Search

Background We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS). Patients and Methods Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events. Results Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity. Conclusion In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.

We previously reported the safety and immunogenicity data from a randomized trial comparing the monovalent (MV) recombinant protein Beta-variant (MVB.1.351) and MV ancestral protein (MVD614) booster vaccines with AS03 adjuvant (Sanofi/GSK) to mRNA BNT162b2 vaccine (Pfizer-BioNTech). First booster of the vaccines was administered in adult participants previously primed with 2 doses of BNT162b2. A subset of these participants with available blood samples collected at Day 0 (D0), at 28 days (D28), and 3 months (M3) post-booster were contacted for additional testing (195/208 participants). The persistence of cross-neutralizing antibodies, including against Omicron BA.1 and BA.4/5, up to 3 months after boosting was evaluated using a validated pseudovirus neutralization assay. The data showed that the MVB.1.351 vaccine induced higher and durable cross-neutralizing antibodies against Omicron subvariants up to 3 months after boosting compared to a MV ancestral and the mRNA BNT162b2 booster vaccine.

Summary Background The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population. Methods In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m2) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m2) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov , NCT02460588 . Findings Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI −3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89–4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12–6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13–0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group. Interpretation In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients. Funding Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014–502), Roche Pharmaceuticals.

The optimal strategy for the diagnosis of pulmonary embolism (PE) in the emergency department (ED) remains debated. To reduce the need of imaging testing, several rules have been recently validated using an elevated D-dimer threshold.To validate the safety of different diagnostic strategies and compare the efficacy in terms of chest imaging testing.Post-hoc analysis of individual data of 3330 adult patients without a high clinical probability of PE in the ED followed-up at 3 months in France and Spain (1916 from the PROPER cohort, 1414 from the MODIGLIANI cohort).Four diagnostic strategies with an elevated D-dimer threshold if PE is unlikely. The YEARS combined with Pulmonary Embolism Rule-out Criteria (PERC) the pulmonary embolism graduated D-dimer (PEGeD) combined with PERC and the 4-level pulmonary embolism probability score (4PEPS) rules were assessed. A modified simplified (MODS) rule with a simplified YEARS reduced to the sole item of "Is PE the most likely diagnosis" combined with PERC was also tested.The primary outcome was the proportion of diagnosed PE or deep venous thrombosis at 3 months in patients in whom PE could have been excluded without chest imaging according to the tested strategy. The safety of a strategy was confirmed if the failure rate was less than 1.85%. The secondary outcome was the use of imaging testing according to each rule.Among 3330 analyzed patients, 150 (4.5%) had a PE. The number of missed PEs were 25, 29, 30 and 26 for the PERC+YEARS, PERC+PEGeD, 4PEPS and MODS rules respectively, with a failure rate of 0.75% (95% CI 0.51% to 1.10%), 0.87% (0.61% to 1.25%), 0.90% (0.63% to 1.28%) and 0.78% (0.53% to 1.14%) respectively. There was no significant difference in the failure rate between rules. Except for a significant lower use of chest imaging for 4PEPS compared to YEARS (14.9% vs 16.3%, difference -1.4% [95%CI -2.1% to -0.8%]), there was no difference in the proportion of imaging testing.In this post-hoc analysis of patients with suspicion of PE, YEARS and PEGeD combined with PERC, and 4PEPS were safe to exclude PE. The safety of the modified simplified MODS strategy was also confirmed. There was no significant difference of the failure rate between strategies.

International audience

Severe hypoxemia in patients with COVID-19 pneumonia might result from hypoxic pulmonary vasoconstriction, contributing to ventilation/perfusion (V/Q) mismatch. Because almitrine improves V/Q, it might reduce the risk for mechanical ventilation (MV) in such patients. Our primary objective was to determine the effect of almitrine on the need for MV at day 7.In a randomised double-blind placebo-controlled trial involving 15 ICUs, patients hospitalized for COVID-19 pneumonia and experiencing acute hypoxemic respiratory failure were randomly assigned to receive 5 days of intravenous low-dose (2 µg.kgBetween September 3, 2020 and September 25, 2021 181 patients were enrolled and randomly assigned to almitrine (n=89) or placebo (n=92). 179 patients (excluding two who withdrew from the study) were included in the intention-to-treat analysis (mean age: 60·1 years; 34% women) and analyzed. On day 7, the primary endpoint occurred in 32 patients assigned to almitrine (36%) and in 37 patients assigned to placebo (41%), for a difference of -4·3% (95% confidence interval: -18·7% to 10·2%). Secondary outcomes (28-day mortality, in-hospital mortality, ventilator-free days at day 28, days in the ICU and the hospital, and treatment discontinuation for pre-specified adverse effects) did not differ between the two groups.In patients with COVID-19 acute hypoxemic respiratory failure, low-dose almitrine failed in reducing the need for MV or death at day 7.Programme Hospitalier de Recherche Clinique (PHRC COVID 2020) funded by the French Ministry of Health, Les Laboratoires Servier (Suresnes, France) providing the study drug free of charge.

Aims To estimate the cost–effectiveness and cost–utility ratios of a restrictive vs. liberal transfusion strategy in acute myocardial infarction (AMI) patients with anaemia. Methods and results Patients (n = 666) with AMI and haemoglobin between 7–8 and 10 g/dL recruited in 35 hospitals in France and Spain were randomly assigned to a restrictive (n = 342) or a liberal (n = 324) transfusion strategy with 1-year prospective collection of resource utilization and quality of life using the EQ5D3L questionnaire. The economic evaluation was based on 648 patients from the per-protocol population. The outcomes were 30-day and 1-year cost-effectiveness, with major adverse cardiovascular events (MACEs) averted as the effectiveness outcome. and a 1-year cost–utility ratio. The 30-day incremental cost–effectiveness ratio was €33 065 saved per additional MACE averted with the restrictive vs. liberal strategy, with an 84% probability for the restrictive strategy to be cost-saving and MACE-reducing (i.e. dominant). At 1 year, the point estimate of the cost–utility ratio was €191 500 saved per quality-adjusted life year gained; however, the cumulated MACE was outside the pre-specified non-inferiority margin, resulting in a decremental cost–effectiveness ratio with a point estimate of €72 000 saved per additional MACE with the restrictive strategy. Conclusion In patients with AMI and anaemia, the restrictive transfusion strategy was dominant (cost-saving and outcome-improving) at 30 days. At 1 year, the restrictive strategy remained cost-saving, but clinical non-inferiority on MACE was no longer maintained. Trial Registration ClinicalTrials.gov Identifier: NCT02648113. One sentence summary The use of a restrictive transfusion strategy in patients with acute myocardial infarction is associated with lower healthcare costs, but more evidence is needed to ascertain its long-term clinical impact.

