ADAM3, a key component of fertilization complex as well as other sperm ADAM proteins are significantly reduced. We hence propose that LYPD4 plays an essential role in mammalian fertilization, and further investigation of its function and its interaction with other sperm membrane complexes may yield insights into human fertilization and novel strategy to improve IVF success. Summary sentence Human LYPD4 protein is localized to sperm acrosome and its mouse homolog is essential for sperm migration and sperm-zona binding. © The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction.The burden of mental illness is excessive, but many countries lack evidence-based policies to improve practice. Mental health research evidence translation into policymaking is a 'wicked problem', often failing despite a robust evidence base. In a recent systematic review, we identified a gap in frameworks on agenda setting and actionability, and pragmatic, effective tools to guide action to link research and policy are needed. Responding to this gap, we developed the new EVITA 1.1 (EVIdence To Agenda setting) conceptual framework for mental health research-policy interrelationships in low- and middle-income countries (LMICs). We (1) drafted a provisional framework (EVITA 1.0); (2) validated it for specific applicability to mental health; (3) conducted expert in-depth interviews to (a) validate components and mechanisms and (b) assess intelligibility, functionality, relevance, applicability and effectiveness. To guide interview validation, we developed a simple evaluation framework. (4) Using deductive framewh researchers, policy agencies/planners, think tanks, NGOs and others within the mental health research-policy interface. Next, EVITA 1.1 will be empirically tested in a case study. © The Author(s) 2020. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.For patients with Amyotrophic Lateral Sclerosis (ALS) who take oral riluzole tablets, approximately 50% experience alanine transaminase (ALT) levels above upper limit of normal (ULN), 8% above 3x ULN, and 2% above 5x ULN. BHV-0223 is a novel 40 mg rapidly sublingually disintegrating (Zydis®) formulation of riluzole, bioequivalent to conventional riluzole 50 mg oral tablets, that averts the need for swallowing tablets and mitigates first-pass hepatic metabolism, thereby potentially reducing risk of liver toxicity. DILIsym is a validated multi-scale computational model that supports evaluation of liver toxicity risks. DILIsym was used to compare the hepatotoxicity potential of oral riluzole tablets (50 mg BID) versus BHV-0223 (40 mg BID) by integrating clinical data and in vitro toxicity data. In a simulated population (SimPops), ALT levels >3x ULN were predicted in 3.9% (11/285) versus 1.4% (4/285) of individuals with oral riluzole tablets and sublingual BHV-0223, respectively. This represents a relative risk reduction of 64% associated with BHV-0223 vs. conventional riluzole tablets. Mechanistic investigations revealed that oxidative stress was responsible for the predicted ALT elevations. The validity of the DILIsym representation of riluzole and assumptions is supported by its ability to predict rates of ALT elevations for riluzole oral tablets comparable to that observed in clinical data. Combining a mechanistic, quantitative representation of hepatotoxicity with inter-individual variability in both susceptibility and liver exposure suggests that sublingual BHV-0223 confers diminished rates of liver toxicity compared to oral tablets of riluzole, consistent with having a lower overall dose of riluzole and bypassing first-pass liver metabolism. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology.BACKGROUND Maternal smoking in pregnancy is associated with low birth weight (LBW), child conduct problems, hyperactivity and lower cognitive attainment, but associations may reflect measured and unmeasured confounding. Cross-cohort designs can aid causal inference through comparison of associations across populations with different confounding structures. We compared associations between maternal smoking in pregnancy and child conduct and hyperactivity problems, cognition and LBW across two cohorts born four decades apart. METHODS Two national UK cohorts born in 1958 (n = 12 415) and 2000/01 (n = 11 800) were compared. Maternal smoking in pregnancy and child birth weight was assessed at or shortly after birth. Parents rated children's conduct problems and hyperactivity, and children completed standardized tests of reading and mathematics. RESULTS Maternal smoking in pregnancy was less common and more strongly associated with social disadvantage in 2000/01 compared with 1958 (interactions P less then 0.001). Maternal smoking in pregnancy was robustly and equivalently associated with infant LBW in both cohorts [interactions boys odds ratio (OR) = 1.01 (0.89, 1.16), P = 0.838; girls OR = 1.01 (0.91, 1.17), P = 0.633]. Maternal smoking was more strongly associated with conduct problems, hyperactivity and reading in the 2000/01 cohort (interactions P less then 0.001). CONCLUSIONS Marked cross-cohort change in associations between maternal smoking and child conduct problems, hyperactivity and reading highlights the likely role of confounding factors. In contrast, association with LBW was unaffected by change in prevalence of maternal smoking and patterns of confounding. The study highlights the utility of cross-cohort designs in helping triangulate conclusions about the role of putative causal risk factors in observational epidemiology. © The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.The incidence and mortality from colorectal cancer in younger adults ( less then 55 years) is increasing. https://www.selleckchem.com/products/mi-773-sar405838.html We reviewed the complete database of a gene-expression test, Oncotype DX Colon Recurrence Score® test, to determine age-related differences in Recurrence Score® (RS) and single-gene results (7 cancer-related of the 12-gene assay). We included 20,478 Stage II & III A/B colon cancer patients submitted to Genomic Health. RS results were grouped by low, intermediate, and high risk groups. Single-gene scores were described using median and interquartile range. Seventy-two and a half percent of all patients and 72.6% of those less then 40 years had low risk RS. Comparing older versus younger patients, RS or single-gene expression did not differ by age group or stage. Young-onset colon cancer does not differ by expression of the RS component genes. Most patients with stage II/III colon cancer have low-risk disease as measured by the 12-gene assay, regardless of age. © The Author(s) 2020. Published by Oxford University Press.