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The use of broad consent to store human biospecimens to be used in future research studies has increased over the years. However, it is currently unknown how young sexual minority men (YSMM) perceive broad consent in these specific types of studies. Therefore, in this study we aimed to determine the extent to which YSMM are comfortable with providing broad consent concerning their identifiable biological specimens to a variety of entities, including external researchers and pharmaceutical companies and to examine the relationship between mistrust based on racial/ethnic identity or sexual orientation and attitudes toward broad consent. YSMM (N = 239) ages 24–27 years were recruited from a prospective cohort study in New York City in 2018 to complete a survey assessing attitudes about the use of broad consent concerning biospecimens for secondary research. We found that YSMM were most willing to provide broad consent to the researcher from the study they were enrolled in (85.3%), other researchers within the same university (82.4%), and researchers at other universities (74.5%). Participants were least willing to provide broad consent to government organizations (64.4%) and pharmaceutical companies (53.8%). Further, we found that medical mistrust based on racial/ethnic identity or sexual orientation was associated with attitudes toward the use of broad consent. Research institutions should consider modifying consent procedures around the use of broad consent in order to maximize recruitment and retention, especially among minority populations. Supplementary Information The online version contains supplementary material available at 10.1007/s10508-021-01964-3.

Background Diminished cognitive control, including reduced behavioral flexibility and behavioral response inhibition, has been repeatedly documented in autism spectrum disorder (ASD). We evaluated behavioral flexibility and response inhibition in probands and their parents using a family trio design to determine the extent to which these cognitive control impairments represent familial traits associated with ASD. Methods We examined 66 individuals with ASD (probands), 135 unaffected biological parents, and 76 typically developing controls. Participants completed a probabilistic reversal learning task (PRL) and a stop-signal task (SST) to assess behavioral flexibility and response inhibition respectively. Rates of PRL and SST errors were examined across groups, within families, and in relation to clinical and subclinical traits of ASD. Based on prior findings that subclinical broader autism phenotypic (BAP) traits may co-segregate within families and reflect heritable risk factors, we also examined whether cognitive control deficits were more prominent in families in which parents showed BAP features (BAP+). Results Probands and parents each showed increased rates of PRL and SST errors relative to controls. Error rates across tasks were not related. SST error rates inter-correlated among probands and their parents. PRL errors were more severe in BAP+ parents and their children relative to BAP− parents and their children. For probands of BAP+ parents, PRL and SST error rates were associated with more severe social-communication abnormalities and repetitive behaviors, respectively. Conclusion Reduced behavioral flexibility and response inhibition are present among probands and their unaffected parents, but represent unique familial deficits associated with ASD that track with separate clinical issues. Specifically, behavioral response inhibition impairments are familial in ASD and manifest independently from parental subclinical features. In contrast, behavioral flexibility deficits are selectively present in families with BAP characteristics, suggesting they co-segregate in families with parental subclinical social, communication, and rigid personality traits. Together, these findings provide evidence that behavioral flexibility and response inhibition impairments track differentially with ASD risk mechanisms and related behavioral traits.

This study assessed the modifying role of primary source of COVID-19 information in the association between knowledge and protective behaviors related to COVID-19 among adults living in the United States (US). Data was collected from 6,518 US adults through an online cross-sectional self-administered survey via social media platforms in April 2020. Linear regression was performed on COVID-19 knowledge and behavior scores, adjusted for sociodemographic factors. An interaction term between knowledge score and primary information source was included to observe effect modification by primary information source. Higher levels of knowledge were associated with increased self-reported engagement with protective behaviors against COVID-19. The primary information source significantly moderated the association between knowledge and behavior, and analyses of simple slopes revealed significant differences by primary information source. This study shows the important role of COVID-19 information sources in affecting people’s engagement in recommended protective behaviors. Governments and health agencies should monitor the use of various information sources to effectively engage the public and translate knowledge into behavior change during an evolving public health crisis like COVID-19.