Background: Anemia is common in patients with acute myocardial infarction (AMI), and is an independent predictor of mortality. The optimal transfusion strategy in these patients is unclear. Hypothesis: We hypothesized that a "restrictive" transfusion strategy (triggered by hemoglobin ≤8 g/dL) is clinically noninferior to a "liberal" transfusion strategy (triggered by hemoglobin ≤10 g/dL), but is less costly. Methods: REALITY is an international, randomized, multicenter, open-label trial comparing a restrictive vs a liberal transfusion strategy in patients with AMI and anemia. The primary outcome is the incremental cost-effectiveness ratio (ICER) at 30 days, using the primary composite clinical outcome of major adverse cardiovascular events (MACE; comprising all-cause death, nonfatal stroke, nonfatal recurrent myocardial infarction, or emergency revascularization prompted by ischemia) as the effectiveness criterion. Secondary outcomes include the ICER at 1 year, and MACE (and its components) at 30 days and at 1 year. Results: The trial aimed to enroll 630 patients. Based on estimated event rates of 11% in the restrictive group and 15% in the liberal group, this number will provide 80% power to demonstrate clinical noninferiority of the restrictive group, with a noninferiority margin corresponding to a relative risk equal to 1.25. The sample size will also provide 80% power to show the cost-effectiveness of the restrictive strategy at a threshold of €50 000 per quality-adjusted life year. Conclusions: REALITY will provide important guidance on the management of patients with AMI and anemia. Sin financiación 3.287 JCR (2021) Q3, 74/143 Cardiac & Cardiovascular Systems 0.983 SJR (2021) Q1, 82/356 Cardiology and Cardiovascular Medicine No data IDR 2021 UEM

171 Background: ICI have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC . Lynch (LS) vs sporadic (Sp) status, BRAFV600E and RAS mutations (mt) are known factors of clinical and molecular heterogeneity in this population. We aimed to evaluate the prognostic value of these parameters in ICI-treated MSI mCRC pts. Methods: Pts are drawn from international cohorts (France, Italy, Spain, and USA). Pts were considered to have cancer linked to LS only in case of determined germline mutation and Sp in case of loss of MLH1/PMS2 protein expression associated with BRAF V600E mutation and/or hypermethylation of MLH1 promoter, or in case of biallelic somatic mutations of MMR genes. Survival analyses: progression-free survival (PFS) per iRECIST criteria and overall survival (OS) were adjusted on prognostic modifiers, selected on unadjusted analysis (p < 0.2) in case of limited number of events. Results: On the 466 pts included, 112 (24%) received ICI in first line, 305 (65%) received anti-PD1 alone, 161 (35%) anti-PD1 plus anti-CTLA4, 129 (29%) had BRAFV600Emt and 153 (34%) RASmt. Median follow-up was 24.0 months. In adjusted analysis of the whole population (n=466; 186 PFS events and 143 OS events), no association with PFS and OS was observed for BRAFV600E mt (PFS HR 1.20 [0.80 to 1.79], p=0.372; OS HR 1.06 [0.66 to 1.70], p= 0.811) and RASmt (PFS HR 0.93 [0.64 to 1.36], p= 0.712; OS HR 0.75 [0.48 to 1.17] p= 0.202). Adjusting factors were age, ECOG status, number of prior chemotherapies, treatment type (bi vs monotherapy), sidness (right vs left + rectum), primary tumor surgery. Concerning the population with determined Lynch status (n= 242; 83 PFS events and 54 OS events), PFS results are displayed. The analysis of impact of LS was not adjusted on BRAFV600E mutational status due to collinearity. In adjusted analysis, LS improved PFS compared with Sp (HR = 0.49, 95%CI (0.25 to 0.96), p = 0.036). Adjusted HR for OS was 0.56 without reaching significance 95%CI (0.25 to 1.22), p = 0.143. Conclusions: In this analysis of ICI-treated MSI/dMMR mCRC pts, RAS/BRAFV600E mutations are not associated with survival while Lynch syndrome pts demonstrated improved PFS. [Table: see text]

At the end of 2021, the B.1.1.529 SARS-CoV-2 variant (Omicron) wave superseded the B.1.617.2 variant (Delta) wave.To compare baseline characteristics and in-hospital outcomes of patients with SARS-CoV-2 infection with the Delta variant versus the Omicron variant in the emergency department (ED).Retrospective chart reviews.13 adult EDs in academic hospitals in the Paris area from 29 November 2021 to 10 January 2022.Patients with a positive reverse transcriptase polymerase chain reaction (RT-PCR) test result for SARS-CoV-2 and variant identification.Main outcome measures were baseline clinical and biological characteristics at ED presentation, intensive care unit (ICU) admission, mechanical ventilation, and in-hospital mortality.A total of 3728 patients had a positive RT-PCR test result for SARS-CoV-2 during the study period; 1716 patients who had a variant determination (818 Delta and 898 Omicron) were included. Median age was 58 years, and 49% were women. Patients infected with the Omicron variant were younger (54 vs. 62 years; difference, 8.0 years [95% CI, 4.6 to 11.4 years]), had a lower rate of obesity (8.0% vs. 12.5%; difference, 4.5 percentage points [CI, 1.5 to 7.5 percentage points]), were more vaccinated (65% vs. 39% for 1 dose and 22% vs. 11% for 3 doses), had a lower rate of dyspnea (26% vs. 50%; difference, 23.6 percentage points [CI, 19.0 to 28.2 percentage points]), and had a higher rate of discharge home from the ED (59% vs. 37%; difference, 21.9 percentage points [-26.5 to -17.1 percentage points]). Compared with Delta, Omicron infection was independently associated with a lower risk for ICU admission (adjusted difference, 11.4 percentage points [CI, 8.4 to 14.4 percentage points]), mechanical ventilation (adjusted difference, 3.6 percentage points [CI, 1.7 to 5.6 percentage points]), and in-hospital mortality (adjusted difference, 4.2 percentage points [CI, 2.0 to 6.5 percentage points]).Patients with COVID-19 illness and no SARS-CoV-2 variant determination in the ED were excluded.Compared with the Delta variant, infection with the Omicron variant in patients in the ED had different clinical and biological patterns and was associated with better in-hospital outcomes, including higher survival.None.

