". The clinical phenotype of BQ1.1-infected patients compared to earlier BA.2 and BA.4/BA.5 sublineages, showed more frequent obesity and less frequent immunosuppression. There was no significant difference between Omicron sublineage groups regarding the severity of the disease at ICU admission, need for organ failure support during ICU stay, nor day 28 mortality (21.7%, n = 10/47 in BQ.1.1 group vs 26.7%, n = 16/61 in BA.4/BA.5 vs 22.0%, n = 11/50 in BA.2, p = 0.791). No significant relationship was found between any SARS-CoV-2 substitution and/or deletion on the one hand and survival on the other hand over hospital follow-up. CONCLUSIONS: Critically-ill patients with Omicron BQ.1.1 infection showed a different clinical phenotype than other patients infected with earlier Omicron sublineage but no day-28 mortality difference.

Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France.

BACKGROUND: Early cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed. AIM: To reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period. METHODS: This was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA. RESULTS: Overall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010-2012 to 308 in 2019-2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013-2014 to 45.9% in 2019-2020). Lastly, among patients diagnosed with ATTRv in 2019-2020, 83.9% had ATTR Val122Ile cardiac phenotype. CONCLUSIONS: This study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement.

Phone contacts and treatment discontinuation predict survival cancer patients in a subsidized drug access program.

Aim: Survival of patients with Hodgkin's lymphoma is lower in in low- and middle-income countries, but factors leading to these outcomes are poorly understood. The objective of this study was to identify predictive factors associated with overall survival among cancer patients undergoing therapy in seven low- and middle-income countries. Materials & methods: A multicenter cohort was conducted in Egypt, Malaysia, Mexico, Peru, Philippines, Thailand and Ukraine. Results. A total of 460 patients were included. Phone-based support during patient follow-up and number of patients seen by the physician provided a positive impact, while the number of adverse events remains a predictor of death and physician decision to stop treatment. Conclusion: Furthers research on the potential benefit of phone-based programs to support patients with chronic diseases treatments should be explored in less developed countries.

Screening of Breast Cancer from Sweat Samples Analyzed by 2-Dimensional Gas Chromatography-Mass Spectrometry: A Preliminary Study.

Breast cancer (BC) remains one of the most commonly diagnosed malignancies in women. There is increasing interest in the development of non-invasive screening methods. Volatile organic compounds (VOCs) emitted through the metabolism of cancer cells are possible novel cancer biomarkers. This study aims to identify the existence of BC-specific VOCs in the sweat of BC patients. Sweat samples from the breast and hand area were collected from 21 BC participants before and after breast tumor ablation. Thermal desorption coupled with two-dimensional gas chromatography and mass spectrometry was used to analyze VOCs. A total of 761 volatiles from a homemade human odor library were screened on each chromatogram. From those 761 VOCs, a minimum of 77 VOCs were detected within the BC samples. Principal component analysis showed that VOCs differ between the pre- and post-surgery status of the BC patients. The Tree-based Pipeline Optimization Tool identified logistic regression as the best-performing machine learning model. Logistic regression modeling identified VOCs that distinguish the pre-and post-surgery state in BC patients on both the breast and hand area with sensitivities close to 1. Further, Shapley additive explanations and the probe variable method identified the most important and pertinent VOCs distinguishing pre- and post-operative status which are mostly of distinct origin for the hand and breast region. Results suggest the possibility to identify endogenous metabolites linked to BC, hence proposing this innovative pipeline as a stepstone to discovering potential BC biomarkers. Large-scale studies in a multi-centered VOC analysis setting must be carried out to validate obtained findings.

Determinants of morbidity and mortality related to health care-associated primary bloodstream infections in neonatal intensive care units: a prospective cohort study from the SEPREVEN trial.

