Rationale and design of the direct oral anticoagulants for prevention of left ventricular thrombus after anterior acute myocardial infarction (APERITIF) trial.

BACKGROUND: Anterior acute myocardial infarction (AMI) is associated with an increased risk of left ventricular (LV) thrombus formation. We hypothesized that adding low-dose oral rivaroxaban to the usual antiplatelet regimen would reduce the risk of LV thrombus in patients with large AMI. STUDY DESIGN: APERITIF is an investigator-initiated, multicenter randomized open-label, blinded end-point (PROBE) trial, nested in the ongoing "FRENCHIE" registry, a French multicenter prospective observational study, in which all consecutive patients admitted within 48 hours of symptom onset in a cardiac Intensive Care Unit (ICU) for AMI are included (NCT04050956). Among them, patients with anterior ST-elevation-myocardial infarction (STEMI) or very high-risk non- ST-elevation-myocardial infarction (NSTEMI) patients with involvement of the left anterior descending artery are randomized into 2 groups: Dual Antiplatelet Therapy (DAPT) alone or DAPT plus rivaroxaban 2.5mg twice daily for 4 weeks, started as soon as possible after completion of the initial percutaneous coronary intervention/angiography procedure. The primary endpoint is the presence of LV thrombus at 1 month, as detected by contrast enhanced CMR (CE-CMR). Secondary endpoints include LV thrombus dimension (greatest diameter), the rate of major bleedings and major cardiovascular events at 1 month. Based on estimated event rates, a sample size of 560 patients is needed to show superiority of DAPT plus rivaroxaban therapy versus DAPT alone, with 80% power. CONCLUSION: The APERITIF trial will determine whether, in patients with large AMIs, the use of rivaroxaban 2.5mg twice daily in addition to DAPT reduces LV thrombus formation, compared with DAPT alone. CLINICALTRIALS: gov Identifier: NCT05077683.

Efficacy and safety of methylprednisolone pulse followed by oral prednisone vs. oral prednisone alone in sarcoidosis tubulointerstitial nephritis: a randomized, open-label, controlled clinical trial.

BACKGROUND: We determine the benefit of pulsed methylprednisolone for improving kidney function in patients with sarcoidosis tubulointerstitial nephritis. METHODS: We conducted a multicenter, prospective, randomized, open-label, controlled trial in patients with biopsy-proven acute tubulointerstitial nephritis caused by sarcoidosis at 21 sites in France. Patients were randomly assigned to receive a methylprednisolone pulse 15 mg/kg/day for 3 days, then oral prednisone (MP group) or oral prednisone 1 mg/kg/day alone (PRD group). The primary end point was a positive response at 3 months, defined as a doubling of estimated glomerular filtration rate (eGFR) compared with the eGFR before randomization. RESULTS: We randomized 40 participants. Baseline eGFR before PRD was 22 mL/min/1.73m2 {interquartile range [IQR], 16-44} and before MP was 25 mL/min/1.73m2 (IQR, 22-36) (P = .3). The two groups did not differ in underlying pathological lesions, including mean percentage of interstitial fibrosis and intensity of interstitial infiltrate. In the intent-to-treat population, the median eGFR at 3 months did not significantly differ between the PRD and MP groups: 45 (IQR, 34-74) and 46 (IQR, 39-65) mL/min/1.73m2. The primary end point at 3 months was achieved in 16 of 20 (80%) PRD patients and 10 of 20 (50%) MP patients (P = .0467). The eGFR was similar between the two groups after 1, 3, 6, and 12 months of treatment. For both groups, eGFR at 1 month was strongly correlated with eGFR at 12 months (P < .0001). The two groups did not differ in severe adverse events. CONCLUSION: Compared with a standard oral steroid regimen, intravenous MP may have no supplemental benefit for renal function in patients with tubulointerstitial nephritis caused by sarcoidosis.Trial Registration: ClinicalTrials.gov: NCT01652417; EudraCT: 2012-000149-11.

Association between combination antibiotic therapy as opposed as monotherapy and outcomes of ICU patients with Pseudomonas aeruginosa ventilator-associated pneumonia: an ancillary study of the iDIAPASON trial.

