SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Periconceptional folic acid may reduce ASD risk in those with inefficient folate metabolism. The replication of these findings and investigations of mechanisms involved are warranted.

Background Causes of autism are unknown. Associations with maternal nutritional factors and their interactions with gene variants have not been reported. Methods Northern California families were enrolled from 2003–2009 in the CHARGE (CHildhood Autism Risks from Genetics and Environment) population-based case-control study. Children aged 24–60 months were evaluated and confirmed to have autism (n = 288), autism spectrum disorder (n = 141), or typical development (n = 278) at the University of California–Davis Medical Investigation of Neurodevelopmental Disorders Institute using standardized clinical assessments. We calculated adjusted odds ratios (ORs) for associations between autism and retrospectively collected maternal vitamin intake before and during pregnancy. We explored interaction effects with functional genetic variants involved in one-carbon metabolism (MTHFR, COMT, MTRR, BHMT, FOLR2, CBS, and TCN2) as carried by the mother or child. Results Mothers of children with autism were less likely than those of typically developing children to report having taken prenatal vitamins during the three months before pregnancy or the first month of pregnancy (OR = 0.62 [95% confidence interval = 0.42–0.93]). Significant interaction effects were observed for maternal MTHFR 677 TT, CBS rs234715 GT+TT, and child COMT 472 AA genotypes, with greater risk for autism when mothers did not report taking prenatal vitamins periconceptionally (4.5 [1.4–14.6]; 2.6 [1.2–5.4]; and 7.2 [2.3–22.4], respectively). Greater risk was also observed for children whose mothers had other one-carbon metabolism pathway gene variants and reported no maternal prenatal vitamin intake. Conclusions Periconceptional use of prenatal vitamins may reduce the risk of having children with autism, especially for genetically susceptible mothers and children. Replication and mechanistic investigations are warranted.

Background and objectives: Dialysis patients are increasingly characterized by older age, multiple comorbidities, and shortened life expectancy. This study investigated whether the "surprise" question, "Would I be surprised if this patient died in the next year?" identifies patients who are at high risk for early mortality.Design, setting, participants, & measurements: This prospective cohort study of 147 patients in three hemodialysis dialysis units classified patients into "yes" and "no" groups on the basis of the ؆surprise؆ question response and tracked patient status (alive or dead) at 12 mo. Demographics, Charlson Comorbidity Index score, and Karnofsky Performance Status score were measured.Results: Initially, 34 (23%) patients were classified in the "no" group. Compared with the 113 patients in the "yes" group, the patients in the "no" group were older (72.5 ؎ 12.8 versus 64.5 ؎ 14.9), had a higher comorbidity score (7.1 ؎ 2.3 versus 5.8 ؎ 2.1), and had a lower performance status score (69.7 ؎ 17.1 versus 81.6 ؎ 15.8). At 12 mo, 22 (15%) patients had died; the mortality rate for the "no" group was 29.4% and for the "yes" group was 10.6%. The odds of dying within 1 yr for the patients in the "no" group were 3.5 times higher than for patients in the "yes" group, (odds ratio 3.507, 95% CI 1.356 to 9.067, P ‫؍‬ 0.01).Conclusions: The ؆surprise؆ question is effective in identifying sicker dialysis patients who have a high risk for early mortality and should receive priority for palliative care interventions.

These results suggest that NO production is low in CRD patients and may contribute to hypertension and disease progression in CRD.

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In the last decade, there has been a marked resurgence of syphilis in the United States despite the availability of effective treatments and previously reliable prevention strategies. The majority of cases are among the population of men who have sex with men (MSM); however, there has also been a recent increase among premenopausal women, coinciding with a concerning rise of congenital cases. The resurgence of syphilis can be largely attributed to changing social and behavioral factors, especially among young MSM. The biological association of syphilis with human immunodeficiency virus (HIV) transmission and acquisition is particularly alarming because of the increased individual and healthcare burden. In addition, some individual actions and public health efforts that are meant to reduce the risk of acquiring HIV may actually lead to risk compensation that facilitates the transmission of syphilis. Untreated syphilis is associated with detrimental health outcomes; therefore, both effective prevention strategies and treatment of this systemic disease have important short-term and long-term public health implications. This article offers a review of social and behavioral factors contributing to the current resurgence and recommendations for reducing syphilis incidence through medical and public health prevention strategies.