Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe ...Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation.
Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH.
PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation).
At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (
= 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval CI, 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range IQR, 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments.
Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).
Hypermutated viruses induced by APOBEC3 (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3) proteins comprise some of the defective viruses in the HIV reservoir. Here, we assessed ...the proportion of APOBEC3-induced defective proviruses in HIV-positive patients before and after receiving dolutegravir + lamivudine dual therapy.
PBMCs of virologically suppressed patients enrolled in the ANRS 167 LAMIDOL trial, evaluating a switch from triple therapy to dolutegravir + lamivudine, were collected 8 weeks before (W-8) and 48 weeks after (W48) dual-therapy initiation. The Vif and RT regions were subject to next-generation sequencing. Bioinformatic algorithms were developed to identify APOBEC3-defective sequences and APOBEC3-related drug resistance mutations (APOMuts). All hypermutated sequences and those containing at least one stop codon were considered as defective.
One hundred and four patients were enrolled (median virological suppression duration: 4.2 years; IQR: 2.0-9.1). Proviral defective reads at W-8 and W48 were detected in Vif in 22% and 29% of patients, respectively, and in RT in 38% and 42% of patients, respectively. At least one APOMut was present in proviruses of 27% and 38% of patients at W-8 and W48, respectively. The ratio of APOMuts/number of potential APOMut sites was significantly higher at W48 (16.5%) than at W-8 (9.8%, P = 0.007). The presence of APOBEC3-defective viruses at W-8 was not associated with HIV total DNA level, nor with the third drug class received prior to switching to dolutegravir + lamivudine, nor with the duration of virological suppression.
Whereas no significant change in the proportion of patients with APOBEC3-defective proviruses was evidenced after 1 year of dolutegravir + lamivudine maintenance, enrichment in APOMuts was observed. Further longer-term studies are needed to assess the other forms of defective viruses with dual-therapy.
Between December 2016 and March 2018, two outbreaks of Group A
(GAS) infection occurred at the Canadian Forces Leadership and Recruit School. A voluntary mass antibiotic prophylaxis (MAP) program was ...implemented in March 2018, to interrupt an ongoing GAS outbreak, and to prevent future outbreaks.
Instructors and recruits were offered a one-time intramuscular injection of 1.2 million units penicillin G benzathine (PGB). Individuals with a penicillin allergy were offered azithromycin; 500 mg orally once weekly for four consecutive weeks. Instructors and recruits were also asked to complete a voluntary and anonymous survey one week after receipt of MAP, to detect MAP-related adverse events.
MAP was offered to 2,749 individuals; 2,707 of whom agreed to receive it (98.5% uptake). The majority of personnel experienced adverse events in the days following MAP; 92.3% of personnel who received PGB reported localized pain at the injection site, and 70.2% of personnel who received azithromycin reported gastrointestinal symptoms. However, only five cases of serious adverse events were reported, and less than 1% of recruits could not complete their basic military training course because of MAP-related adverse events.
The MAP program implemented in March 2018 was the first of its kind in the Canadian Armed Forces, and the largest single use of PGB in a defined group in Canada. It resulted in very few serious adverse events and with minimal impact on military recruits' successful completion of recruit training.
Contexte : Entre décembre 2016 et mars 2018, deux éclosions d’infections par le streptocoque du groupe A se sont produites à l’École de leadership et de recrues des Forces canadiennes. Un programme ...volontaire de prophylaxie antibiotique de masse a été mis en œuvre en mars 2018, afin d’interrompre une éclosion de streptocoque du groupe A continuelle et d’empêcher des éclosions à venir. Méthodes : On a offert aux instructeurs et aux recrues une injection intramusculaire unique de 1,2 million d’unités de pénicilline G benzathine (PGB). Les personnes ayant une allergie à la pénicilline se sont vues offrir de l’azithromycine; 500 mg par voie orale une fois par semaine pendant quatre semaines consécutives. On a également demandé aux instructeurs et aux recrues de remplir un sondage volontaire et anonyme une semaine après l’administration de la prophylaxie antibiotique de masse afin de détecter les événements indésirables liés à cette dernière. Résultats : La prophylaxie antibiotique de masse a été offerte à 2 749 personnes; 2 707 d’entre elles ont accepté de la recevoir (98,5 %). La majorité du personnel a connu des événements indésirables dans les jours suivants la prophylaxie antibiotique de masse; 92,3 % des personnes qui ont reçu de la PGB ont signalé une douleur localisée au site d’injection et 70,2 % des personnes qui ont reçu de l’azithromycine ont signalé des symptômes gastro-intestinaux. Toutefois, on a seulement signalé cinq cas d’événements indésirables graves et moins de 1 % des recrues n’ont pas pu suivre leur formation militaire de base en raison d’événements indésirables liés à la prophylaxie antibiotique de masse. Conclusion : Le programme de prophylaxie antibiotique de masse mis en œuvre en mars 2018 est le premier du genre dans les Forces armées canadiennes et le plus grand usage de la PGB dans un groupe défini au Canada. Il n’a entraîné que très peu d’événements indésirables graves et n’a eu que peu d’incidence sur la réussite de la formation des recrues.