BACKGROUND: The optimal treatment duration and the nature of regimen of antibiotics (monotherapy or combination therapy) for Pseudomonas aeruginosa ventilator­associated pneumonia (PA-VAP) remain debated. The aim of this study was to evaluate whether a combination antibiotic therapy is superior to a monotherapy in patients with PA-VAP in terms of reduction in recurrence and death, based on the 186 patients included in the iDIAPASON trial, a multicenter, randomized controlled trial comparing 8 versus 15 days of antibiotic therapy for PA-VAP. METHODS: Patients with PA-VAP randomized in the iDIAPASON trial (short-duration-8 days vs. long-duration-15 days) and who received appropriate antibiotic therapy were eligible in the present study. The main objective is to compare mortality at day 90 according to the antibiotic therapy received by the patient: monotherapy versus combination therapy. The primary outcome was the mortality rate at day 90. The primary outcome was compared between groups using a Chi-square test. Time from appropriate antibiotic therapy to death in ICU or to censure at day 90 was represented using Kaplan-Meier survival curves and compared between groups using a Log-rank test. RESULTS: A total of 169 patients were included in the analysis. The median duration of appropriate antibiotic therapy was 14 days. At day 90, among 37 patients (21.9%) who died, 17 received monotherapy and 20 received a combination therapy (P = 0.180). Monotherapy and combination antibiotic therapy were similar for the recurrence rate of VAP, the number of extra pulmonary infections, or the acquisition of multidrug-resistant (MDR) bacteria during the ICU stay. Patients in combination therapy were exposed to mechanical ventilation for 28 ± 12 days, as compared with 23 ± 11 days for those receiving monotherapy (P = 0.0243). Results remain similar after adjustment for randomization arm of iDIAPASON trial and SOFA score at ICU admission. CONCLUSIONS: Except longer durations of antibiotic therapy and mechanical ventilation, potentially related to increased difficulty in achieving clinical cure, the patients in the combination therapy group had similar outcomes to those in the monotherapy group. TRIAL REGISTRATION: NCT02634411 , Registered 15 December 2015.

Feasibility of a repositioning schedule on pressure ulcer prevention in a French Intensive Care Unit: A pre and post-intervention pilot study.

AIMS: As a prerequisite of a multicentre study, we conducted a pilot study to assess the feasibility of a daily repositioning schedule in critically ill patients. The schedule was adapted to the patient's clinical condition, and the estimated risk for developing a pressure ulcer using the Braden scale. DESIGN: A single-center pre and post-intervention pilot study in a French Intensive Care Unit of a university teaching hospital. This study followed TREND guidelines. METHODS: During the first period (March to May 2018), pressure ulcer prevention was performed according to usual care. During the second period (June to August 2018), the repositioning schedule was adapted to the estimated risk for developing a pressure ulcer according to the Braden scale. Eligible patients had no pressure ulcer at baseline, were intubated within 24 hours of admission and expected to receive mechanical ventilation for at least 24 hours. The primary outcome was the rate of pressure ulcer development at 28 days of hospitalization or at discharge or death, as compared with usual care. Secondary outcomes included the feasibility and safety of the schedule, as assessed by caregivers' adherence and workload, and the rate of adverse events. RESULTS: In the pre-intervention period 20 participants were included, and 14 patients were included in the post-intervention period. There was no decrease in the pressure ulcers incidence with the intervention (25% vs. 28.6%; P = 1). The number of daily repositioning performed increased from 3.3 [IQR 3.0; 3.9] during the pre-intervention period to 4.3 [IQR 3.8; 5.2] during the post-intervention period (P < 0.05), where it differed from the number scheduled by 0.6 [IQR 0.1; 1.4] per day, indicating satisfactory adherence of caregivers to the protocol. Adverse events rate did not differ between the two periods (55.9% vs. 57.1%; P = 0.90). CONCLUSION: A personalised daily repositioning schedule in critically ill patients is feasible and safe. The efficacy of such a strategy, together with its economic impact, need to be assessed in a multicentre randomized trial.

Does hyaluronic acid gel reduce intrauterine adhesions after dilation and curettage in women with miscarriage? A Multicentric randomized controlled trial (HYFACO Study).

BACKGROUND: Miscarriage is a frequent problem that requires dilation and curettage in 30% of cases. This routine surgery may lead to intrauterine adhesions and severe infertility. Hyaluronic acid gel is known to reduce intrauterine adhesions after hysteroscopic surgery. OBJECTIVE: This study aimed to evaluate the rate of intrauterine adhesions after dilation and curettage for miscarriage with and without hyaluronic acid gel. STUDY DESIGN: This was a multicentric (9 hospitals in France), prospective, open-label randomized trial. Patients who had a miscarriage between weeks 7 and 14 of gestation, required dilation and curettage, and wanted another pregnancy were eligible for the study. Women were randomly assigned in a 1:1 ratio to surgery alone (control group) or surgery with intrauterine instillation of hyaluronic acid gel (gel group). An office hysteroscopy was planned at 6 to 8 weeks after surgery. The primary endpoint was the rate of intrauterine adhesions during this office follow-up hysteroscopy. Two different follow-up fertility surveys were sent at 6 months and 1 year after the end of the intervention, respectively. RESULTS: Among the 343 patients who had curettage, 278 had hysteroscopy. After multiple imputation, the rate of intrauterine adhesions was lower in the gel group than in the control group (9.1% vs 18.4%, respectively; P=.0171). Among the 110 responders to the surveys, the overall pregnancy rate at 12 months after surgery was 64.5% (71/110), and similar in both groups (57.4% [27/47] in the control group vs 69.8% [44/63] in the gel group; P=.1789). CONCLUSION: Intrauterine instillation of hyaluronic acid gel reduces the rate of intrauterine adhesions in women treated with dilation and curettage for miscarriage.

Impact of COVID-19 lockdown on maternal psychological status, the couple's relationship and mother-child interaction: a prospective study.

BACKGROUND: To compare the rate of postpartum depression (PPD) during the first COVID-19 lockdown with the rate observed prior to the pandemic, and to examine factors associated with PPD. METHODS: This was a prospective study. Women who gave birth during the first COVID-19 lockdown (spring 2020) were offered call-interviews at 10 days and 6-8 weeks postpartum to assess PPD using the Edinburgh Postnatal Depression Scale (EPDS). Post-traumatic symptoms (Perinatal Post-traumatic Stress Disorder Questionnaire, PPQ), couple adjustment, and interaction and mother-to-infant bonding were also evaluated. The observed PPD rate was compared to the one reported before the pandemic. Factors associated with an increased risk of PPD were studied. The main outcome measures were comparison of the observed PPD rate (EPDS score > 12) to pre-pandemic rate. RESULTS: Of the 164 women included, 27 (16.5% [95%CI: 11.14-23.04]) presented an EPDS score > 12 either at 10 days or 6-8 weeks postpartum. This rate was similar to the one of 15% reported prior to the pandemic (p = 0.6). Combined EPDS> 12 or PPQ > 6 scores were observed in 20.7% of the mothers [95%CI: 14.8-0.28]. Maternal hypertension/preeclampsia (p = 0.007), emergency cesarean section (p = 0.03), and neonatal complications (p = 0.008) were significantly associated with an EPDS> 12 both in univariate and multivariate analysis (OR = 10 [95%CI: 1.5-68.7], OR = 4.09[95%CI: 1.2-14], OR = 4.02[95%CI: 1.4-11.6], respectively). CONCLUSIONS: The rate of major PPD in our population did not increase during the first lockdown period. However, 20.7% of the women presented with post-traumatic/depressive symptoms. TRIAL REGISTRATION: NCT04366817.

HPV status and therapeutic initial strategy impact on survival and oncologic outcomes: 5-year results from the multicentric prospective cohort of oropharyngeal cancers Papillophar.

PURPOSE: After the 2 years of follow-up, we aimed to evaluate at 5 years the impact of human papillomavirus (HPV) status, tobacco, and initial treatment approach on progression-free survival (PFS) and overall survival (OS) of patients with oropharyngeal cancer (OPC) in France. METHODS: Papillophar study was designed as a prospective cohort of 340 OPC patients in 14 French hospitals. HPV-positive status (21.7%) was defined with PCR (positivity for HPV DNA and E6/E7 mRNA). Cox proportional hazard models were used to assess the relationship between PFS, OS, HPV, and other prognostic factors. The combined effect of HPV status with smoking, stage, or initial treatment on PFS was also evaluated. RESULTS: HPV-pos patients had better PFS than HPV-neg patients (HR = 0.46; 95% CI: 0.29-0.74), and worse for older patients (HR for 5-year age increase = 1.14), UICC stage 4 from the 7th TNM classification compared to stage 1-2 (HR = 2.58; CI: 1.33-5.00), and those having had radiotherapy (HR = 2.07; 95% CI: 1.36-3.16) or induction chemotherapy (HR = 2.11; 95% CI: 1.32-3.38) instead of upfront surgery. HPV-neg patients encountered a larger incidence of loco-regional disease than HPV-pos patients (31.5% and 14.0%, respectively, p = 0.0001). Distant metastases proportion was similar. HPV-neg patients developed more second primary tumor than HPV-pos patients (11.7% vs. 3.3%, p = 0.02). CONCLUSIONS: 5-year follow-up confirms the specifically improved prognosis in HPV-positive patients. The prognosis is nevertheless significantly modified through clinical and therapeutical variations.

A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.

BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).

Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial.

Importance: The optimal transfusion strategy in patients with acute myocardial infarction and anemia is unclear. Objective: To determine whether a restrictive transfusion strategy would be clinically noninferior to a liberal strategy. Design, Setting, and Participants: Open-label, noninferiority, randomized trial conducted in 35 hospitals in France and Spain including 668 patients with myocardial infarction and hemoglobin level between 7 and 10 g/dL. Enrollment could be considered at any time during the index admission for myocardial infarction. The first participant was enrolled in March 2016 and the last was enrolled in September 2019. The final 30-day follow-up was accrued in November 2019. Interventions: Patients were randomly assigned to undergo a restrictive (transfusion triggered by hemoglobin ≤8; n = 342) or a liberal (transfusion triggered by hemoglobin ≤10 g/dL; n = 324) transfusion strategy. Main Outcomes and Measures: The primary clinical outcome was major adverse cardiovascular events (MACE; composite of all-cause death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia) at 30 days. Noninferiority required that the upper bound of the 1-sided 97.5% CI for the relative risk of the primary outcome be less than 1.25. The secondary outcomes included the individual components of the primary outcome. Results: Among 668 patients who were randomized, 666 patients (median [interquartile range] age, 77 [69-84] years; 281 [42.2%] women) completed the 30-day follow-up, including 342 in the restrictive transfusion group (122 [35.7%] received transfusion; 342 total units of packed red blood cells transfused) and 324 in the liberal transfusion group (323 [99.7%] received transfusion; 758 total units transfused). At 30 days, MACE occurred in 36 patients (11.0% [95% CI, 7.5%-14.6%]) in the restrictive group and in 45 patients (14.0% [95% CI, 10.0%-17.9%]) in the liberal group (difference, -3.0% [95% CI, -8.4% to 2.4%]). The relative risk of the primary outcome was 0.79 (1-sided 97.5% CI, 0.00-1.19), meeting the prespecified noninferiority criterion. In the restrictive vs liberal group, all-cause death occurred in 5.6% vs 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs 3.1%, emergency revascularization prompted by ischemia occurred in 1.5% vs 1.9%, and nonfatal ischemic stroke occurred in 0.6% of patients in both groups. Conclusions and Relevance: Among patients with acute myocardial infarction and anemia, a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of MACE after 30 days. However, the CI included what may be a clinically important harm. Trial Registration: ClinicalTrials.gov Identifier: NCT02648113.

Phospholipase A2 Receptor 1 Epitope Spreading at Baseline Predicts Reduced Likelihood of Remission of Membranous Nephropathy.

The phospholipase A2 receptor (PLA2R1) is the major autoantigen in primary membranous nephropathy. Several PLA2R1 epitopes have been characterized, and a retrospective study identified PLA2R1 epitope spreading as a potential indicator of poor prognosis. Here, we analyzed the predictive value of anti-PLA2R1 antibody (PLA2R1-Ab) titers and epitope spreading in a prospective cohort of 58 patients positive for PLA2R1-Ab randomly allocated to rituximab (n=29) or antiproteinuric therapy alone (n=29). At baseline, the epitope profile (CysR, CysRC1, CysRC7, or CysRC1C7) did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer (P<0.001). Ten (58.8%) of the 17 patients who had epitope spreading at baseline and were treated with rituximab showed reversal of epitope spreading at month 6. In adjusted analysis, epitope spreading at baseline was associated with a decreased remission rate at month 6 (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.72; P=0.02) and last follow-up (median, 23 months; odds ratio, 0.14; 95% confidence interval, 0.03 to 0.64; P=0.01), independently from age, sex, baseline PLA2R1-Ab level, and treatment group. We propose that epitope spreading at baseline be considered in the decision for early therapeutic intervention in patients with primary membranous nephropathy.

Targeted HIV Screening in Eight Emergency Departments: The DICI-VIH Cluster-Randomized Two-Period Crossover Trial.

