Assessing research gaps and unmet needs in endometriosis.

Endometriosis, a systemic disease that is often painful and chronic, affects ∼10% of reproductive-age women. The disease can have a negative impact on a patient's physical and emotional well-being, quality of life, and productivity. Endometriosis also places significant economic and social burden on patients, their families, and society as a whole. Despite its high prevalence and cost, endometriosis remains underfunded and underresearched, greatly limiting our understanding of the disease and slowing much-needed innovation in diagnostic and treatment options. Due in part to the societal normalization of women's pain and stigma around menstrual issues, there is also a lack of disease awareness among patients, health care providers, and the public. The Society for Women's Health Research convened an interdisciplinary group of expert researchers, clinicians, and patients for a roundtable meeting to review the current state of the science on endometriosis and identify areas of need to improve a woman's diagnosis, treatment, and access to quality care. Comprehensive and interdisciplinary approaches to disease management and increased education and disease awareness for patients, health care providers, and the public are needed to remove stigma, increase timely and accurate diagnosis and treatment, and allow for new advancements.

Understanding the impact of sex and gender in Alzheimer's disease: A call to action.

INTRODUCTION: Precision medicine methodologies and approaches have advanced our understanding of the clinical presentation, development, progression, and management of Alzheimer's disease (AD) dementia. However, sex and gender have not yet been adequately integrated into many of these approaches. METHODS: The Society for Women's Health Research Interdisciplinary Network on AD, comprised of an expert panel of scientists and clinicians, reviewed ongoing and published research related to sex and gender differences in AD. RESULTS: The current review is a result of this Network's efforts and aims to: (1) highlight the current state-of-the-science in the AD field on sex and gender differences; (2) address knowledge gaps in assessing sex and gender differences; and (3) discuss 12 priority areas that merit further research. DISCUSSION: The exclusion of sex and gender has impeded faster advancement in the detection, treatment, and care of AD across the clinical spectrum. Greater attention to these differences will improve outcomes for both sexes.

Domain-Specific Cognitive Impairments in Humans and Flies With Reduced CYFIP1 Dosage.

BACKGROUND: Deletions encompassing a four-gene region on chromosome 15 (BP1-BP2 at 15q11.2), seen at a population frequency of 1 in 500, are associated with increased risk for schizophrenia, epilepsy, and other common neurodevelopmental disorders. However, little is known in terms of how these common deletions impact cognition. METHODS: We used a Web-based tool to characterize cognitive function in a novel cohort of adult carriers and their noncarrier family members. Results from 31 carrier and 38 noncarrier parents from 40 families were compared with control data from 6530 individuals who self-registered on the Lumosity platform and opted in to participate in research. We then examined aspects of sensory and cognitive function in flies harboring a mutation in Cyfip, the homologue of one of the genes within the deletion. For the fly studies, 10 or more groups of 50 individuals per genotype were included. RESULTS: Our human studies revealed profound deficits in grammatical reasoning, arithmetic reasoning, and working memory in BP1-BP2 deletion carriers. No such deficits were observed in noncarrier spouses. Our fly studies revealed deficits in associative and nonassociative learning despite intact sensory perception. CONCLUSIONS: Our results provide new insights into outcomes associated with BP1-BP2 deletions and call for a discussion on how to appropriately communicate these findings to unaffected carriers. Findings also highlight the utility of an online tool in characterizing cognitive function in a geographically distributed population.

Sex and Gender Differences in Migraine-Evaluating Knowledge Gaps.

Migraine is a common chronic neurological disease that disproportionately affects women. Migraine has significant negative effects on physical, emotional, and social aspects of health, and can be costly for patients, employers, and society as a whole. Growing evidence supports the roles of sex and gender in migraine risk, pathophysiology, presentation, diagnosis, treatment, and management. However, sex and gender differences in migraine have received limited attention, which can impede advancements in migraine detection, treatment, care, and education. The Society for Women's Health Research convened an interdisciplinary expert panel of researchers, clinicians, and advocates for a roundtable meeting to review the current research on sex and gender differences in migraine. This review summarizes discussions from the roundtable and prioritizes areas of need that warrant further attention in migraine research, care, and education. Examining sex and gender differences in migraine and addressing knowledge gaps will decrease the health and economic burden of migraine for both women and men.

Sex differences in lower urinary tract biology and physiology.

Females and males differ significantly in gross anatomy and physiology of the lower urinary tract, and these differences are commonly discussed in the medical and scientific literature. However, less attention is dedicated to investigating the varied development, function, and biology between females and males on a cellular level. Recognizing that cell biology is not uniform, especially in the lower urinary tract of females and males, is crucial for providing context and relevance for diverse fields of biomedical investigation. This review serves to characterize the current understanding of biological sex differences between female and male lower urinary tracts, while identifying areas for future research. First, the differences in overall cell populations are discussed in the detrusor smooth muscle, urothelium, and trigone. Second, the urethra is discussed, including anatomic discussions of the female and male urethra followed by discussions of cellular differences in the urothelial and muscular layers. The pelvic floor is then reviewed, followed by an examination of the sex differences in hormonal regulation, the urinary tract microbiome, and the reticuloendothelial system. Understanding the complex and dynamic development, anatomy, and physiology of the lower urinary tract should be contextualized by the sex differences described in this review.

Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks.

Deletions encompassing the BP1-2 region at 15q11.2 increase schizophrenia and epilepsy risk, but only some carriers have either disorder. To investigate the role of CYFIP1, a gene within the region, we performed knockdown experiments in human neural progenitors derived from donors with 2 copies of each gene at the BP1-2 locus. RNA-seq and cellular assays determined that knockdown of CYFIP1 compromised cytoskeletal remodeling. FMRP targets and postsynaptic density genes, each implicated in schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs). Schizophrenia and/or epilepsy genes, but not those associated with randomly selected disorders, were likewise significantly overrepresented. Mirroring the variable expressivity seen in deletion carriers, marked between-line differences were observed for dysregulation of disease genes. Finally, a subset of DEGs showed a striking similarity to known epilepsy genes and represents novel disease candidates. Results support a role for CYFIP1 in disease and demonstrate that disease-related biological signatures are apparent prior to neuronal differentiation.

A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus.

Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci.

Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L.

Microcephaly and macrocephaly are overrepresented in individuals with autism and are thought to be disease-related risk factors or endophenotypes. Analysis of DNA microarray results from a family with a low functioning autistic child determined that the proband and two additional unaffected family members who carry a rare inherited 760 kb duplication of unknown clinical significance at 19p13.12 are macrocephalic. Consideration alongside overlapping deletion and duplication events in the literature provides support for a strong relationship between gene dosage at this locus and head size, with losses and gains associated with microcephaly (p=1.11x10(-11)) and macrocephaly (p=2.47x10(-11)), respectively. Data support A kinase anchor protein 8 and 8-like (AKAP8 and AKAP8L) as candidate genes involved in regulation of head growth, an interesting finding given previous work implicating the AKAP gene family in autism. Towards determination of which of AKAP8 and AKAP8L may be involved in the modulation of head size and risk for disease, we analyzed exome sequencing data for 693 autism families (2591 individuals) where head circumference data were available. No predicted loss of function variants were observed, precluding insights into relationship to head size, but highlighting strong evolutionary conservation. Taken together, findings support the idea that gene dosage at 19p13.12, and AKAP8 and/or AKAP8L in particular, play an important role in modulation of head size and may contribute to autism risk. Exome sequencing of the family also identified a rare inherited variant predicted to disrupt splicing of TPTE / PTEN2, a PTEN homologue, which may likewise contribute to both macrocephaly and autism risk.