BACKGROUNDBetween December 2016 and March 2018, two outbreaks of Group A Streptococcus (GAS) infection occurred at the Canadian Forces Leadership and Recruit School. A voluntary mass antibiotic ...prophylaxis (MAP) program was implemented in March 2018, to interrupt an ongoing GAS outbreak, and to prevent future outbreaks. METHODSInstructors and recruits were offered a one-time intramuscular injection of 1.2 million units penicillin G benzathine (PGB). Individuals with a penicillin allergy were offered azithromycin; 500 mg orally once weekly for four consecutive weeks. Instructors and recruits were also asked to complete a voluntary and anonymous survey one week after receipt of MAP, to detect MAP-related adverse events. RESULTSMAP was offered to 2,749 individuals; 2,707 of whom agreed to receive it (98.5% uptake). The majority of personnel experienced adverse events in the days following MAP; 92.3% of personnel who received PGB reported localized pain at the injection site, and 70.2% of personnel who received azithromycin reported gastrointestinal symptoms. However, only five cases of serious adverse events were reported, and less than 1% of recruits could not complete their basic military training course because of MAP-related adverse events. CONCLUSIONThe MAP program implemented in March 2018 was the first of its kind in the Canadian Armed Forces, and the largest single use of PGB in a defined group in Canada. It resulted in very few serious adverse events and with minimal impact on military recruits' successful completion of recruit training.
Objective structured clinical examinations (OSCEs) are known to be a fair evaluation method. These recent years, the use of online OSCEs (eOSCEs) has spread. This study aimed to compare remote versus ...live evaluation and assess the factors associated with score variability during eOSCEs.
We conducted large-scale eOSCEs at the medical school of the Université de Paris Cité in June 2021 and recorded all the students' performances, allowing a second evaluation. To assess the agreement in our context of multiple raters and students, we fitted a linear mixed model with student and rater as random effects and the score as an explained variable.
One hundred seventy observations were analyzed for the first station after quality control. We retained 192 and 110 observations for the statistical analysis of the two other stations. The median score and interquartile range were 60 out of 100 (IQR 50-70), 60 out of 100 (IQR 54-70), and 53 out of 100 (IQR 45-62) for the three stations. The score variance proportions explained by the rater (ICC rater) were 23.0, 16.8, and 32.8%, respectively. Of the 31 raters, 18 (58%) were male. Scores did not differ significantly according to the gender of the rater (p = 0.96, 0.10, and 0.26, respectively). The two evaluations showed no systematic difference in scores (p = 0.92, 0.053, and 0.38, respectively).
Our study suggests that remote evaluation is as reliable as live evaluation for eOSCEs.
Abstract Background Objective structured clinical examinations (OSCEs) are known to be a fair evaluation method. These recent years, the use of online OSCEs (eOSCEs) has spread. This study aimed to ...compare remote versus live evaluation and assess the factors associated with score variability during eOSCEs. Methods We conducted large-scale eOSCEs at the medical school of the Université de Paris Cité in June 2021 and recorded all the students’ performances, allowing a second evaluation. To assess the agreement in our context of multiple raters and students, we fitted a linear mixed model with student and rater as random effects and the score as an explained variable. Results One hundred seventy observations were analyzed for the first station after quality control. We retained 192 and 110 observations for the statistical analysis of the two other stations. The median score and interquartile range were 60 out of 100 (IQR 50–70), 60 out of 100 (IQR 54–70), and 53 out of 100 (IQR 45–62) for the three stations. The score variance proportions explained by the rater (ICC rater) were 23.0, 16.8, and 32.8%, respectively. Of the 31 raters, 18 (58%) were male. Scores did not differ significantly according to the gender of the rater ( p = 0.96, 0.10, and 0.26, respectively). The two evaluations showed no systematic difference in scores ( p = 0.92, 0.053, and 0.38, respectively). Conclusion Our study suggests that remote evaluation is as reliable as live evaluation for eOSCEs.