STUDY OBJECTIVE: This study compares the effectiveness and cost-effectiveness of nurse-driven targeted HIV screening alongside physician-directed diagnostic testing (intervention strategy) with diagnostic testing alone (control strategy) in 8 emergency departments. METHODS: In this cluster-randomized, 2-period, crossover trial, 18- to 64-year-old patients presenting for reasons other than potential exposure to HIV were included. The strategy applied first was randomly assigned. During both periods, diagnostic testing was prescribed by physicians following usual care. During the intervention periods, patients were asked to complete a self-administered questionnaire. According to their answers, the triage nurse suggested performing a rapid test to patients belonging to a high-risk group. The primary outcome was the proportion of new diagnoses among included patients, which further refers to effectiveness. A secondary outcome was the intervention's incremental cost (health care system perspective) per additional diagnosis. RESULTS: During the intervention periods, 74,161 patients were included, 16,468 completed the questionnaire, 4,341 belonged to high-risk groups, and 2,818 were tested by nurses, yielding 13 new diagnoses. Combined with 9 diagnoses confirmed through 97 diagnostic tests, 22 new diagnoses were established. During the control periods, 74,166 patients were included, 92 were tested, and 6 received a new diagnosis. The proportion of new diagnoses among included patients was higher during the intervention than in the control periods (3.0 per 10,000 versus 0.8 per 10,000; difference 2.2 per 10,000, 95% CI 1.3 to 3.6; relative risk 3.7, 95% CI 1.4 to 9.8). The incremental cost was €1,324 per additional new diagnosis. CONCLUSION: The combined strategy of targeted screening and diagnostic testing was effective.

Effectiveness and costs of non-invasive foetal RHD genotyping in rhesus-D negative mothers: a French multicentric two-arm study of 850 women.

BACKGROUND: The determination of foetal Rhesus D (RHD) status allows appropriate use of IgRh prophylaxis by restricting its use to cases of RHD feto-maternal incompatibilities. There is a degree of uncertainty about the cost-effectiveness of foetal RHD determination, yet screening programs are being introduced into clinical practice in many countries. This paper evaluates the impact of non-invasive foetal Rhesus D (RHD) status determination on the costs of managing RHD-negative pregnant women and on the appropriate use of anti-D prophylaxis in a large sample of RHD-negative pregnant women using individual prospectively collected clinical and economic data. METHODS: A prospective two-armed trial of RHD negative pregnant women was performed in 11 French Obstetric Departments. Non-invasive foetal RHD genotyping was performed before 26 weeks' gestation in the experimental arm whereas the control arm participants received usual care. The costs associated with patient management in relation to their RHD negative status (biological tests, anti-D prophylaxis and visits) were calculated from inclusion to the end of the postpartum period. The costs of hospital admissions during pregnancy and delivery were also determined. RESULTS: A total of 949 patients were included by 11 centres between 2009 and 2012, and 850 completed follow-up, including medical and biological monitoring. Patients were separated into two groups: the genotyping group (n=515) and the control group (n=335). The cost of the genotyping was estimated at 140 euros per test. The total mean cost per patient was estimated at €3,259 (SD ± 1,120) and €3,004 (SD ± 1,004) in the genotyping and control groups respectively. The cost of delivery represented three quarters of the total cost in both groups. The performance of managing appropriately RHD negative anti-D prophylaxis was 88% in the genotyping group, versus 65% in the control group. Using the costs related to RHD status (biological tests, anti-D immunoglobulin injections and visits) the incremental cost-effectiveness ratio (ICER) was calculated to be €578 for each percentage gain in women receiving appropriate management. CONCLUSION: Early knowledge of the RHD status of the foetus using non-invasive foetal RHD genotyping significantly improved the management of RHD negative pregnancies with a small increase in cost. TRIAL REGISTRATION: Clinical trials registry- NCT00832962 -13 January 2009 - retrospectively registered.

Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up.

Randomized trials of rituximab in primary membranous nephropathy (PMN) have not been conducted. We undertook a multicenter, randomized, controlled trial at 31 French hospitals (NCT01508468). Patients with biopsy-proven PMN and nephrotic syndrome after 6 months of nonimmunosuppressive antiproteinuric treatment (NIAT) were randomly assigned to 6-month therapy with NIAT and 375 mg/m2 intravenous rituximab on days 1 and 8 (n=37) or NIAT alone (n=38). Median times to last follow-up were 17.0 (interquartile range, 12.5-24.0) months and 17.0 (interquartile range, 13.0-23.0) months in NIAT-rituximab and NIAT groups, respectively. Primary outcome was a combined end point of complete or partial remission of proteinuria at 6 months. At month 6, 13 (35.1%; 95% confidence interval [95% CI], 19.7 to 50.5) patients in the NIAT-rituximab group and eight (21.1%; 95% CI, 8.1 to 34.0) patients in the NIAT group achieved remission (P=0.21). Rates of antiphospholipase A2 receptor antibody (anti-PLA2R-Ab) depletion in NIAT-rituximab and NIAT groups were 14 of 25 (56%) and one of 23 (4.3%) patients at month 3 (P<0.001) and 13 of 26 (50%) and three of 25 (12%) patients at month 6 (P=0.004), respectively. Eight serious adverse events occurred in each group. During the observational phase, remission rates before change of assigned treatment were 24 of 37 (64.9%) and 13 of 38 (34.2%) patients in NIAT-rituximab and NIAT groups, respectively (P<0.01). Positive effect of rituximab on proteinuria remission occurred after 6 months. These data suggest that PLA2R-Ab levels are early markers of rituximab effect and that addition of rituximab to NIAT does not affect safety.

Effect of the Pulmonary Embolism Rule-Out Criteria on Subsequent Thromboembolic Events Among Low-Risk Emergency Department Patients: The PROPER Randomized Clinical Trial.

Importance: The safety of the pulmonary embolism rule-out criteria (PERC), an 8-item block of clinical criteria aimed at ruling out pulmonary embolism (PE), has not been assessed in a randomized clinical trial. Objective: To prospectively validate the safety of a PERC-based strategy to rule out PE. Design, Setting, and Patients: A crossover cluster-randomized clinical noninferiority trial in 14 emergency departments in France. Patients with a low gestalt clinical probability of PE were included from August 2015 to September 2016, and followed up until December 2016. Interventions: Each center was randomized for the sequence of intervention periods. In the PERC period, the diagnosis of PE was excluded with no further testing if all 8 items of the PERC rule were negative. Main Outcomes and Measures: The primary end point was the occurrence of a thromboembolic event during the 3-month follow-up period that was not initially diagnosed. The noninferiority margin was set at 1.5%. Secondary end points included the rate of computed tomographic pulmonary angiography (CTPA), median length of stay in the emergency department, and rate of hospital admission. Results: Among 1916 patients who were cluster-randomized (mean age 44 years, 980 [51%] women), 962 were assigned to the PERC group and 954 were assigned to the control group. A total of 1749 patients completed the trial. A PE was diagnosed at initial presentation in 26 patients in the control group (2.7%) vs 14 (1.5%) in the PERC group (difference, 1.3% [95% CI, -0.1% to 2.7%]; P = .052). One PE (0.1%) was diagnosed during follow-up in the PERC group vs none in the control group (difference, 0.1% [95% CI, -∞ to 0.8%]). The proportion of patients undergoing CTPA in the PERC group vs control group was 13% vs 23% (difference, -10% [95% CI, -13% to -6%]; P < .001). In the PERC group, rates were significantly reduced for the median length of emergency department stay (mean reduction, 36 minutes [95% CI, 4 to 68]) and hospital admission (difference, 3.3% [95% CI, 0.1% to 6.6%]). Conclusions and Relevance: Among very low-risk patients with suspected PE, randomization to a PERC strategy vs conventional strategy did not result in an inferior rate of thromboembolic events over 3 months. These findings support the safety of PERC for very low-risk patients presenting to the emergency department. Trial Registration: clinicaltrials.gov Identifier: NCT02375919.

Epithelial to mesenchymal transition and HPV infection in squamous cell oropharyngeal carcinomas: the papillophar study.

