Grandparental genotyping enhances exome variant interpretation

Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband‐only sequencing, mainly due to the rapid identification of de novo disease‐causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X‐inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X‐inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.     

Determinants and Inequities in Sexual and Reproductive Health (SRH) Care Access Among Im/Migrant Women in Canada: Findings of a Comprehensive Review (2008–2018)

Given growing concerns of im/migrant women’s access to sexual and reproductive health (SRH) services, we aimed to (1) describe inequities and determinants of their engagement with SRH services in Canada; and (2) understand their lived experiences of barriers and facilitators to healthcare. Using a comprehensive review methodology, we searched the quantitative and qualitative peer-reviewed literature of im/migrant women’s access to SRH care in Canada from 2008 to 2018. Of 782 studies, 38 met inclusion criteria. Ontario (n?=?18), British Columbia (n?=?6), and Alberta (n?=?6) were primary settings represented. Studies focused primarily on maternity care (n?=?20) and sexual health screenings (n?=?12). Determinants included health system navigation and service information; experiences with health personnel; culturally safe and language-specific care; social isolation and support; immigration-specific factors; discrimination and racialization; and gender and power relations. There is a need for research that compares experiences across diverse groups of racialized im/migrants and a broader range of SRH services to inform responsive, equity-focused programs and policies.

     

Future health of AYA survivors

Adolescent and young adult (AYA) oncology patients (ages 15–39) have been identified as a group with healthcare disparities including gaps and challenges in diagnosis, access to care, research, clinical trial participation, and cure rates. Like other patient groups with cancer or other chronic illnesses, disparities can lead to poor future health and outcomes, which is a well‐recognized concern within the AYA population. Cancer is the leading disease‐related cause of death in this age range. Numerous interested groups including the National Cancer Institute have met to address the research and cancer care needs of AYAs. This review highlights how these gaps in care during and after treatment can affect future health of this population of patients. Access to care, models of survivorship care, and lack of provider education are discussed. Survivorship care and use of guidelines, and promotion of psychosocial support and health behaviors during treatment and beyond are essential to optimizing future health of AYA patients.     

Mortality in bullous pemphigoid: A systematic review and meta‐analysis of standardized mortality ratios

There are inconsistent data on mortality rates in patients with bullous pemphigoid (BP). Trends in mortality in BP throughout the years are yet to be established. The aim of the present study was to study the mortality in BP patients relative to the general population and to estimate trends in standardized mortality over the past 30 years. We performed a systematic review and meta‐analysis of observational studies in Medline, Embase and Scopus (1823–2017). Reference lists of included studies were also searched for eligible studies. Quality of evidence was assessed using the Newcastle–Ottawa Scale (NOS). A meta‐analysis was performed using random‐effects models to estimate pooled standardized mortality ratios (SMR) with 95% confidence intervals (CI). Meta‐regression models were used to investigate the secular trends in SMR. Ten studies were included covering the period 1960–2015 (1736 patients, 746 deaths). Pooled all‐cause SMR was 3.6 (95% CI, 2.6–5.0). There was no trend in all‐cause SMR across the last three decades (regression coefficient 0.02 [change in logSMR/year]; 95% CI, 0.04–0.08; P = 0.545). In conclusion, there is a 3.6‐fold increased mortality among patients with BP as compared with the age‐matched general population. The excess mortality in BP has not changed significantly over the past 30 years.     

Effects of Cortisol on Reconsolidation of Reactivated Fear Memories

The return of conditioned fear after successful extinction (eg, following exposure therapy) is a significant problem in the treatment of anxiety disorders and posttraumatic stress disorder (PTSD). Targeting the reconsolidation of fear memories may allow a more lasting effect as it intervenes with the original memory trace. Indeed, several pharmacological agents and behavioral interventions have been shown to alter (enhance, impair, or otherwise update) the reconsolidation of reactivated memories of different types. Cortisol is a stress hormone and a potent modulator of learning and memory, yet its effects on fear memory reconsolidation are unclear. To investigate whether cortisol intervenes with the reconsolidation of fear memories in healthy males and how specific this effect might be, we built a 3-day reconsolidation design with skin conductance response (SCR) as a measure of conditioned fear: Fear acquisition on day 1; reactivation/no-reactivation of one conditioned stimulus and pharmacological intervention on day 2; extinction learning followed by reinstatement and reinstatement test on day 3. The groups differed only in the experimental manipulation on day 2: Reactivation+Cortisol Group, Reactivation+Placebo Group, or No-reactivation+Cortisol Group. Our results revealed an enhancing effect of cortisol on reconsolidation of the reactivated memory. The effect was highly specific, strengthening only the memory of the reactivated conditioned stimulus and not the non-reactivated one. Our findings are in line with previous findings showing an enhancing effect of behavioral stress on the reconsolidation of other types of memories. These results have implications for the understanding and treatment of anxiety disorders and PTSD.