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The m6A epitranscriptomic mark is the most abundant and widespread internal RNA chemical modification, which through the control of RNA acts as an important factor of eukaryote reproduction, growth, morphogenesis and stress response. The main m6A readers constitute a super family of proteins with hundreds of members that share a so-called YTH RNA binding domain. The majority of YTH proteins carry no obvious additional domain except for an Intrinsically Disordered Region (IDR). In Arabidopsis thaliana IDRs are important for the functional specialization among the different YTH proteins, known as Evolutionarily Conserved C-Terminal region, ECT 1 to 12. Here by studying the ECT2 protein and using an in vitro biochemical characterization, we show that full-length ECT2 and its YTH domain alone have a distinct ability to bind m6A, conversely to previously characterized YTH readers. We identify peptide regions outside of ECT2 YTH domain, in the N-terminal IDR, that regulate its binding to m6A-methylated RNA. Furthermore, we show that the selectivity of ECT2 binding for m6A is enhanced by a high uridine content within its neighbouring sequence, where ECT2 N-terminal IDR is believed to contact the target RNA in vivo. Finally, we also identify small structural elements, located next to ECT2 YTH domain and conserved in a large set of YTH proteins, that enhance its binding to m6A-methylated RNA. We propose from these findings that some of these regulatory regions are not limited to ECT2 or YTH readers of flowering plants but may be widespread among eukaryotic YTH readers.

ABSTRACT Objective This study aims to analyse high‐grade intraepithelial lesions (LIEHG) observed in a screening programme from 2010 to 2018 to more accurately describe them and formulate recommendations for best practices in the context of screening evolution following the introduction of an HPV test in primary cervical cancer screening in 2020. Methods This study included 305,940 asymptomatic women aged 25–65 years. The eligible population was invited to undergo a screening cervico‐uterine‐smear every 3 years. If this smear was normal, the woman received a new invitation. In the case of a positive screen, the patient underwent further diagnostic procedures, such as colposcopy and biopsy to confirm the diagnosis. Only those diagnosed with LIEHG and above proceeded to treatment. The diagnoses associated with LIEHG were those related to the WHO Classification of tumours of the uterine cervix. Results Positive smears led to the diagnosis of 3230 LIEHG. The prevalence of LIEHG in the screened population was 0.4%. The LIEHG distribution varied significantly according to the age of the women. The probability of diagnosing LIEHG in young women was 12.2% at 25–29 years. This probability decreased by half after 50 years. We observed that the type of smear was significantly associated with LIEHG detection. The positive predictive value for diagnosing LIEHG was 70.3% for high‐grade squamous intraepithelial lesion (HSIL) smears and 35.1% for atypical squamous cells cannot exclude HSIL (ASC‐H) smears. Conclusion In the study population, the prevalence of LIEHG was high in women under 35 years. Low‐grade smears were correlated with the risk of LIEHG and should prompt screening facilities to allocate resources to ensure active follow‐up of LSIL and ASC‐US smears. Adherence to cytological screening recommendations was associated with a reduced risk of LIEHG in multivariate analysis.

Introduction Many patients referred for suspicion of myelodysplastic neoplasm (MDS) are subjected to unnecessary discomfort from bone marrow aspiration, due to the low disease prevalence in this population. Flow cytometric analysis of peripheral blood neutrophil myeloperoxidase expression could rule out MDS with sensitivity and negative predictive value estimates close to 100%, ultimately obviating the need for bone marrow aspiration in up to 35% of patients. However, the generalisability of these findings is uncertain due to the limited sample size, the enrolment of patients at a single study site, and the reliability issues associated with laboratory-developed tests and varying levels of operator experience. This study aims to validate the accuracy attributes of peripheral blood neutrophil myeloperoxidase expression quantified by flow cytometric analysis in an independent multicentre sample.Methods and analysis The MPO-MDS-Valid project is a cross-sectional diagnostic accuracy study comparing an index test to a reference standard. Consecutive adult patients referred for suspicion of MDS are being recruited at seven university hospitals and one cancer centre in France. At each site, flow cytometric analysis of peripheral blood samples is performed by operators who are blinded to the reference diagnosis. A central adjudication committee whose members are unaware of the index test results will determine the reference diagnosis of MDS, based on cytomorphological evaluation of bone marrow performed in duplicate by experienced hematopathologists. The target sample size is 400 patients and the anticipated study recruitment completion date is 31 December 2025.Ethics and dissemination An institutional review board (Comité de Protection des Personnes Nord-Ouest III, Caen, France) approved the protocol, prior to the start of the study. Participants are recruited using an opt-out approach. Efforts will be made to publish the primary results within 6 months after study completion.Trial registration number NCT05175469.

Summary: Here, we present a detailed protocol to study the role of a human nuclear m6A RNA reader, YTHDC1, on chromatin-associated RNA targets. We describe steps for RNA extraction coupled to subnuclear fractionation to identify and study RNA-based regulations that take place in the chromatin-associated fraction. We then detail an RNA immunoprecipitation procedure adapted to identify chromatin-associated RNA targets. This protocol can be adapted to other human or mammalian chromatin-associated RNA binding proteins.For complete details on the use and execution of this protocol, please refer to Timcheva et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background The worldwide incidence of invasive breast cancer in women is increasing according to several studies. This increase in incidence seems to be higher in young women (

Objective: This study aims to analyse high‐grade intraepithelial lesions (LIEHG) observed in a screening programme from 2010 to 2018 to more accurately describe them and formulate recommendations for best practices in the context of screening evolution following the introduction of an HPV test in primary cervical cancer screening in 2020. Methods: This study included 305,940 asymptomatic women aged 25–65 years. The eligible population was invited to undergo a screening cervico‐uterine‐smear every 3 years. If this smear was normal, the woman received a new invitation. In the case of a positive screen, the patient underwent further diagnostic procedures, such as colposcopy and biopsy to confirm the diagnosis. Only those diagnosed with LIEHG and above proceeded to treatment. The diagnoses associated with LIEHG were those related to the WHO Classification of tumours of the uterine cervix. Results: Positive smears led to the diagnosis of 3230 LIEHG. The prevalence of LIEHG in the screened population was 0.4%. The LIEHG distribution varied significantly according to the age of the women. The probability of diagnosing LIEHG in young women was 12.2% at 25–29 years. This probability decreased by half after 50 years. We observed that the type of smear was significantly associated with LIEHG detection. The positive predictive value for diagnosing LIEHG was 70.3% for high‐grade squamous intraepithelial lesion (HSIL) smears and 35.1% for atypical squamous cells cannot exclude HSIL (ASC‐H) smears. Conclusion: In the study population, the prevalence of LIEHG was high in women under 35 years. Low‐grade smears were correlated with the risk of LIEHG and should prompt screening facilities to allocate resources to ensure active follow‐up of LSIL and ASC‐US smears. Adherence to cytological screening recommendations was associated with a reduced risk of LIEHG in multivariate analysis. [ABSTRACT FROM AUTHOR]

Background: The impact of geographical accessibility on cancer survival has been investigated in few studies, with most research focusing on access to reference care centers, using overall mortality and limited to specific cancer sites. This study aims to examine the association of access to primary care with mortality in excess of patients with the 10 most frequent cancers in France, while controlling for socioeconomic deprivation. Methods: This study included a total of 151,984 cases diagnosed with the 10 most common cancer sites in 21 French cancer registries between 2013 and 2015. Access to primary care was estimated using two indexes: the Accessibilité Potentielle Localisée index (access to general practitioners) and the Scale index (access to a range of primary care clinicians). Mortality in excess was modelized using an additive framework based on expected mortality based on lifetables and observed mortality. Findings: Patients living in areas with less access to primary care had a greater mortality in excess for some very common cancer sites like breast (women), lung (men), liver (men and women), and colorectal cancer (men), representing 46% of patients diagnosed in our sample. The maximum effect was found for breast cancer; the excess hazard ratio was estimated to be 1.69 (95% CI, 1.20–2.38) 1 year after diagnosis and 2.26 (95% CI, 1.07–4.80) 5 years after diagnosis. Interpretation: This study revealed that this differential access to primary care was associated with mortality in excess for patients with cancer and should become a priority for health policymakers to reduce these inequalities in health care accessibility. This study aims to examine the association of access to primary care with mortality in excess of patients with the 10 most frequent cancers in France, while controlling for socioeconomic deprivation. Patients living in areas with less access to primary care had a greater mortality in excess for some very common cancer sites like breast (women), lung (men), liver (men and women), and colorectal cancer (men), representing 46% of patients diagnosed in our sample. [ABSTRACT FROM AUTHOR]

Introduction 30-day readmission rate is considered an adverse outcome reflecting suboptimal quality of care during index hospitalisation for community-acquired pneumonia (CAP). However, potentially avoidable readmission would be a more relevant metric than all-cause readmission for tracking quality of hospital care for CAP. The objectives of this study are (1) to estimate potentially avoidable 30-day readmission rate and (2) to develop a risk prediction model intended to identify potentially avoidable readmissions for CAP.Methods and analysis The study population consists of consecutive patients admitted in two hospitals from the community or nursing home setting with pneumonia. To qualify for inclusion, patients must have a primary or secondary discharge diagnosis code of pneumonia. Data sources include routinely collected administrative claims data as part of diagnosis-related group prospective payment system and structured chart reviews. The main outcome measure is potentially avoidable readmission within 30 days of discharge from index hospitalisation. The likelihood that a readmission is potentially avoidable will be quantified using latent class analysis based on independent structured reviews performed by four panellists. We will use a two-stage approach to develop a claims data-based model intended to identify potentially avoidable readmissions. The first stage implies deriving a clinical model based on data collected through retrospective chart review only. In the second stage, the predictors comprising the medical record model will be translated into International Classification of Diseases, 10th revision discharge diagnosis codes in order to obtain a claim data-based risk model.The study sample consists of 1150 hospital stays with a diagnosis of CAP. 30-day index hospital readmission rate is 17.5%.Ethics and dissemination The protocol was reviewed by the Comité de Protection des Personnes Sud Est V (IRB#6705). Efforts will be made to release the primary study results within 6 months of data collection completion.Trial registration number ClinicalTrials.gov Registry (NCT02833259).

Abstract Background Survival rates of lung cancer remains poor and the impact of comorbidities on the prognosis is discussed. The objective of this study was to assess if the Charlson Comorbidity Index (CCI) was associated with 8-year survival rates by histological type. Methods A cohort study was conducted using randomly selected cases from 10 French cancer registries. Net survival rates were computed using the Pohar-Perme estimator of the net cumulative rate. Three Cox models were independently built for adenocarcinomas, squamous cell and small cell cancers to estimate prognostic factors including CCI grade. Results A total of 646 adenocarcinomas, 524 squamous cell and 233 small cell cancers were included in the analysis. The net 8-year survival rate ranged from 12.6% (95% CI: 9.8–15.4%) for adenocarcinomas and 13.4% (95% CI: 10.1–16.7%) for squamous cell carcinomas, to 3.7% (95% CI: 1.1–6.3%) for small cell cancers. Observed and net survival rates decreased for CCI grades ≥3 for all histological group considered. After adjustment for sex, age group, stage and diagnostic mode, CCI grades 1 (HR = 1.6 [95% CI: 1.1–2.3]), 2 (HR = 1.7 [95% CI: 1.1–2.7]) and ≥ 3 (HR = 2.7 [95% CI: 1.7–4.4]) were associated with lower survival rates only for small cell cancers. Conclusion After adjustment for age, sex, stage and diagnostic mode, the presence of comorbidity based on CCI grades 1–2 and ≥ 3 was associated with lower survival rates for small cell cancers whereas no differences were observed for adenocarcinomas and squamous cell cancers.

BACKGROUND:The experience feedback committee (EFC) is a tool designed to involve medical teams in patient safety management, through root cause analysis (RCA) within the team. OBJECTIVES:To investigate the functioning of EFCs in the departments of a large university-affiliated hospital in France and to consider its potential contribution to the management of patient safety. METHODS:Cross-sectional, observational study, based on an analysis of the documents produced by the EFCs for 1 year. Data were collected independently by two investigators in meeting minutes, adverse event reports and event analysis reports. RESULTS:The study included all 20 EFCs operating in the hospital's medical departments. During the study year, committees held 164 meetings, reviewed 1707 adverse events, conducted 91 event analyses and decided on 206 corrective actions. The median number of corrective actions adopted by each EFC was five actions (range, 0-62). A root cause analysis (RCA) was present in 76% of the analysis reports, and these analyses were complete in only 23% of the reports. There was also a lack of planning corrective actions: an implementation deadline was only defined in 26% of the actions. CONCLUSIONS:Healthcare professionals adhered to the system-based approach to patient safety, but we observed difficulties in holding regular meetings and deviations from the theoretical framework. These findings confirm the difficulties of practicing RCA in the healthcare setting. Nevertheless, EFCs can be vectors of safety culture and teamwork.