BACKGROUND: Human Papillomavirus (HPV) infection is recognised as aetiological factor of carcinogenesis in oropharyngeal squamous cell carcinomas (OPC). HPV-related OPC respond better to treatments and have a significantly favourable outcome. Epithelial to mesenchymal transition (EMT) implicated in tumour invasion, is a hallmark of a poor prognosis in carcinomas. METHODS: We have studied the relationship of EMT markers (E-cadherin, ß-catenin and vimentin) with HPV infection (DNA and E6/E7 mRNA detection), p16INK4a expression and survival outcomes in a cohort of 296 patients with OPC. RESULTS: Among the 296 OPSSC, 26% were HPV positive, 20.3% had overt EMT (>25% of vimentin positive tumour cells). Lower E-cadherin expression was associated with a higher risk of distant metastasis in univariate (P=0.0110) and multivariate analyses (hazard ratios (HR)=6.86 (1.98; 23.84)). Vimentin expression tends towards worse metastasis-free survival (MFS; HR=2.53 (1.00; 6.41)) and was an independent prognostic factor of progression-free survival (HR=1.55 (1.03; 2.34)). CONCLUSIONS: There was a non significant association of EMT with HPV status. This may be explained by a mixed subpopulation of patients HPV positive with associated risk factors (HPV, tobacco and alcohol). Thus, the detection of EMT in OPC represents another reliable approach in the prognosis and the management of OPC whatever their HPV status.

Multicenter prospective evaluation of the reliability of the combined use of two models to predict non-sentinel lymph node status in breast cancer patients with metastatic sentinel lymph nodes: the MSKCC nomogram and the Tenon score. Results of the NOTEGS study.

BACKGROUND: The purpose of this study was to prospectively evaluate the combined use of The Memorial Sloan Kettering Cancer Center nomogram and Tenon score to select, in patients with metastatic sentinel lymph node (SN), those at low risk of metastatic non-SN for whom additional axillary lymph node dissection (ALND) could be avoided. METHODS: From January 2011 to July 2012, a prospective non-interventional nationwide study was conducted (NCT01509963). We sought to identify the false reassurance rate (FRR, a negative test result is false) in patients with both a ⩽10% probability of metastatic non-SN with the MSKCC nomogram and a Tenon score ⩽3.5 (low risk): the proportion of patients with metastatic non-SN at additional ALND. Our hypothesis was that these patients would have a FRR⩽5%. RESULTS: Data on 2822 patients with breast cancer from 53 institutions were prospectively recorded. At least one SN was metastatic (isolated tumour cells, micro- or macrometastases) in 696 patients (24.7%). Among patients with ALND and complete data to calculate combined risk (n=504), 67 and 437 patients had low and high combined risk, respectively. Patients at low risk had less ALND (47%) compared to patients at high risk (P<0.001). This study did not meet its primary objective because the FRR in patients with low risk was 16.4% (11 out of 67) (95% confidence interval (CI): 9.7-23.1%). In the high-risk group, 33.9% (148 out of 437) (95% CI: 29.6-38.4%) had non-SN metastases (P=0.004). CONCLUSIONS: In this controlled prospective study, metastatic SN patients with both a ⩽10% probability of metastatic non-SN with the MSKCC nomogram and a Tenon score ⩽3.5 failed to identify patients at low risk of metastatic non-SN when completion ALND was not systematic.

Intermittent catheterization acceptance test (I-CAT): A tool to evaluate the global acceptance to practice clean intermittent self-catheterization.

AIM: In certain cases, a patient's anxiety, fear, or misconceptions can represent significant obstacles to the learning of Clean Intermittent Self Catheterization (CISC), and little is known about these psychological barriers. The aim of the present study is thus to construct and validate an "Intermittent Catheterization Acceptance Test (I-CAT)" to evaluate the psychological acceptance of CISC. METHODS: A study was carried out in nine neuro-rehabilitation and urology departments in French university hospitals. Fifty-five items were identified, following a comprehensive review of the literature and cognitive debriefing interviews with patients. Following an initial expert panel meeting (EPM) with a French-speaking neuro-urology study group (GENULF), this list was refined and reduced to a draft I-CAT comprising 34 items. The face validity of the draft I-CAT was determined, and the results were then analyzed in a second EPM, leading to the elaboration of a second version of the I-CAT (23 items, 5 dimensions). Psychometric validation of this second version was established from a longitudinal, non-randomized study involving 201 neurological and non-neurological patients. Linguistic validation was carried out in English. RESULTS: Following the construct validity analyses, several items were deleted due to item overlap, ceiling effects, or poor content validity and 14 items were retained. Confirmatory factor analysis shows that this version has 2 dimensions. Cronbach's alpha was 0.93. The ICC demonstrated good test-retest reliability and satisfactory responsiveness. CONCLUSION: The upstream identification and solving of potential psychological barriers prior to the learning of CISC could improve patients' acceptance of this procedure.