Standardized Definitions of In Utero Human Immunodeficiency Virus and Antiretroviral Drug Exposure Among Children

In countries with high human immunodeficiency virus (HIV) prevalence, up to 30% of pregnant women are living with HIV, with fetal exposure to both HIV and antiretroviral therapy during pregnancy. In addition, pregnant women without HIV but at high risk of HIV acquisition are increasingly receiving HIV preexposure antiretroviral prophylaxis (PrEP). Investments are being made to establish and follow cohorts of children to evaluate the long-term effects of in utero HIV and antiretroviral exposure. Agreement on a key set of definitions for relevant exposures and outcomes is important both for interpreting individual study results and for comparisons across cohorts. Harmonized definitions of in utero HIV and antiretroviral drug (maternal treatment or PrEP) exposure will also facilitate improved classification of these exposures in future observational studies and clinical trials. The proposed definitions offer a uniform approach to facilitate the consistent description and estimation of effects of HIV and antiretroviral exposures on key child health outcomes

Cross-Canada Differences in Early-Stage Breast Cancer Treatment and Acute-Care Use

Background: Chemotherapy has improved outcomes in early-stage breast cancer, but treatment practices vary, and use of acute care is common. We conducted a pan-Canadian study to describe treatment differences and the incidence of emergency department visits (EDVS), edvs leading to hospitalization (EDVHS), and direct hospitalizations (HS) during adjuvant chemotherapy. Methods: The cohort consisted of women diagnosed with early-stage breast cancer (stages I–III) during 2007–2012 in British Columbia, Manitoba, Ontario, or Nova Scotia who underwent curative surgery. Parallel provincial analyses were undertaken using linked clinical, registry, and administrative databases. The incidences of edvs, edvhs, and hs in the 6 months after treatment initiation were examined for patients treated with adjuvant chemotherapy. Results: The cohort consisted of 50,224 patients. The proportion of patients who received chemotherapy varied by province, with Ontario having the highest proportion (46.4%), and Nova Scotia, the lowest proportion (38.0%). Age, stage, receptor status, comorbidities, and geographic location were associated with receipt of chemotherapy in all provinces. Ontario had the highest proportion of patients experiencing an EDV (36.1%), but the lowest proportion experiencing H (6.4%). Conversely, British Columbia had the lowest proportion of patients experiencing an EDV (16.0%), but the highest proportion experiencing H (26.7%). The proportion of patients having an edvh was similar across provinces (13.9%–16.8%). Geographic location was associated with EDVS, EDVHS, and HS in all provinces. Conclusions: Intra- and inter-provincial differences in the use of chemotherapy and acute care were observed. Understanding variations in care can help to identify gaps and opportunities for improvement and shared learnings

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators