Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by 'reader' proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia 1 . Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour 2,3 , the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.The eleven-nineteen-leukaemia protein (ENL) is a chromatin reader that maintains the oncogenic state in leukaemia 1,4 . ENL interacts with acetylated histone proteins via its well conserved YEATS (Yaf9, ENL, AF9, Taf14, Sas5) domain, and, in so doing, helps to recruit and stabilize its associated transcriptional machinery to drive the transcription of target genes. Recently, somatic mutations in the ENL gene (also known as MLLT1) were found in about 5% of people with Wilms tumour, making ENL one of the most frequently mutated genes in this cancer type. These mutations are recurrent, heterozygous and highly clustered in the ENL YEATS domain. Interestingly, these 'hotspot' mutations all involve small inframe insertions or deletions (Fig. 1a and Extended Data Fig. 1a). Whether and how such ENL mutations promote the formation of Wilms tumour was unclear and is the focus of our study. Wan et al.

BackgroundResearch shows that adults with intellectual and developmental disabilities (IDD) increasingly outlive caregivers, who often struggle to plan for the future and have little support and knowledge surrounding long‐term care planning.MethodsThe study team conducted interviews with parents and siblings of adults with IDD and performed qualitative coding using a modified grounded theory to explore domains of future planning and identify barriers and facilitators.ResultsThemes from the interviews revealed seven major domains of future planning that should be considered by caregivers of adults with IDD. These domains are housing, legal planning, identification of primary caregiver(s), financial planning, day‐to‐day care, medical management and transportation. Approaches to planning within each domain varied greatly.ConclusionsThe study team dentified the domain of “identification of primary caregiver(s)” as potentially the most important step for caregivers when planning for the future, but also observed that the domains identified are significantly interrelated and should be considered together.

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The endocannabinoid system is involved in pain perception and inflammation. Cannabis contains delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which are cannabinoids that bind to endocannabinoid system receptors. A fatty acid amide called palmitoylethanolamide (PEA) enhances endogenous cannabinoids. Given that use of medical cannabis is increasing, we sought to characterize patterns of cannabis use for gynecologic pain and its effectiveness as an analgesic.DATA SOURCES: We searched PubMed, EMBASE, Scopus, Cochrane, and ClinicalTrials.gov using terms for "woman," "cannabis," and "pain" or "pelvic pain" or "endometriosis" or "bladder pain" or "cancer." The search was restricted to English-language articles published between January 1990 and April 2021 and excluded animal studies. METHODS OF STUDY SELECTION:The initial search yielded 5,189 articles with 3,822 unique citations. Studies were included if they evaluated nonpregnant adult women who used cannabinoids for gynecologic pain conditions (eg, chronic pelvic pain, vulvodynia, endometriosis, interstitial cystitis, malignancy). Study types included were randomized controlled trials (RCTs), cohort studies, and cross-sectional studies. Covidence systematic review software was used.

We characterized a case of neonatal conjunctivitis in New York, USA, caused by Neisseria meningitidis by using whole-genome sequencing. The case was a rare occurrence, and the isolate obtained belonged to an emerging clade ( N. meningitidis US nongroupable urethritis) associated with an increase in cases of urethritis since 2015.

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Background The COVID-19 pandemic disrupted medical care in the US, leading to a significant drop in utilization of some types of health services. We sought to quantify how the pandemic influenced obstetrics and gynecology care at two large health care organizations. Materials and methods Comparing 2020 to 2019, we quantified changes to obstetrics and gynecology care at two large health care organizations in the United States, Allegheny Health Network (in western Pennsylvania) and Johns Hopkins University (in Maryland). The analysis considered the numbers of surgical encounters, in-person visits, and telemedicine visits. For each system, we quantified temporal changes in surgical volume, in-person and telemedicine visits, and financial impact related to professional fee revenues. We used segmented regression to evaluate longitudinal effects. Results At both institutions, the volume of care was similar in the first few months of 2020 compared to 2019 but dropped precipitously in March 2020. From April to June 2020, surgical volumes were 67% of the same period in 2019 at Allegheny Health and 48% of the same period in 2019 at Johns Hopkins. During that same interval, televisits accounted for approximately 21% of all ambulatory care at both institutions. Although surgical and ambulatory volumes recovered in the second half of 2020, annual surgical volumes in 2020 were significantly lower than 2019 at both institutions (p<0.05) and 2020 ambulatory volumes remained significantly lower at Johns Hopkins (p = .0006). Overall, revenues in 2020 were 91% of 2019 revenues for both institutions. Conclusions Obstetrical and gynecologic ambulatory visits and gynecologic surgeries were sharply reduced during the COVID-19 pandemic. Although care volumes returned to 2019 levels in late 2020, we observed an overall reduction in the volume of care provided and a 9% reduction in professional revenue for both institutions.

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