Background: Health care-associated primary bloodstream infections (BSIs), defined as not secondary to an infection at another body site, including central line-associated BSI, are a leading cause of morbidity and mortality in patients in neonatal intensive care units (NICUs). Our objective was to identify factors associated with severe morbidity and mortality after these infections in neonates in NICUs. Methods: This ancillary study of the SEPREVEN trial included neonates hospitalized ≥2 days in one of 12 French NICUs and with ≥ 1 BSI during the 20-month study period. BSIs (all primary and health care-associated) were diagnosed in infants with symptoms suggestive of infection and classified prospectively as possible (one coagulase-negative staphylococci (CoNS)-growing blood culture) or proven (two same CoNS, or ≥1 recognized pathogen-growing blood culture). BSI consequences were collected prospectively as moderate morbidity (antibiotic treatment alone) or severe morbidity/mortality (life-saving procedure, permanent damage, prolonged hospitalization, and/or death). Results: Of 557 BSIs identified in 494 patients, CoNS accounted for 378/557 (67.8%) and recognized bacterial or fungal pathogens for 179/557 (32.1%). Severe morbidity/mortality was reported in 148/557 (26.6%) BSIs. Independent factors associated with severe morbidity/mortality were corrected gestational age <28 weeks (CGA) at infection (P < .01), fetal growth restriction (FGR) (P = .04), and proven pathogen-related BSI vs. CoNS-related BSI (P < .01). There were no differences in severe morbidity and mortality between proven and possible CoNS BSIs. In possible BSI, S. epidermidis was associated with a lower risk of severe morbidity than other CoNS (P < .01), notably S. capitis and S. haemolyticus. Conclusions: In BSIs in the NICU, severe morbidity/mortality was associated with low CGA at infection, FGR, and proven pathogen-related BSIs. When only one blood culture was positive, severe morbidity/mortality were less frequent if it grew with S. epidermidis compared to other CoNS. Further studies to help distinguish real CoNS BSIs from contaminations are needed. Study registration: ClinicalTrials.gov (NCT02598609).

Determinants of ventricular arrhythmias in sickle cell anemia: toward better prevention of sudden cardiac death.

Sudden death is 1 of the leading causes of death in adults with sickle cell anemia (SCA) but its etiology remains mostly unknown. Ventricular arrhythmia (VA) carries an increased risk of sudden death; however, its prevalence and determinants in SCA are poorly studied. This study aimed to identify the prevalence and predictors of VA in patients with SCA. From 2019 to 2022, 100 patients with SCA were referred to the physiology department to specifically analyze cardiac function and prospectively included in the DREPACOEUR registry. They underwent a 24-hour electrocardiogram monitoring (24h-Holter), transthoracic echocardiography, and laboratory tests on the same day. The primary end point was the occurrence of VA, defined as sustained or nonsustained ventricular tachycardia (VT), >500 premature ventricular contractions (PVCs) on 24h-Holter, or a recent history of VT ablation. The mean patient age was 46 ± 13 years, and 48% of the patients were male. Overall, VA was observed in 22 (22%) patients. Male sex (81% vs 34%; P = .02), impaired global longitudinal strain (GLS): -16% ± 1.9% vs -18.3% ± 2.7%; P = .02), and decreased platelet count (226 ± 96 giga per liter [G/L] vs 316 ± 130 G/L) were independently associated with VA. GLS correlated with PVC load every 24 hours (r = 0.39; P < .001) and a cutoff of -17.5% could predict VA with a sensitivity of 82% and a specificity of 63%. VAs are common in patients with SCA, especially in men. This pilot study uncovered GLS as a valuable parameter for improving rhythmic risk stratification.

Effectiveness of Simulation-Based Training on Transesophageal Echocardiography Learning: The SIMULATOR Randomized Clinical Trial.

Importance: Evidence is scarce on the effectiveness of simulation-based training in transesophageal echocardiography (TEE). Objective: To assess the effectiveness of simulation-based teaching vs traditional teaching of TEE knowledge and skills of cardiology fellows. Design, Setting, and Participants: Between November 2020 and November 2021, all consecutive cardiology fellows inexperienced in TEE from 42 French university centers were randomized (1:1; n = 324) into 2 groups with or without simulation support. Main Outcomes and Measures: The co-primary outcomes were the scores in the final theoretical and practical tests 3 months after the training. TEE duration and the fellows' self-assessment of their proficiency were also assessed. Results: While the theoretical and practical test scores were similar between the 2 groups (324 participants; 62.6% male; mean age, 26.4 years) before the training (33.0 [SD, 16.3] points vs 32.5 [SD, 18.5] points; P = .80 and 44.2 [SD, 25.5] points vs 46.1 [SD, 26.1] points; P = .51, respectively), the fellows in the simulation group (n = 162; 50%) displayed higher theoretical test and practical test scores after the training than those in the traditional group (n = 162; 50%) (47.2% [SD, 15.6%] vs 38.3% [SD, 19.8%]; P < .001 and 74.5% [SD, 17.7%] vs 59.0% [SD, 25.1%]; P < .001, respectively). Subgroup analyses showed that the effectiveness of the simulation training was even greater when performed at the beginning of the fellowship (ie, 2 years or less of training) (theoretical test: an increase of 11.9 points; 95% CI, 7.2-16.7 vs an increase of 4.25 points; 95% CI, -1.05 to 9.5; P = .03; practical test: an increase of 24.9 points; 95% CI, 18.5-31.0 vs an increase of 10.1 points; 95% CI, 3.9-16.0; P < .001). After the training, the duration to perform a complete TEE was significantly lower in the simulation group than in the traditional group ( 8.3 [SD, 1.4] minutes vs 9.4 [SD, 1.2] minutes; P < .001, respectively). Additionally, fellows in the simulation group felt more ready and more confident about performing a TEE alone after the training (mean score, 3.0; 95% CI, 2.9-3.2 vs mean score, 1.7; 95% CI, 1.4-1.9; P < .001 and mean score, 3.3; 95% CI, 3.1-3.5 vs mean score, 2.4; 95% CI, 2.1-2.6; P < .001, respectively). Conclusions and Relevance: Simulation-based teaching of TEE showed a significant improvement in the knowledge, skills, and self-assessment of proficiency of cardiology fellows, as well as a reduction in the amount of time needed to complete the examination. These results should encourage further investigation of clinical performance and patient benefits of TEE simulation training.