International audience; No abstract available

International audience; Background: There have been reports of procoagulant activity in patients with COVID-19. Whether there is an association between pulmonary embolism (PE) and COVID-19 in the emergency department (ED) is unknown. The aim of this study was to assess whether COVID-19 is associated with PE in ED patients who underwent a computed tomographic pulmonary angiogram (CTPA).Methods: A retrospective study in 26 EDs from six countries. ED patients in whom a CTPA was performed for suspected PE during a 2-month period covering the pandemic peak. The primary endpoint was the occurrence of a PE on CTPA. COVID-19 was diagnosed in the ED either on CT or reverse transcriptase-polymerase chain reaction. A multivariable binary logistic regression was built to adjust with other variables known to be associated with PE. A sensitivity analysis was performed in patients included during the pandemic period.Results: A total of 3,358 patients were included, of whom 105 were excluded because COVID-19 status was unknown, leaving 3,253 for analysis. Among them, 974 (30%) were diagnosed with COVID-19. Mean (±SD) age was 61 (±19) years and 52% were women. A PE was diagnosed on CTPA in 500 patients (15%). The risk of PE was similar between COVID-19 patients and others (15% in both groups). In the multivariable binary logistic regression model, COVID-19 was not associated with higher risk of PE (adjusted odds ratio = 0.98, 95% confidence interval = 0.76 to 1.26). There was no association when limited to patients in the pandemic period.Conclusion: In ED patients who underwent CTPA for suspected PE, COVID-19 was not associated with an increased probability of PE diagnosis. These results were also valid when limited to the pandemic period. However, these results may not apply to patients with suspected COVID-19 in general.

Paramount to guide the diagnostic strategy, the prevalence of pulmonary embolism in patients with syncope and no other symptoms is uncertain. We aimed to assess the pulmonary embolism prevalence in patients that present to the emergency department (ED) with syncope and no chest pain nor dyspnea.Multicenter prospective cohort study in seven EDs in France. Adult patients who presented to the ED with syncope (transient loss of consciousness) were included. Patients with chest pain or dyspnea were excluded. Included patients underwent formal work-up for pulmonary embolism, including D-dimer testing and further imaging if positive. Cases of pulmonary embolism were adjudicated by two independent expert radiologists with the review of imaging studies. Secondary objectives included the pulmonary embolism prevalence in the subgroup of patients with cancer, in patients with negative Pulmonary Embolism Rule Out criteria (PERC) score, and according to the clinical probability assessed either by Wells or revised Geneva score.We analyzed 411 patients, in whom 128 (31%) underwent a computed tomographic pulmonary angiogram and 9 (2%) a ventilation-perfusion scan. A pulmonary embolism was confirmed in nine patients (prevalence of 2.2%, 95% confidence interval, 1.1-4.3%), including one subsegmental pulmonary embolism. This prevalence was of 18% (3-52%) in patients with cancer and 0.7% (0.1-4%) in PERC negative patients.In our sample of patients with isolated syncope, the prevalence of pulmonary embolism was 2.2%. This value is not sufficiently low to negate the requirement for a formal work up in the ED, even in the absence of chest pain or dyspnea. However, the large confidence interval precludes any strong conclusion.

IMPORTANCE Uncontrolled studies suggest that pulmonary embolism (PE) can be safely ruled out using the YEARS rule, a diagnostic strategy that uses varying D-dimer thresholds. OBJECTIVE To prospectively validate the safety of a strategy that combines the YEARS rule with the pulmonary embolism rule-out criteria (PERC) rule and an age-adjusted D-dimer threshold. DESIGN, SETTINGS, AND PARTICIPANTS A cluster-randomized, crossover, noninferiority trial in 18 emergency departments (EDs) in France and Spain. Patients (N = 1414) who had a low clinical risk of PE not excluded by the PERC rule or a subjective clinical intermediate risk of PE were included from October 2019 to June 2020, and followed up until October 2020. INTERVENTIONS Each center was randomized for the sequence of intervention periods. In the intervention period (726 patients), PE was excluded without chest imaging in patients with no YEARS criteria and a D-dimer level less than 1000 ng/mL and in patients with 1 or more YEARS criteria and a D-dimer level less than the age-adjusted threshold (500 ng/mL if age = 50 years). In the control period (688 patients), PE was excluded without chest imaging if the D-dimer level was less than the age-adjusted threshold. MAIN OUTCOMES AND MEASURES The primary end point was venous thromboembolism (VTE) at 3 months. The noninferiority margin was set at 1.35%. There were 8 secondary end points, including chest imaging, ED length of stay, hospital admission. nonindicated anticoagulation treatment, all-cause death, and all-cause readmission at 3 months. RESULTS Of the 1414 included patients (mean age, 55 years; 58% female), 1217 (86%) were analyzed in the per-protocol analysis. PE was diagnosed in the ED in 100 patients (7.1%). At 3 months, VTE was diagnosed in 1 patient in the intervention group (0.15% [95% CI, 0.0% to 0.86%]) vs 5 patients in the control group (0.80% [95% CI, 0.26% to 1.86%]) (adjusted difference, -0.64% [1-sided 97.5% CI, -infinity to 0.21%), within the noninferiority margin). Of the 6 analyzed secondary end points, only 2 showed a statistically significant difference in the intervention group compared with the control group: chest imaging (30.4% vs 40.0%; adjusted difference, -8.7% [95% CI, -13.8% to -3.5%]) and ED median length of stay (6 hours [IQR, 4 to 8 hours] vs 6 hours [IQR, 5 to 9 hours]; adjusted difference, -1.6 hours [95% CI, -2.3 to -0.9]). CONCLUSIONS AND RELEVANCE Among ED patients with suspected PE, the use of the YEARS rule combined with the age-adjusted D-dimer threshold in PERC-positive patients, compared with a conventional diagnostic strategy, did not result in an inferior rate of thromboembolic events.

Background The efficacy of immune checkpoint inhibitors (ICIs) in microsatellite instability-high/DNA mismatch repair (MSI/dMMR) metastatic colorectal cancer (mCRC) is well established. ICIs are responsible for pseudoprogression (PSPD) that complicates clinical decisions. We evaluated the PSPD frequency in patients with MSI/dMMR mCRC treated with ICIs. Patients and methods Consecutive patients with MSI/dMMR mCRC treated with ICIs from February 2015 to December 2019 at Saint-Antoine Hospital were included. Imaging was retrospectively and centrally reviewed according to Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1) and immune RECIST (iRECIST). PSPD was defined as an unconfirmed disease progression by iRECIST. Results One hundred twenty-three patients with MSI/dMMR mCRC were included. Thirty-six patients (29%) had radiological PD according to RECIST 1.1 during the median follow-up of 22.3 months (95% confidence interval [CI], 1.5–62.2), including 22 in the first 3 months (the primary radiological PD). Twenty-nine patients continued ICIs beyond PD. Twelve patients experienced PSPD, representing 10% of the population and 52% of the primary radiological PD. The median time to PSPD was 5.7 weeks (95% CI, 4.1–11.4). No PSPD was observed after 3 months. The PSPD incidence was 14.8% in patients treated with anti-PD1 alone (n = 9/61) and 4.8% in case of anti-PD1 plus anti-CTLA-4 (n = 3/62). Eight patients with PSPD experienced an objective response. The 2-year progression-free survival and overall survival rates for patients with PSPD were 70.0% (95% CI, 32.9–89.2) and 75.0% (95% CI, 29.8–93.4), respectively. Conclusion Patients with MSI/dMMR mCRC treated with ICIs experienced PSPDs. PSPD occurred within the first 3 months and represented most of the primary radiological PDs. The use of iRECIST criteria should be questioned after 3 months.

Key Points Question Does an intervention aimed at improving guideline adherence for the management of acute heart failure, including intensive intravenous nitrate therapy and management of precipitating factors, improve hospital discharge and survival at 30 days? Findings In this stepped-wedge cluster randomized trial that included 503 patients 75 years and older who presented to the emergency department with acute heart failure, implementation of an early and comprehensive care bundle compared with usual care improved guideline adherence, but had no significant effect on number of days alive and out of hospital at 30 days (median of 19 d in both groups). Meanings This emergency department care bundle did not improve 30-day outcomes among older patients with acute heart failure. Abstract Importance Clinical guidelines for the early management of acute heart failure in the emergency department (ED) setting are based on only moderate levels of evidence, with subsequent low adherence to these guidelines. Objective To test the effect of an early guideline-recommended care bundle on short-term prognosis in older patients with acute heart failure in the ED. Design, Setting, and Participants Stepped-wedge cluster randomized trial in 15 EDs in France of 503 patients 75 years and older with a diagnosis of acute heart failure in the ED from December 2018 to September 2019 and followed up for 30 days until October 2019. Interventions A care bundle that included early intravenous nitrate boluses; management of precipitating factors, such as acute coronary syndrome, infection, or atrial fibrillation; and moderate dose of intravenous diuretics (n = 200). In the control group, patient care was left to the discretion of the treating emergency physician (n = 303). Each center was randomized to the order in which they switched to the “intervention period.” After the initial 4-week control period for all centers, 1 center entered in the intervention period every 2 weeks. Main Outcomes and Measures The primary end point was the number of days alive and out of hospital at 30 days. Secondary outcomes included 30-day all-cause mortality, 30-day cardiovascular mortality, unscheduled readmission, length of hospital stay, and kidney impairment. Results Among 503 patients who were randomized (median age, 87 years; 298 [59%] women), 502 were analyzed. In the intervention group, patients received a median (interquartile range) of 27.0 (9-54) mg of intravenous nitrates in the first 4 hours vs 4.0 (2.0-6.0) mg in the control group (adjusted difference, 23.8 [95% CI, 13.5-34.1]). There was a significantly higher percentage of patients in the intervention group treated for their precipitating factors than in the control group (58.8% vs 31.9%; adjusted difference, 31.1% [95% CI, 14.3%-47.9%]). There was no statistically significant difference in the primary end point of the number of days alive and out of hospital at 30 days (median [interquartile range], 19 [0- 24] d in both groups; adjusted difference, −1.9 [95% CI, −6.6 to 2.8]; adjusted ratio, 0.88 [95% CI, 0.64-1.21]). At 30 days, there was no significant difference between the intervention and control groups in mortality (8.0% vs 9.7%; adjusted difference, 4.1% [95% CI, −17.2% to 25.3%]), cardiovascular mortality (5.0% vs 7.4%; adjusted difference, 2.1% [95% CI, −15.5% to 19.8%]), unscheduled readmission (14.3% vs 15.7%; adjusted difference, −1.3% [95% CI, −26.3% to 23.7%]), median length of hospital stay (8 d in both groups; adjusted difference, 2.5 [95% CI, −0.9 to 5.8]), and kidney impairment (1% in both groups). Conclusions and Relevance Among older patients with acute heart failure, use of a guideline-based comprehensive care bundle in the ED compared with usual care did not result in a statistically significant difference in the number of days alive and out of the hospital at 30 days. Further research is needed to identify effective treatments for acute heart failure in older patients. Trial Registration ClinicalTrials.gov Identifier: NCT03683212

Background The COVID-19 pandemic has had a profound effect on general health care. We aimed to evaluate the effect of a nationwide lockdown in France on admissions to hospital for acute myocardial infarction, by patient characteristics and regional prevalence of the pandemic. Methods In this registry study, we collected data from 21 centres participating in the ongoing French Cohort of Myocardial Infarction Evaluation (FRENCHIE) registry, which collects data from all patients admitted for ST segment elevation myocardial infarction (STEMI) or non-ST segment elevation myocardial infarction (NSTEMI) within 48 h of symptom onset. We analysed weekly hospital admissions over 8 weeks: the 4 weeks preceding the institution of the lockdown and the 4 weeks following lockdown. The primary outcome was the change in the number of hospital admissions for all types of acute myocardial infarction, NSTEMI, and STEMI between the 4 weeks before lockdown and the 4 weeks after lockdown. Comparisons between categorical variables were made using χ2 tests or Fisher's exact tests. Comparisons of continuous variables were made using Student's t tests or Mann-Whitney tests. Poisson regression was used to determine the significance of change in hospital admissions over the two periods, after verifying the absence of overdispersion. Age category, region, and type of acute myocardial infarction (STEMI or NSTEMI) were used as covariables. The FRENCHIE cohort is registered with ClinicalTrials.gov, NCT04050956. Findings Between Feb 17 and April 12, 2020, 1167 patients were consecutively admitted within 48 h of acute myocardial infarction (583 with STEMI, 584 with NSTEMI) and were included in the study. Admissions for acute myocardial infarction decreased between the periods before and after lockdown was instituted, from 686 before to 481 after lockdown (30% decrease; incidence rate ratio 0·69 [95% CI 0·51–0·70]). Admissions for STEMI decreased from 331 to 252 (24%; 0·72 [0·62–0·85]), and admissions for NSTEMI decreased from 355 to 229 (35%; 0·64 [0·55–0·76]) following institution of the lockdown, with similar trends according to sex, risk factors, and regional prevalence of hospital admissions for COVID-19. Interpretation A marked decrease in hospital admissions was observed following the lockdown, irrespective of patient characteristics and regional prevalence of COVID-19. Health authorities should be aware of these findings, in order to adapt their message if the COVID-19 pandemic persists or recurs, or in case of future major epidemics. Funding Recherche Hospitalo-Universitaire en Santé iVasc.

Acute myocardial infarction (MI) is a common condition responsible for heart failure and sudden death. Here, we show that following acute MI in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue, and release Granzyme B leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function was confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of Granzyme B in patients with acute MI predict increased risk of death at 1-year follow-up. Our work unravels an unsuspected deleterious role of CD8+ T lymphocytes following acute ischemia, and identifies novel therapeutic strategy targeting pathogenic CD8+ T lymphocytes in the setting of acute MI.

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction., Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8+ lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.

Introduction In the work-up strategy for pulmonary embolism (PE) in the ED, the recently introduced YEARS rule allows the raising of the D-dimer threshold to 1000 ng/ml in patients with no signs of deep venous thrombosis and no hemoptysis and in whom PE is not the most likely diagnosis. However, this decision rule has never been prospectively compared to the usual strategy. Furthermore, it is unclear if the YEARS rule can be used on top of the Pulmonary Embolism Rule-out Criteria (PERC). We aim to assess the non-inferiority of YEARS compared to current guidelines to rule out PE among PERC-positive ED patients with suspicion of PE. Methods/design The MODIGLIANI study is a multicenter, European, non-inferiority, cluster-randomized, two periods cross-over, controlled trial. Each center will be randomized for the sequence of two 4-month periods: intervention (MOdified Diagnostic Strategy: MODS) followed by control (usual care), or control followed by intervention with 1 month of “wash-out” between the two periods. In the control period, the threshold will be as usual (500 ng/ml for patients aged 50 years or younger and age × 10 for older patients). In the MODS period, the threshold of D-dimers to rule out PE will be raised to 1000 ng/ml if no item of the YEARS score is present or will remain unchanged otherwise. Patients will be included if they have a suspicion of PE, defined as chest pain, dyspnea, or syncope. Non-inclusion criteria comprise a high clinical probability of PE or PERC-negative patients with low clinical probability. Ethics and dissemination The study has received the following approvals: Comité de protection des personnes Ile de France XI (France) and Comité de Ética de la Investigación con medicamentos del Hospital Clínic de Barcelona (Spain). Results will be made available to all included participants and other researchers. Trial registration ClinicalTrials.gov, NCT04032769. Registered on 24 July 2019.

Aim: to evaluate the impact of a nationwide lockdown in France on acute myocardial infarction (AMI) admissions, by patient characteristics and regional prevalence of the pandemic. Methods and Results: We collected data from 21 centres participating in the on-going FRENCHIE registry (NCT04050956), which collects data from all patients admitted for STEMI or NSTEMI within 48 hours of symptom onset. We compared weekly admissions in the 4 weeks preceding and the 4 weeks following institution of the lockdown. We observed a brutal 30% decrease in AMI admissions (24% for STEMI and 36% for NSTEMI, P=0.14) following institution of the lockdown, with similar trends according to gender (30% decrease in both men and women), risk factors, and regional prevalence of COVID-19. The decrease was numerically greater in patients aged 80 years or more (44% vs 27%, P=0.10). Patient characteristics, including time to hospital admission in STEMI patients, did not differ between the 2 periods. In-hospital mortality was numerically higher following institution of the lockdown (5.2% vs 3.4%, P=0.12), with similar trends for STEMI and NSTEMI. Conclusion: A marked decrease in hospital admissions was observed following the lockdown, irrespective of patient characteristics and regional prevalence of COVID-19. Health authorities should be aware of these findings, in order to adapt their message in case of a second wave of the pandemic or future major epidemics. Funding Statement: The FRENCHIE registry is supported by Recherche Hospitalo-universitaire en sante (RHU) iVasc within the programme "Investissements d'avenir", and sponsored by Assistance Publique – Hopitaux de Paris (Delegation a la Recherche Clinique et a l'Innovation). Declaration of Interests: YC reports research Grants to the Institution or Consulting/Lecture Fees from : Novartis , Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sanofi-Aventis, outside the submitted work. P. Coste reports having received fees from Amgen, AstraZeneca, Bayer and Servier, outside the submitted work G. Lemesle reports personal fees from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, BristolMyers Squibb, MSD, Novartis, Pfizer, Sanofi-Aventis, Servier, and The Medicine Co, outside the submitted work. FS reports personal fees from Amgen, Astra Zeneca, Bayer, BMS, MSD, Pfizer, and Sanofi, outside the submitted work D. Angoulvant reports receiving consulting and lecture fees from AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Sanofi, Amgen, Novartis, Novo-Nordisk, Servier and MSD, outside the submitted work C. Bouleti reports receiving consulting and lecture fees from Novartis and AstraZeneca, outside the submitted work. G. Cayla has received research grants/consultant fees/lectures fees from Amgen, AstraZeneca, Abbott, Bayer, Biotronik, Bristol-Myers Squibb, Pfizer, Sanofi-Aventis, outside the submitted work. P. Goube reports receiving consulting and lecture fees from AMGEN, SANOFI, BMS, ABBOT, outside the submitted work. T. Lhermusier has received research grants/consultant fees/lectures fees from AstraZeneca, Boston scientifics and Abbott, outside the submitted work A. Saib reports lectures fees from Novartis, outside the submitted work JG Dillinger reports receiving consulting and lecture fees from AstraZeneca, Bayer, BoehringerIngelheim, Bristol-Myers Squibb/Pfizer, Sanofi, and Daiichi-Sankyo and grants from Bayer, BristolMyers Squibb/Pfizer and Biosensors, outside the submitted work. F. Boccara reports research grants from Amgen; lecture fees from Janssen, Gilead, ViiV Healthcare, Amgen, Sanofi, MSD, and Servier outside the submitted work. And personal consultant or lecture fees from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Intercept, MSD, Novartis, Pfizer, Sanofi, and Servier, outside the submitted work. T. Simon reports grants from Astrazeneca, Daiichi-Sankyo, Eli-Lilly, GSK, MSD, Novartis, Sanofi, and personal fees for board membership and/or consultancy and/or lectures from AstraZeneca, BMS, Sanofi, and Novartis, outside the submitted work. N. Danchin has received research grants, or speaking and consulting fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli-Lilly, Intercept, MSD, Novartis, Novo-Nordisk, Pfizer, Sanofi, Servier, outside the submitted work. The other authors have nothing to report. Ethics Approval Statement: FRENCHIE has been approved by the Comite de Protection des Personnes and by the French data regulatory authority (Commission Nationale de l'Informatique et des Libertes).

The aim of this study was to report the 3-year survival results of the GRECCAR-6 trial.Current data on the effect of an extended interval between radiochemotherapy (RCT) and resection for rectal cancer on the rate of complete pathological response (pCR = ypT0N0) is controversial. Furthermore, its effect on oncological outcomes is unknown.The GRECCAR-6 trial was a phase III, multicenter, randomized, open-label, parallel-group, controlled trial. Patients with cT3/T4 or TxN+ tumors of the mid or lower rectum who had received RCT (45-50 Gy with 5-fluorouracil or capecitabine) were included and randomized into a 7- or 11-week waiting period. Primary endpoint was the pCR rate. Secondary endpoints were 3-year overall (OS), disease-free survival (DFS), and recurrence rates.A total of 265 patients from 24 participating centers were enrolled. A total of 253 patients underwent a mesorectal excision. Overall pCR rate was 17% (43/253). Mean follow-up from surgical resection was 32 ± 8 months. Twenty-four deaths occurred with an 89% OS at 3 years. DFS was 68.7% at 3 years (75 recurrences). Three-year local and distant recurrences were 7.9% and 23.8%, respectively. The randomization group had no impact on the 3-year OS (P = 0.8868) or DFS (P = 0.9409). Distant (P = 0.7432) and local (P = 0.3944) recurrences were also not influenced by the waiting period. DFS was independently influenced by 3 factors: circumferential radial margin (CRM) ≤1 mm [hazard ratio (HR) = 2.03; 95% confidence interval (CI), 1.17-3.51], ypT3-T4 (HR = 2.69; 95% CI, 1.19-6.08) and positive lymph nodes (HR = 3.62; 95% CI, 1.89-6.91).Extending the waiting period by 4 weeks following RCT has no influence on the oncological outcomes of T3/T4 rectal cancers.

3580 Background: Immune checkpoint inhibitors (ICI) have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC. We aimed to evaluate clinical, pathological and molecular factors associated with progression-free survival (PFS) and overall survival (OS) in ICI-treated pretreated mCRC patients (pts). Methods: Pts are drawn from a prospective cohort of all patients treated with ICI for MSI/dMMR mCRC at Saint-Antoine Hospital, Paris, France. All MSI/dMMR mCRC pts with disease progression after ≥ 1 prior systemic treatment (fluoropyrimidine and oxaliplatin or irinotecan ± targeted therapy) were included. MSI/dMMR status was centrally reviewed. Lynch syndrome or sporadic status was determined according to MMR gene germline mutational testing, MLH1 methylation status and BRAFV600E mutation. PFS and objective response rate (ORR) were assessed using iRECIST criteria. The impact of Lynch syndrome on PFS was analyzed apart from the multivariate analysis due to the interaction with the BRAFV600E mutation status. Results: Of 130 included pts, 66 received anti-PD1 alone, 1 anti-PDL1 alone and 63 anti-PD1 plus anti-CTLA4. 71% have had at least 2 prior lines of treatment. 33 patients (25%) have BRAFV600Emutation (mt) and 49 (38%) RASmt. The ORR for the whole population was 62.8 % IC95% [53.8; 71.1]. Median follow-up was 21.0 months, median PFS and OS were not reached. Results of PFS unadjusted and adjusted analysis are displayed in the table. BRAFV600E and RAS mutation were not associated with PFS and OS in multivariate analyses. After adjustment for the treatment type, Hazard Ratio (HR) for PFS between patients with proven Lynch syndrome (N=44) and patients with proven sporadic tumors (n= 44) was 0.57 (95%IC 0.26 -1.26). Conclusions: In this cohort, main known clinical, pathological and molecular factors do not influence the efficacy of ICI in pre-treated MSI/dMMR mCRC.[Table: see text]

Introduction: The prevalence of pulmonary embolism (PE) in patients that present to the Emergency Department (ED) with isolated syncope is unclear. Conflicting results were recently reported with a prevalence ranging from less than 1% to up to 17%. However, these studies included patients that may also have had other symptoms suggestive of PE (chest pain or dyspnea), or patients that had no systematic assessment for the presence of PE. Since a low prevalence ( Aims: to evaluate the prevalence of PE in ED patients with isolated syncope. Methods: Multicenter prospective cohort study in seven EDs in France. Adult patients who presented to the ED with syncope (transient loss of consciousness) were included. Patients with chest pain or dyspnea were excluded. Included patients underwent formal work-up for PE, including D-dimer testing and further imaging if positive. Cases of PE were adjudicated by two independent expert radiologists with the review of imaging studies. Results: 411 patients were recruited and tested with D-dimer, in whom 137 (33%) underwent a computed tomographic pulmonary angiogram or a ventilation-perfusion scan. A PE was confirmed in nine patients (prevalence of 2.2%, 95% confidence interval 1.1% to 4.3%), including one sub-segmental PE. Conclusion: In our sample of patients with isolated syncope, the prevalence of PE was 2.2%. This value is not sufficiently low to negate the requirement for a formal work up in the ED, even in the absence of chest pain or dyspnea.

BACKGROUND. Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We explored a strategy to shape the adaptive immune response by targeting innate immune cells through novel immunization routes. METHODS. This randomized phase I/II clinical study (n = 60 healthy subjects aged 18–45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV, season 2012–2013, 1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition [HI], microneutralization [MN] antibodies, and CD4+ and CD8+ effector T cells) were measured at baseline day 0 (d0) and at d21. Blood transcriptome was analyzed at d0 and d1. RESULTS. TIV-specific CD8+ granzyme B+ (GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, whereas immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating 2 clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy and confirmed that 9 genes and the serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T cell or antibody responses. A logistic regression analysis demonstrated that these 9 genes and the serum levels of CXCL10 at d1/d0 best predicted TIV-specific CD8+GRZ+ T cell and antibody responses at d21. CONCLUSION. This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses. TRIAL REGISTRATION. This study has been registered at ClinicalTrials.gov (NCT01707602). FUNDING. This work was supported by grants from the French Ministry of Health PHRCN 2012 – RCT 12061, INSERM-DGOS, the Fondation pour la Recherche Médicale, and the Société Française de Dermatologie (to AS). These funding sources had no direct role in any aspect of the research or article.

Background: Acute heart failure (AHF) is one of the most common diagnoses for elderly patients in the emergency department (ED), with an admission rate higher than 80% and 1-month mortality around 10%. The European guidelines for the management of AHF are based on moderate levels of evidence, due to the lack of randomized controlled trials and the scarce evidence of any clinical added value of a specific treatment to improve outcomes. Recent reports suggest that the very early administration of full recommended therapy may decrease mortality. However, several studies highlighted that elderly patients often received suboptimal treatment. Our hypothesis is that an early care bundle that comprises early and comprehensive management of symptoms, along with prompt detection and treatment of precipitating factors should improve AHF outcome in elderly patients. Method/design: ELISABETH is a stepped-wedge, controlled cluster randomized, clinical trial in 15 emergency departments in France recruiting all patients aged 75 years and older with a diagnosis of AHF. The tested intervention is a care bundle with a checklist that mandates detection and early treatment of AHF precipitating factors, early and intensive treatment of congestion with intravenous nitrates boluses, and application of other recommended treatment (low dose diuretics, non-invasive ventilation when indicated, and preventive low molecular weight heparin). Each centre are randomized to the order in which they will switch from “control period” to “intervention period”. All centers begin the trials with the control period for two weeks, then after each two-weeks step a new centre will be in the intervention period. At the end of the trial, all clusters will receive the intervention regimen. The primary outcome is the number of days alive and out of the hospital at 30 days. Discussion: If our hypothesis is confirmed, this trial will strengthen the level of evidence of AHF guidelines and stress the importance of the associated early and comprehensive treatment of precipitating factors. This trial could be the first to report a reduction in short term morbidity and mortality in elderly AHF patients. Registration: NCT03683212, prospectively registered on September 25th 2018 Keywords: Elderly, acute heart failure, emergency department

International audience; We thank « John Doe » et al. for their interest and comments on our paper “Association between Pulmonary Embolism and COVID‐19 in ED patients: the PEPCOV international retrospective study”. The authors raised the important issue of a possible bias, because we only analyzed patients that were tested for pulmonary embolism (PE) with computed tomography pulmonary angiogram (CTPA). We acknowledge that this is a limitation, and accordingly highlighted in our manuscript that whether these results apply to the general population is unknown.

BACKGROUND In countries with concentrated HIV epidemics, optimizing screening to reach individuals with undiagnosed infection is essential. The DICI-VIH study, a cluster-randomized crossover trial conducted in eight French emergency departments (EDs), found that a strategy combining nurse-driven targeted HIV screening with routine diagnostic testing was effective. AIM The aim was to investigate factors associated with the implementation of HIV screening targeting key populations in EDs. METHODS A self-administered questionnaire was distributed at registration to patients aged 18-64 years and able to give consent during the DICI-VIH intervention. Based on their responses, those belonging to key populations were offered a rapid test by triage nurses. Two key stages of the process were evaluated: questionnaire distribution by providers and test acceptance by patients. Patient information, daily workload, and ED characteristics were collected. The associations between these variables and (a) the proportion of questionnaires distributed and (b) the proportion of tests accepted were evaluated using multilevel modeling in order to examine differences in screening implementation between EDs. RESULTS Questionnaire distribution proportions varied from 23% to 48% across EDs. They were higher on weekdays than weekends (odds ratio, OR: 3.77; 95% CI: 3.57-3.99) and when research staff participated (OR: 1.31; 95% CI: 1.26-1.37). They decreased over time (OR: 0.76; 95% CI: 0.71-0.82; 4th [Q3] vs. 1st quartile [Q0] of intervention days) and with increased patient flow (OR: 0.61; 95% CI: 0.56-0.67; Q3 vs. Q0 of eligible patients). Test acceptance varied from 64% to 77% across EDs, increased with research staff participation (OR 1.20; 95% CI: 1.03-1.40), and decreased over time (OR: 0.75; 95% CI: 0.60-0.92; Q3 vs. Q0). Patients who accepted were more likely to be younger (OR: 0.76; 95% CI: 0.61-0.96; 50-64-year-old vs. 30-39-year-old patients). LINKING EVIDENCE TO ACTION Patient flow, intervention duration, weekdays, and research staff participation were important determinants of targeted screening implementation. These findings could help guide future implementation in similar settings.

International audience; BACKGROUND: This study aimed to determine the failure rate of a combination of the PERC and the YEARS rules for the diagnosis of pulmonary embolism (PE) in the emergency department (ED).METHODS: We performed a retrospective analysis of two European cohorts of emergency patients with low gestalt clinical probability of PE (PROPER and PERCEPIC). All patients we included were managed using a conventional strategy (D-dimer test, followed, if positive, by computed tomographic pulmonary angiogram (CTPA). We tested a diagnostic strategy that combined PERC and YEARS to rule out PE. The primary endpoint was a thromboembolic event diagnosed in the ED or at 3-months follow-up. Secondary endpoints included a thromboembolic event at baseline in the ED and a CTPA in the ED. Ninety-five percent confidence intervals (CIs) of proportions were calculated with the use of Wilson's continuity correction.RESULTS: We analyzed 1,951 patients (mean±SD age= 47±18years, 56% women) with an overall proportion of patients with PE of 3.5%. Both PERC and YEARS strategies were associated with 11 missed PE in the ED: failure rate 0.57 (95% CI= 0.32-1.02). At 3-month follow-up, the overall failure rate was 0.83% (95% CI= 0.51-1.35). Among the 503 patients who underwent a CTPA (26%), the use of the PERC-YEARS combination would have ruled out PE without CTPA in 249 patients (50% [95%CI= 45%-54%], absolute reduction13% (95% CI= 11%-14%]).CONCLUSION: The combination of PERC then YEARS was associated with a low risk of PE diagnostic failure and would have resulted in a relative reduction of almost half of CTPA.

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.To prospectively validate the safety of a PERC-based strategy to rule out PE.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.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.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.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%]).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.clinicaltrials.gov Identifier: NCT02375919.

on behalf of the GEMRITUX Study; International audience; 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

483 Background: There are controversial data on the impact of a long waiting period between radiochemotherapy (RCT) and resection for rectal cancer on the rate of complete pathological response (pCR = ypT0N0). The impact on the oncological prognosis is also unknown. We present the 3 years survival results of the GRECCAR6 trial. Methods: The GRECCAR6 trial was a phase III, multicentre, randomized, open-label, parallel-group, controlled trial. Patients with cT3/T4 or TxN+ tumours assessed by radiological examination (MRI and/or endo-ultrasound) of the mid or lower rectum who had received RCT (45-50 Gy with intravenous 5-FU or capecitabine) were included and randomized between 7 weeks or 11 weeks of waiting period. Primary endpoint was the pCR rate. Secondary endpoints were overall, disease-free survival and rate of recurrences. Results: A total of 265 patients from 24 participating centres were enrolled between October 2012 and February 2015. Among them, 253 patients underwent surgery with mesorectal excision. The rate of pCR was 17% (43/253). Mean follow-up from surgical resection was 32±8 months. 25 deaths occurred with a 89% OS at 3 years. DFS was 67.7% at 3 years due to 77 deaths or recurrences. 3-years local and distant recurrences rates were 9.2% and 24.9%, respectively. The group of randomization had no impact on the OS (p = 0.9486) and the DFS (p = 0.8672). Distant (p = 0.8589) and local (p = 0.5780) recurrences were also not influenced by the waiting period. Patients with a pCR had an excellent prognosis with an overall survival of 94.5% versus 87.9% for the remaining patients at 3 years (p = 0.232) and a DFS of 89.6% versus 63.4% (p = 0.0025). On multivariate analysis, DFS was influenced by low rectal tumors (OR=1.74; [1.03; 2.94], p = 0.037), R1 resection (OR = 2.03; [1.18; 3.50], p = 0.011), ypT3-T4 (OR = 2.4; [1.12; 5.19], p = 0.0245) and N+ (OR = 2.85; [1.76; 4.61], p < 0.001). Conclusions: Waiting 4 weeks longer after radiochemotherapy has no influence on the oncological outcomes of T3/T4 rectal cancers. Clinical trial information: NCT01648894.

Despite significant progress in the treatment of pediatric acute myeloblastic leukemia (AML), relapse remains the commonest cause of death. Randomized ELAM02 trial questioned if maintenance therapy with interleukin-2 (IL2), for 1 year, improves disease-free survival (DFS). Patients aged 0 to 18 years, with newly diagnosed AML (excluding patients with acute promyelocytic leukemia or down syndrome AML) were enrolled. They received 1 course of induction treatment (cytarabine and mitoxantrone) and 3 courses of consolidation treatment (high-dose cytarabine in courses 1 and 3). According to the cytogenetics risk, patients not undergoing hematopoietic stem cell transplantation, still in complete remission (CR) after the third course of consolidation treatment, were eligible for randomization to 1 year of maintenance therapy with monthly courses of IL2 or no maintenance treatment. There were 438 evaluable patients, 154 of whom were randomized to the IL2/no maintenance groups. Relapse occurred in 28 patients from the IL2+ group and 29 patients in the IL2- group. Survival was similar in the 2 groups, with a 4-year DFS of 62% without IL2 and 66% with IL2 (P = 0.75). In the CBF population, 4-year DFS was 55% without IL2 and 78% with IL2 (P = 0.07). No deaths from toxicity or excess of serious adverse events related to IL2 treatment were recorded. Prolonged IL2 for maintenance therapy after intensive chemotherapy is feasible and safe in pediatric AML patients in their first CR. Such treatment did not improve DFS in this study, but a positive trend was observed in favor of IL2 maintenance therapy among core binding factor acute myeloblastic leukemia.

Background The incidence of biliary complications following liver transplantation (LT) remains high, ranging from 10 to 50 % of patients, especially when the diameter of the bile duct is smaller than 7 mm. Biliary reconstruction is most often performed by duct-to-duct anastomosis. In a preliminary study (n = 20), we previously reported a technique of biliary reconstruction using an intraductal stent tube followed by its endoscopic removal and showed both the feasibility and safety of this innovative procedure. The next step is to validate the potential benefit of this procedure in a randomized controlled trial. Design This is a multicenter randomized controlled trial in France comparing the efficacy of biliary reconstruction with or without a removable intraductal stent on reducing biliary complications. Inclusion and randomization are performed during LT when a duct-to-duct biliary anastomosis smaller than 7 mm in diameter is envisioned. In the intraductal stent group, a custom-made segment of a T-tube is placed into the bile duct and removed endoscopically 4 to 6 months later. The surgical technique is described in a video during randomization and is available on the secure website used for inclusion and randomization. The primary endpoint is the occurrence of biliary complications, including biliary fistulae and strictures, during the 6 months of follow-up. Secondary evaluation criteria are the incidence of complications related to the stent placement and its extraction by endoscopy. The inclusion of 248 patients in total has been determined based on an expected incidence of biliary complications of 25 % in the non-IST group and a 60 % reduction of biliary complications (10 %) in the IST group. Discussion Biliary complications following LT are significant causes of morbidity, retransplantation, and mortality. Although controversial, the use of a T-tube has been proven to be useless and even responsible for specific complications related to the external part of the tube in many studies, including several randomized trials. However, several studies have identified a small bile duct diameter as a risk factor for biliary stenosis. A threshold of 7 mm was found to be significantly associated with biliary stenosis. Our team published a preliminary study that included 20 patients using a new technique of intraductal stenting. Only four complications were reported in the overall study population, whereas no biliary complication occurred in the subgroup of patients who received a whole graft LT. Moreover, no technical failures and no procedure-related complications were noted before and during the drain removal. Although an intraductal stent tube in duct-to duct biliary anastomosis seems feasible and safe, a multicenter randomized controlled trial is needed to validate its benefit as a protective tool against the occurrence of biliary complications. One original aspect of this protocol is the video demonstration of the surgical procedure, which is available on the web to standardize and homogenize the technique. The surgical community may be inspired by this type of tool in the future to minimize technical bias related to technical issues. Trial registration NCT02356939, date of registration 2 February 2015.

Importance Emergency departments (ED) are environments that are at high risk for medical errors. Previous studies suggested that the proportion of medical errors may decrease when more than 1 physician is involved. Objective To reduce the proportion of medical errors by implementing systematic cross-checking between emergency physicians. Design, Setting, and Participants This cluster randomized crossover trial includes a random sample of 14 adult patients (age ≥18 years) per day during two 10-day period in 6 EDs (n = 1680 patients) in France. Interventions Systematic cross-checking between emergency physicians, 3 times a day, which included a brief presentation of one physician’s case to another, followed by the second physician’s feedback to the first. Main Outcomes and Measures Medical error in the ED, defined as an adverse event (either a near miss or a serious adverse event). The primary end point was identified using a 2-level error detection surveillance system, blinded to the strategy allocation. Results Among the 1680 included patients (mean [SD] age, 57.5 [21.7] years), 144 (8.6%) had an adverse event. There were 54 adverse events among 840 patients (6.4%) in the cross-check group compared with 90 adverse events among 840 patients (10.7%) in the standard care group (relative risk reduction [RRR], 40% [95% CI, 12% to 59%]; absolute risk reduction [ARR], 4.3%; number needed to treat [NNT], 24). There was also a significant reduction rate of near misses (RRR, 47% [95% CI, 15% to 67%]; ARR, 2.7%; NNT, 37) but not of the rate of preventable serious adverse events (RRR, 29% [95% CI, −18% to 57%]; ARR, 1.2%; NNT, 83). Conclusions and Relevance The implementation of systematic cross-checking between emergency physicians was associated with a significant reduction in adverse events, mainly driven by a reduction in near misses. Trial Registration ClinicalTrials.gov Identifier:NCT02356926