Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

A randomized clinical trial of how to best position retropubic slings for stress urinary incontinence: Development of a study protocol for the mid-urethral sling tensioning (MUST) trial

The goal of this trial is to compare two techniques for tensioning retropubic midurethral slings: a Mayo scissor between the tape and urethra vs. a Babcock clamp creating a measured loop underneath the urethra. The primary outcome is a composite of abnormal bladder function at 12 months post surgery. Abnormal bladder function is defined as bothersome stress incontinence or worsening over active bladder symptoms, a positive cough stress test, re-treatment of stress urinary incontinence, post-operative urinary retention requiring either catheterization beyond 6 weeks or surgical intervention. Secondary outcomes include the duration of post operative urinary retention, quality of life scores, and physical examination. This article describes the rationale and design of this clinical trial, which will be of interest to those who care for patient with pelvic floor disorders such as stress urinary incontinence

Female Pelvic Medicine & Reconstructive Surgery (FPMRS) Challenges on Behalf of the Collaborative Research in Pelvic Surgery Consortium (CoRPS): Managing Complicated Cases Series 2: Management of Urinary Incontinence in a Neurogenic Patient

Discussion and management of incontinence in a patient with spina bifida by four international experts followed by a literature review

Les Canadiennes autochtones et la santé

Obesity is prevalent among the First Nations population in Canada, with serious associated health risks. Recent studies also indicate that a high percentage of First Nations women are overweight or obese at the start of their pregnancies, with a tendency to retain weight after their children are born. In response to these concerns, a community-based study was conducted in two Cree communities, using qualitative methods to investigate young mothers’ perceptions and concerns about weight gain during pregnancy and challenges to postpartum weight loss. Female Elders were also interviewed to provide some historical context and to give some insight into culturally appropriate responses to the current weight-related health challenges being faced by young mothers. Overall, the study showed that most of the participants—young and old— associated “healthy foods” with traditional foods and “healthy living” with bush life. However, while Elders recounted staying active and eating traditional foods throughout their pregnancies, the younger women tended not to put their knowledge of what constitutes a healthy lifestyle into practice, mainly due to various individual and societal barriers. Some of the barriers identified related to lifestyle changes, including increased consumption of “white man’s foods” and decreased physical activity, as well as to larger social changes, such as the medicalization of pregnancy and diminished community support networks for young mothers. Participants provided insight into how traditional practices could be intertwined with the benefits of contemporary life to help address some of the health issues currently affecting young Cree mothers

Female Pelvic Medicine and Reconstructive Surgery Challenges on Behalf of the Collaborative Research in Pelvic Surgery Consortium: Managing Complicated Cases : Series 5: Management of Recurrent Stress Urinary Incontinence After Midurethral Sling Exposure

This case presents the work-up and management of a patient requesting surgical intervention for recurrent stress urinary incontinence after previous excision of a portion of her midurethral sling because of mesh exposure. Four international experts provide their approach to this complex case. There is little consensus regarding further surgery in a patient who has required mesh excision. Treatment by fascial sling was commonly considered and the literature review outlines the pros and cons of autologous fascia versus donor fascia for this specific case

Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression

Depression is a common disorder that affects women at twice the rate of men. Here we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans, and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene, LINC00473, as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression

Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk.

To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type-specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type-specific disease risk vulnerabilities in spatial genome organization