This report examines associations between everyday discrimination, microaggressions, and CRP to gain insight on potential mechanisms that may underlie increased CVD risk among sexual minority male young adults. The sample consisted of 60 participants taken from the P18 cohort between the ages of 24 and 28 years. Multinomial logistic regression models were used to examine the association between perceived everyday discrimination and LGBQ microaggressions with C-reactive protein cardiovascular risk categories of low-, average-, and high-risk, as defined by the American Heart Association and Centers for Disease Control. Adjustments were made for BMI. Individuals who experienced more everyday discrimination had a higher risk of being classified in the high-risk CRP group compared to the low-risk CRP group (RRR = 3.35, p = 0.02). Interpersonal LGBQ microaggressions were not associated with CRP risk category. Everyday discrimination, but not specific microaggressions based on sexual orientation, were associated with elevated levels of CRP among young sexual minority men (YSMM). Thus, to implement culturally and age-appropriate interventions, further researcher is needed to critically examine the specific types of discrimination and the resultant impact on YSMM's health.

Adult attachment, or the ways in which individuals develop and maintain trusting and loving relationships with peers and romantic partners, has been demonstrated to influence hypothalamic-pituitary-adrenal (HPA) axis functioning among young sexual minority men (YSMM). Theory and preliminary evidence suggest that differences in the lived experiences of White and Black sexual minority young adults may influence the way in which adult attachment influences the HPA-axis functioning. We sought to further this field of inquiry by examining if race moderates the association between adult attachment insecurity (i.e., avoidance and anxiety) and HPA-axis functioning among YSMM. Sixty-three YSMM participated in a 5-day daily diary study in which they completed a baseline survey to assess adult attachment orientation and provided saliva samples 4 times per day over a 5-day period in order to measure cortisol across the day. Three-level hierarchical linear modeling was used to examine the association between adult attachment, the cortisol awakening response (CAR), diurnal cortisol, and the moderating effect of race. We found no main effect of attachment anxiety or avoidance on HPA-axis functioning. However, we found that race moderated the association between adult attachment avoidance and the CAR such that Black YSMM with higher attachment avoidance had a lower CAR as compared to White YSMM. Results suggest that there may be key differences between White and Black YSMM men's lived experiences that should be explored in future research.

We seek to move beyond a deficits-based approach, which has dominated our understanding of health and well-being in in young sexual minority males (YSMM), by examining how indicators of positive development are associated with development of positive self-rated health in YSMM. Using data from a prospective cohort study of YSMM (n=514; 18 – 22 years old; 36.9% Hispanic/Latino, 15.6% non-Hispanic Black, 30.2% White, 16.9% other/multi-racial), we examined how three measures of positive development – the Life Orientation Test (LOT), the Satisfaction with Life Scale (SWLS) and the Social Responsibility Scale (SRS) were associated with self-rated health (SRH), a valid and reliable measure of self-assessed general health status. Findings suggest that YSMM who self-identified as homosexual reported higher SRH while those who reported higher levels of substance use and mental health burdens reported lower SRH. Second, in linear growth models controlling for mental health burdens and substance use, higher scores on all measures of positive development were associated with higher ratings of SRH over time. In conclusion, the presence of positive development characteristics, specifically generalized optimism, life satisfaction and social responsibility, may buffer against negative SRH assessments. Health promotion programs focusing on positive development may more effectively promote health and well-being among YSMM.

Purpose: To evaluate the agreement of selected higher order aberration measurements between aberrometers based on three different wavefront technologies. Methods: Twenty-three eyes of 23 participants were compared between Zywave, OPD-Scan III, and iDesign aberrometers, for total ocular aberrations. Participants were between 19 and 69 years of age, and exclusion criteria were previous ocular surgery or trauma, contact lens wear within the preceding 2 weeks, and ocular or systemic disease. Corneal aberrations were compared between the OPD-Scan III and GALILEI™ G2 aberrometers. Zernike coefficients of vertical and oblique trefoil, vertical and horizontal coma, and spherical aberration were analyzed in R software. Results: In all, 276 scans were captured in total, with a male-to-female ratio of 11:12. Total ocular vertical coma [mean difference (MD) = 0.026 μm, P < 0.005], vertical trefoil (MD = 0.033 μm, P < 0.05), and spherical aberration (MD = 0.022 μm, P < 0.05) differed significantly between the iDesign and OPD-Scan III. Differences in total vertical (MD = 0.072 μm, P < 0.05) and oblique trefoil (MD = 0.058 μm, P < 0.05) were demonstrated between the Zywave and OPD-Scan III, and spherical aberration (MD = 0.030 μm, P < 0.005) between iDesign and Zywave. iDesign corneal horizontal coma (MD = 0.025 μm, P < 0.05) and spherical aberration (MD = 0.043 μm, P < 0.005) measurements were significantly different between the GALILEI™ G2 and the OPD-Scan III. Conclusion: Zywave, iDesign, and OPD-Scan III, and GALILEITM G2 and OPD-Scan III may be used interchangeably for their total ocular and corneal wavefront functions, respectively; however, care must be taken if using these devices for guiding ablation or monitoring corneal disease.