Guided Self-rehabilitation Contract vs conventional therapy in chronic peripheral facial paresis: VISAGE, a multicenter randomized controlled trial.

BACKGROUND: One year after persistent peripheral facial paresis (PFP), prescriptions of conventional rehabilitation are often downgraded into maintenance rehabilitation or discontinued, the patient entering what is seen as a chronic stage. This therapeutic choice is not consistent with current knowledge about behavior-induced plasticity, which is available all life long and may allow intense sensorimotor rehabilitation to remain effective. This prospective, randomized, multicenter single-blind study in subjects with chronic unilateral PFP evaluates changes in facial motor function with a Guided Self-rehabilitation Contract (GSC) vs. conventional therapy alone, carried out for six months. METHODS: Eighty-two adult subjects with chronic unilateral PFP (> 1 year since facial nerve injury) will be included in four tertiary, maxillofacial surgery (2), otolaryngology (1) and rehabilitation (1) centers to be randomized into two rehabilitation groups. In the experimental group, the PM&R specialist will implement the GSC method, which for PFP involves intensive series of motor strengthening performed daily on three facial key muscle groups, i.e. Frontalis, Orbicularis oculi and Zygomatici. The GSC strategy involves: i) prescription of a daily self-rehabilitation program, ii) teaching of the techniques involved in the program, iii) encouragement and guidance of the patient over time, in particular by requesting a quantified diary of the work achieved to be returned by the patient at each visit. In the control group, participants will benefit from community-based conventional therapy only, according to their physician's prescription. The primary outcome measure is the composite score of Sunnybrook Facial Grading System. Secondary outcome measures include clinical and biomechanical facial motor function quantifications (Créteil Scale and 3D facial motion analysis through the Cara system), quality of life (Facial Clinimetric Evaluation and Short-Form 12), aesthetic considerations (FACE-Q scale) and mood representations (Hospital Anxiety and Depression scale). Participants will be evaluated every three months by a blinded investigator, in addition to four phone calls (D30/D60/D120/D150) to monitor compliance and tolerance to treatment. DISCUSSION: This study will increase the level of knowledge on the effects of intense facial motor streng-          Facial paralysisthening prescribed through a GSC in patients with chronic peripheral facial paresis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04074018 . Registered 29 August 2019. PROTOCOL VERSION: Version N°4.0-04/02/2021.

Dynamic personalized prediction of the individual liver-related risk after sustained viral response in HCV patients.

Sustained viral response (SVR) significantly improves the prognosis in patients with hepatitis C virus (HCV) chronic infection but does not totally alleviate the risk of liver-related complications (LRC). We aimed to evaluate whether the dynamics of multiple measurements of simple parameters after SVR enable the development of a personalized prediction of prognosis in HCV patients. HCV mono-infected patients who experienced SVR in two prospective cohorts (ANRS CO12 CirVir cohort: derivation set; ANRS CO22 HEPATHER cohort: validation set) were included. The study outcome was LRC, a composite criterion including decompensation of cirrhosis and/or hepatocellular carcinoma. Joint latent class modelling accounting for both biomarker trajectory and event occurrence during follow-up was developed in the derivation set to compute individual dynamic predictions, with further evaluation in the validation set. In the derivation set (n = 695; 50 LRC during the median 3.8 [1.6-7.5] years follow-up), FIB4 was identified as a biomarker associated with LRC occurrence after SVR. Joint modelling used sex and the dynamics of FIB4 and diabetes status to develop a personalized prediction of LRC. In the validation set (n = 7064; 273 LRC during the median 3.6 [2.5-4.9] years follow-up), individual dynamic predictions from the model accurately stratified the risk of LRC. Time-dependent Brier Score showed good calibration that improved with the accumulation of visits, justifying our modelling approach considering both baseline and follow-up measurements. Dynamic modelling using repeated measurements of simple parameters predicts the individual residual risk of LRC and improves personalized medicine after SVR in HCV patients.