Citations

AbstractBackgroundBRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data.MethodsData of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided.Results430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non–BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16; P = .98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18; P = .96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non–BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97; P = .02; OS: HR = 0.80, 95% CI = 0.63 to 1.00; P = .05) on mixed-effects modeling.ConclusionBRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.

Abstract Objectives The association of bipolar disorder with early and excessive cardiovascular disease was identified over a century ago. Nonetheless, the vascular‐bipolar link remains underrecognized, particularly with regard to how this link can contribute to our understanding of pathogenesis and treatment. Methods An international group of experts completed a selective review of the literature, distilling core themes, identifying limitations and gaps in the literature, and highlighting future directions to bridge these gaps. Results The association between bipolar disorder and vascular disease is large in magnitude, consistent across studies, and independent of confounding variables where assessed. The vascular‐bipolar link is multifactorial and is difficult to study given the latency between the onset of bipolar disorder, often in adolescence or early adulthood, and subsequent vascular disease, which usually occurs decades later. As a result, studies have often focused on risk factors for vascular disease or intermediate phenotypes, such as structural and functional vascular imaging measures. There is interest in identifying the most relevant mediators of this relationship, including lifestyle (eg, smoking, diet, exercise), medications, and systemic biological mediators (eg, inflammation). Nonetheless, there is a paucity of treatment studies that deliberately engage these mediators, and thus far no treatment studies have focused on engaging vascular imaging targets. Conclusions Further research focused on the vascular‐bipolar link holds promise for gleaning insights regarding the underlying causes of bipolar disorder, identifying novel treatment approaches, and mitigating disparities in cardiovascular outcomes for people with bipolar disorder.

Background and objectives Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices. Design, setting, participants, & measurements We purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically. Results Across 16 focus groups, 134 participants (range, 19–85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family. Conclusions Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.

INTRODUCTION: Testicular sperm extraction (TESE) has traditionally been reserved for couples with azoospermia. However, recent data suggests TESE may be beneficial for men with abnormal semen parameters without azoospermia. The objective of this study was to compare in vitro fertilization (IVF) outcomes between TESE and ejaculated sperm (ES) for non-azoospermic male factor infertility. METHODS: Following IRB exemption, couples undergoing IVF for non-azoospermic male factor infertility with total motile sperm (TMS) <25 million motile/ejaculate from 1/2016 to 1/2019 were included. Men were grouped by whether TESE or ES was utilized for insemination. Couple characteristics and cycle outcomes were analyzed. Wilcoxon rank sum and Fisher exact tests were utilized as appropriate. Values are reported in medians. RESULTS: The analysis included 36 men who utilized ES and 23 men who utilized TESE. The median female age was 32 while the median male age was 35 with ES and 37 with TESE. TMS (6.1 vs 3.9 million motile/ejaculate, P=.46), motility (40% vs 30%, P=.07), and strict morphology (2.5% vs 1.0%, P=.15) were similar between ES and TESE. The total mature oocytes retrieved was similar between the groups but compared to ES, TESE was associated with 20% decrease in fertilization (80.6% vs 60.0%, P=.02) and half the number of blastocyst embryos (4 vs 2 embryos, P=.02). Although not statistically significant, TESE also had >10% decrease in live birth (48.5% vs 36.8%, P=.56). CONCLUSION: TESE is associated with lower fertilization and blastocyst embryos as well as decreased live birth rates compared to ES use for non-azoospermic male factor infertility.

Abstract Up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with an accumulation of chronic conditions, frailty, and/or cognitive impairments resulting from cancer and its treatment. Thus, survivors often show an accelerated development of multiple geriatric syndromes and need therapeutic interventions. To advance progress in this area, the National Cancer Institute convened the second of 2 think tanks under the auspices of the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Experts assembled to share evidence of promising strategies to prevent, slow, or reverse the aging consequences of cancer and its treatment. The meeting identified research and resource needs, including geroscience-guided clinical trials; comprehensive assessments of functional, cognitive, and psychosocial vulnerabilities to assess and predict age-related outcomes; preclinical and clinical research to determine the optimal dosing for behavioral (eg, diet, exercise) and pharmacologic (eg, senolytic) therapies; health-care delivery research to evaluate the efficacy of integrated cancer care delivery models; optimization of intervention implementation, delivery, and uptake; and patient and provider education on cancer and treatment-related late and long-term adverse effects. Addressing these needs will expand knowledge of aging-related consequences of cancer and cancer treatment and inform strategies to promote healthy aging of cancer survivors.

Aerobic exercise and thermal stress instigate robust challenges to the immune system. Various attempts to modify or supplement the diet have been proposed to bolster the immune system responses. The purpose of this study was to identify the impact of yeast beta-glucan (Saccharomyces cerevisiae) supplementation on exercise-induced muscle damage and inflammation. Healthy, active men (29.6 ± 6.7 years, 178.1 ± 7.2 cm, 83.2 ± 11.2 kg, 49.6 ± 5.1 mL/kg/min, n = 16) and women (30.1 ± 8.9 years, 165.6 ± 4.1 cm, 66.7 ± 10.0 kg, 38.7 ± 5.8 mL/kg/min, n = 15) were randomly assigned in a double-blind and cross-over fashion to supplement for 13 days with either 250 mg/day of yeast beta-glucan (YBG) or a maltodextrin placebo (PLA). Participants arrived fasted and completed a bout of treadmill exercise at 55% peak aerobic capacity (VO2Peak) in a hot (37.2 ± 1.8 °C) and humid (45.2 ± 8.8%) environment. Prior to and 0, 2, and 72 h after completing exercise, changes in white blood cell counts, pro- and anti-inflammatory cytokines, markers of muscle damage, markers of muscle function, soreness, and profile of mood states (POMS) were assessed. In response to exercise and heat, both groups experienced significant increases in white blood cell counts, plasma creatine kinase and myoglobin, and soreness along with reductions in peak torque and total work with no between-group differences. Concentrations of serum pro-inflammatory cytokines in YBG were lower than PLA for macrophage inflammatory protein 1β (MIP-1β) (p = 0.044) and tended to be lower for interleukin 8 (IL-8) (p = 0.079), monocyte chemoattractment protein 1 (MCP-1) (p = 0.095), and tumor necrosis factor α (TNF-α) (p = 0.085). Paired samples t-tests using delta values between baseline and 72 h post-exercise revealed significant differences between groups for IL-8 (p = 0.044, 95% Confidence Interval (CI): (0.013, 0.938, d = −0.34), MCP-1 (p = 0.038, 95% CI: 0.087, 2.942, d = −0.33), and MIP-1β (p = 0.010, 95% CI: 0.13, 0.85, d = −0.33). POMS outcomes changed across time with anger scores in PLA exhibiting a sharper decline than YBG (p = 0.04). Vigor scores (p = 0.04) in YBG remained stable while scores in PLA were significantly reduced 72 h after exercise. In conclusion, a 13-day prophylactic period of supplementation with 250 mg of yeast-derived beta-glucans invoked favorable changes in cytokine markers of inflammation after completing a prolonged bout of heated treadmill exercise.