Abstract
Pulmonary grade-1 typical (TC) and grade-2 atypical (AC) carcinoids share molecular characteristics with grade-3 large-cell neuroendocrine carcinoma (LCNEC) despite the distinct clinical ...behaviors. Most carcinoids can be surgically resected, however, limited treatment options exist for metastatic disease, present in 10-23% of TC and 40-50% of AC. Comprehensive genomic studies could help identify better therapeutic opportunities, novel diagnostic markers, and provide insight on the mechanisms responsible for the increased aggressiveness of AC versus TC. Such studies are rare due to the limited availability of suitable material.
We have established a multi-center collaboration that has given us access to a unique collection of samples. We have already characterized 40 TC and 60 LCNEC genomes/exomes, and 61 TC, 8 AC and 69 LCNEC trancriptomes (published data). In the present study, we have performed whole-exome and transcriptome sequencing on 20 AC patients. Methylation data from 850K Illumina arrays were also generated for these samples, and for a subset of 20 TC and 20 LCNEC previously mentioned.
When comparing the mutational data on AC with that of TC and LCNEC, we have found that similar to TC, AC harbor recurrent alterations in chromatin remodeling genes (such as MEN1 and ARID1A). They also carry alterations in genes involved in other cancer-related pathways (based on STRING), such as cell motility and cell death explaining their more aggressive phenotype. Integrative clustering analysis (MOFA and iCLUSTER) based on expression and methylation data tends to classify carcinoids into four groups: groups 1 and 2 are mostly composed of females with TC, and differ by their age composition and smoking status (Fisher's exact test p=0.008 and 0.03, respectively). Groups 3 and 4 are mostly composed of males with AC (Fisher's exact test for tumor type p=8x10-5). When including the LCNEC data, the samples from group 3 cluster with LCNEC, suggesting that AC can display a variety of expression and methylation patterns that may be linked to aggressiveness. This result was supported by the better survival of groups 1 and 2 compared to groups 3 and 4 (log-rank p=0.02), for which survival was similar to that of patients with LCNEC.
Here, we present for the first time: (i) a multi-omics study on AC; (ii) the methylome characterization of TC, AC, and LCNEC; and (iii) the results of a comparative analysis of TC, AC, and LCNEC based on their molecular characteristics. We have identified the genes and pathways that might explain the progression from low-grade TC to intermediate-grade AC. Our expression and methylation data also supports the existence of a “super-AC” group, which clusters with LCNEC. Finally, we have identified a panel of molecular alterations that may help pathologist distinguishing between these three entities.
NL and NA contributed equally. LFC and MF jointly supervised this work.
Citation Format: Noémie Leblay, Nicolas Alcala, David Hervás Marin, Tiffany M. Delhomme, Théo Giffon, Akram Ghantous, Amélie Chabrier, Cyrille Cuenin, Janine Altmueller, Geoffroy Durand, Catherine Voegele, Philippe Lorimier, Anne-Claire Toffart, Jules Derks, Odd Terje Brustugun, Joachim H. Clement, Joerg Saenger, John K. Field, Alex Soltermann, Gavin M. Wright, Luca Roz, Lucia Anna Muscarella, Paolo Graziano, Zdenko Herceg, Ernst-Jan Speel, Peter Nuernberg, James McKay, Nicolas Girard, Sylvie Lantuejoul, Juan Sandoval, Elisabeth Brambilla, Matthieu Foll, Lynnette Fernandez-Cuesta. Multi-omics comparative analyses of pulmonary typical carcinoids, atypical carcinoids, and large-cell neuroendocrine carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5358.
Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several ...antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches.
This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per μL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants.
Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47–66) in the ritonavir-boosted lopinavir group and 59% (49–68) in the raltegravir group.
The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen.
ANRS MIE.
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