Objective The serotonin (5-hydroxytryptamine [HT]) system has long been implicated in autism spectrum disorder (ASD). Whole-blood 5-HT level (WB5-HT) is a stable, heritable biomarker that is elevated in more than 25% of children with ASD. Recent findings indicate that the maternal 5-HT system may influence embryonic neurodevelopment, but maternal WB5-HT has not been examined in relation to ASD phenotypes. Method WB5-HT levels were obtained from 181 individuals (3–27 years of age) diagnosed with ASD, 99 of their fathers, and 119 of their mothers. Standardized assessments were used to evaluate cognitive, behavioral, and language phenotypes. Results Exploratory regression analyses found relationships between maternal WB5-HT and nonverbal IQ (NVIQ), Autism Diagnostic Interview-Revised (ADI-R) Nonverbal Communication Algorithm scores, and overall adaptive function on the Vineland Adaptive Behavior Scales−II. Latent class analysis identified a three-class structure in the assessment data, describing children with low, intermediate, and high severity across measures of behavior, cognition, and adaptive function. Mean maternal WB5-HT differed across classes, with the lowest maternal WB5-HT levels seen in the highest-severity group (Welch F2,46.048 = 17.394, p Conclusion Maternal WB5-HT is associated with neurodevelopmental outcomes in offspring with ASD. Prospective, longitudinal studies will be needed to better understand the relationship between the function of the maternal serotonin system during pregnancy and brain development. Further studies in animal models may be able to reveal the mechanisms underlying these findings.

Objective The objective of this study was to examine the association between perceived stress and sleep health among a sample of sexual minority men (SMM). Design Cross-sectional survey. Setting Paris, France. Participants Gay, bisexual and other SMM users ≥18 years on a geosocial networking application in Paris, France (N = 580). Measurements Participants were directed to a web-based survey measuring stress, sleep health, and socio-demographics. Multivariate log-binomial regression models were used to estimate the adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) to examine how stress may affect different dimensions of sleep health: 1) poor sleep quality, 2) short sleep duration, 3) problems falling asleep, and 4) problems staying awake in the daytime. Results Most participants (69.9%) reported at least sometimes feeling stressed (compared to never or rarely). Additionally, results demonstrate that higher perceived stress was associated with poorer sleep health; compared with those who reported feeling stress never or rarely, those who felt stress sometimes, often, or always were more likely to experience poor sleep quality (aRR = 6.67; 95% CI = 3.61–12.3), short sleep duration (aRR = 1.67; 95% CI = 1.17–2.38), problems falling asleep (aRR = 3.20; 95% CI = 2.26–4.52), and problems staying awake during the daytime (aRR = 3.52; 95% CI = 1.64–7.53). Conclusion Elevated perceived stress can negatively influence sleep health among SMM in Paris, France.

Previous research has used cortisol, the major hormonal byproduct of the hypothalamic pituitary adrenal (HPA) axis system, to explore how environmental stressors influence daily physiological functioning. Most of the research focused on diurnal cortisol has examined specific cortisol markers, with little consideration of how different components of the diurnal pattern may co-occur. Morning level, cortisol awakening response (CAR), bedtime level, as well as the diurnal slope and total cortisol exposure throughout the day (area under the curve; AUC), are five common parameters of diurnal HPA axis functioning that have been individually linked to physical and mental health outcomes, with mixed results. The current study introduces a novel approach to capture heterogeneity in HPA axis activity by using latent profile analysis to generate empirically-derived, theoretically supported diurnal cortisol profiles based on all five indicators. We analyzed salivary cortisol data from 278 young adults during a time of heightened sociopolitical stress – the 2016 U.S. presidential election – and examined whether profiles differentially predicted mental health trajectories across six months. Findings suggest that a specific combination of cortisol parameters (i.e., flat slope, high AUC, and high CAR) may predict worse mental health risk over time. Overall, this work suggests that diurnal cortisol profiles likely reflect distinct physiological underpinnings with unique health consequences that may not be observed by studying individual cortisol parameters.

International audience; We 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 analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most 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 cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

We reviewed 62 new cases and 18 published reports of Dracunculus infections in domestic dogs and cats to describe the epidemiology of this parasite in dogs and cats in North America. We collected host and parasite data when available, including age, sex, and breed of dog, nematode location in the host, and any clinical signs at presentation and/or description of the apparent lesion. For dogs, infections were noted in six of the AKC breed groups, but none was reported from the toy group or the miscellaneous breed class. Age of infected dogs ranged from 7 months to 19 years (median 4 years; average 5.3 years), and infection rates were similar in male and female dogs. Most nematodes were associated with the distal extremities, but worms were also found in the chest/thorax, abdomen, head, and flank. Although most infected dogs had a single worm, three dogs had two or more worms that were collected from multiple lesions. Three new cat cases, with similar lesions, presentations and seasonality, were detected in Alabama, North Carolina and Texas. Cases were reported from a wide geographic range throughout eastern North America, during every month of the year, but 72% of infections were diagnosed in the late winter to early spring (December to May). All collected worms were larvigerous females which cannot be identified to species based on morphologic characters. Thus, we attempted to amplify and sequence a portion of the cytochrome c oxidase subunit I (COI) gene for specific identification. Although 13 worms from 12 cases were available, sequences were obtained for only eight worms from seven cases. These eight worms were D. insignis, a common parasite of raccoons (Procyon lotor) and other primarily carnivorous mammals. Female worms are the most likely to be detected in dogs and cats because male worms do not emerge, parasites should be preserved in ethanol for molecular identification. Although this study used convenience sampling of available data, we found that the parasite is widespread throughout the eastern US and Canada and that Dracunculus infections in dogs are more common than is revealed in published literature. However, more research is needed to understand the epidemiology, including transmission route(s), prevalence, and distribution of this parasite.

Background Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP), have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explores polygenic scores related to the BAP. Methods Phenotypic and genotypic information were obtained from 2614 trios from the Simons Simplex Collection. Polygenic scores of ASD (ASD-PGSs) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and paternal ASD-PGSs were explored in relation to BAP traits and their child's ASD symptomatology. Results Maternal pragmatic language was related to child’s social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGSs were related to the pragmatic language and rigid BAP domains. Conclusions Associations emerged between parent and child phenotypes, with more associations emerging in mothers than in fathers. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.

International audience; Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced non-verbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities.

Background Receptive and expressive vocabulary in adult and adolescent males with fragile X syndrome (FXS) have been shown as significantly lower than their chronological age; however, receptive vocabulary has been considered a strength relative to mental age. This has not been formally examined, however, and data are needed to compare receptive vocabulary with other language skills and with mental age in individuals with FXS. This is especially important as vocabulary measures are sometimes used as a proxy to estimate language ability. Methods This preliminary study examined receptive vocabulary, global language, and cognitive skills in 42 adults (33 males and 9 females) with FXS as a portion of the baseline evaluation prior to randomization in a clinical trial of ampakine CX516. The battery of standardized tests addressed receptive vocabulary with the Peabody Picture Vocabulary Test, Third Edition (PPVT-III), receptive and expressive language (termed henceforth as global language) via the Preschool Language Scale, Fourth Edition or the Clinical Evaluation of Language Fundamentals, Third Edition, and non-verbal cognition via the Stanford-Binet Intelligence Scales, Fourth Edition (SB-IV). Results Results showed (1) significantly higher receptive vocabulary than global language, (2) significantly better receptive vocabulary than non-verbal cognition, (3) equivalent non-verbal cognition and global language, and (4) severity of autism symptomatology was not correlated to receptive vocabulary or global language once non-verbal cognition was removed as factor. The scores from the PPVT-III did not represent the global language skills in our sample of adults with FXS. Conclusions Findings from this investigation strongly suggest that the PPVT-III should not be used as a screening tool for language levels or cognitive function in clinical studies since the scores from the PPVT-III were not representative of global language or non-verbal cognitive skills in adults with intellectual disabilities. This finding is critical in order to understand how to evaluate, as well as to treat, language in individuals with FXS. Development of efficient and appropriate tools to measure language, cognition, and behavior in individuals with FXS is essential.

Fungi frequently are isolated in intra-abdominal infections (IAI). The Study to Optimize Peritoneal Infection Therapy (STOP-IT) recently suggested short-course treatment for patients with IAI. It remains unclear whether the presence of fungi in IAI affects the optimal duration of Antimicrobial therapy. We hypothesized that a shorter treatment course in IAI with fungal organisms would be associated with a higher rate of treatment failure.Patients enrolled in the STOP-IT trial were stratified according to the presence or absence of a fungal isolate. They were analyzed as a subgroup based on original randomization to either the control group or an experimental group that received a four-day course of Antimicrobial therapy and by comparison with those without a fungal component to their infection. Descriptive comparisons were performed using a χA total of 411 patients in the study (79%) had available culture data, of which 58 (14%) had positive fungal cultures. The most common organisms were Candida albicans and C. glabrata. The treatment failure rate was equivalent in the experimental and control arms (29.6% vs. 22.6%; p = 0.54). Patients with fungal isolates were more likely to have malignant disease (25.9% vs. 9.6%; p = 0.0004) and coronary artery disease (22% vs. 12%; p = 0.04), but were otherwise similar to those without fungal isolates. Patients with fungal isolates had more hospital days (median 10 vs. 7; p 0.0001) and more days to resumption of enteral intake (median 5 vs. 3; p = 0.0006), but there was no difference in the composite outcome.Patients with IAI involving fungal organisms randomized to a shorter course of Antimicrobial therapy had no difference in the rate of treatment failure. These results suggest that the presence of fungi in IAI may not indicate independently the need for a longer course of Antimicrobial therapy.

We conducted a mixed-methods study to identify factors that influence transitions in attachment style between childhood and adulthood among 28 young Black gay and bisexual men (YBGBM) in the United States. We used a phenomenological approach to data integration, with the major component to the results being garnered from the qualitative interviews. We organized our results by four attachment transition groups: stable-secure (secure attachment in childhood and young adulthood), stable-insecure (insecure attachment in childhood and young adulthood), secure-to-insecure (secure in childhood and insecure in adulthood) and insecure-to-secure (insecure in childhood and secure in adulthood). Within each of the typologies, two major themes emerged: (a) social support and (b) religion. Generally, transitions from secure-to-insecure attachment were related to experiences of perceived rejection by a parental figure during adolescence that corresponded with sexual orientation disclosure. Transitions from insecure-to-secure attachment appeared to be related to the absence of an attachment figure early in life, but with the acquisition of an attachment figure during early-to-late adolescence. The findings from our study suggest a need for attachment-based approaches to social support interventions, as well as for an increased understanding of social and cultural factors that impact attachment changes among practitioners who use attachment-based therapy models for YBGBM.

The relationship between trauma volumes and patient outcomes continues to be controversial, with limited data available regarding the effect of month-to-month trauma volume variability on clinical results. This study examines the relationship between monthly trauma volume variations and patient mortality at seven Level I Trauma Centers located in the Eastern United States. We hypothesized that higher monthly trauma volumes may be associated with lower corresponding mortality.Monthly patient volume data were collected from seven Level I Trauma Centers. Additional information retrieved included monthly mortality, demographics, mean monthly injury severity (ISS), and trauma mechanism (blunt versus penetrating). Mortality was utilized as the primary study outcome. Statistical corrections for mean age, gender distribution, ISS, and mechanism of injury were made using analysis of co-variance (ANCOVA). Center-specific, annually-adjusted median monthly volumes (CSAA-MMV) were calculated to standardize patient volume differences across participating institutions. Statistical significance was set at α 0.05.A total of 604 months of trauma admissions, encompassing 122,197 patients, were analyzed. Controlling for patient age, gender, ISS, and mechanism of injury, aggregate data suggested that monthly trauma volumes 100 were associated with significantly greater mortality (3.9%) than months with volumes 400 (mortality 2.9%, p 0.01). To account for differences in monthly volumes between centers, as well as for temporal bias associated with potential differences over the entire study duration period, data were normalized using CSAA-MMV as a standardized reference point. Monthly volumes ≤ 33% of the CSAA-MMV were associated with adjusted mortality of 5.0% whereas monthly volumes ≥ 134% CSAA-MMV were associated with adjusted mortality of 2.7% (p 0.01).This hypothesis-generating study suggests that greater monthly trauma volumes appear to be associated with lower mortality. In addition, our data also suggest that across all participating centers mortality may be a function of relative month-to-month volume variation. When normalized to institution-specific, annually-adjusted "median" monthly trauma contacts, we show that months with patient volumes ≤ 33% median may be associated with subtly but not negligibly (1.4-2.3%) higher mortality than months with patient volumes ≥ 134% median.

Objective Sexual minority men (SMM) in the United States continue to experience adverse health problems and psychosocial burdens. However, there is limited psychometric research seeking to quantify the life worries of this population. Informed by syndemic theory, the Life Worries Scale (LWS) was developed to measure the concerns of young SMM. Method Analyses of the scale were undertaken using baseline data (n = 665) from an ongoing cohort study of emerging adult, SMM. Results Exploratory factor analyses (EFA) of an initial set of 24 Likert-type items, followed by confirmatory factor analysis (CFA) and an exploratory structural equation model (ESEM), indicated a structure consisting of 6 domains of worries: financial stability, social stability, self esteem, loneliness, physical appearance, and physical health. These 6 subscales were highly correlated and also demonstrated high levels of internal consistency. Differences in life worries were noted across demographic states, specifically HIV serostatus, sexual attraction, housing status, and self-rated health. High levels of association were also detected between all 6 subscales with both depression and PTSD, while significant correlations were detected between suicidality and both self esteem and loneliness related worries. Conclusions The results of our analyses provide evidence for the strong psychometric characteristics of the LWS. This newly developed instrument should be utilized in research to examine the extent to which life worries explain health outcomes and risk behaviors in sexual minority males, and may be potentially extended for use in other populations. (PsycINFO Database Record

Enterococci are isolated frequently as pathogens in patients with intra-abdominal infections (IAIs) and may predict poor clinical outcomes. It remains controversial whether enterococci warrant an altered treatment approach with regard to antimicrobial treatment.The study population was derived from the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial database. Through post hoc analysis subjects were stratified into two groups based on isolation of Enterococcus. Fifty subjects of the cohort (n = 518) had Enterococcus isolated. Uni-variable and multi-variable analyses were conducted to determine whether isolation of Enterococcus constituted an independent predictor of the pre-defined STOP-IT composite outcome (surgical site infection, recurrent IAI, or death) and the individual components of the composite outcome.From the cohort of 50 subjects, we identified 52 isolates of Enterococcus spp. with a predominance of Enterococcus faecalis (40%) followed by other Enterococcus spp. (37%) and Enterococcus faecium (17%). Baseline demographic characteristics were statistically similar between the two groups. Antibiotic utilization distribution remained balanced between the Enterococcus and no Enterococcus groups with the majority receiving piperacillin-tazobactam (62% and 54%, respectively). The groups had comparable infection characteristics including setting of acquisition (50% community acquired) and origin of infection (predominantly colon or rectum). Individual and composite clinical outcomes were not different statistically between the Enterococcus and no Enterococcus groups: surgical site infection (10% vs. 7.5%; p = 0.53), recurrent IAI (20% vs. 14.1%; p = 0.26), death (2% vs. 1%; p = 0.40), and composite of all three (30% vs. 20.9%; p = 0.14], respectively. Multi-variable analysis revealed that isolation of Enterococcus did not predict independently the incidence of the composite outcome (odds ratio [OR] 1.53 [95% confidence interval {CI} = 0.78-3.01]; p = 0.22; c-statistic = 0.65; goodness of fit, p = 0.71).Enterococcus was not a more common pathogen in health-care-associated IAIs and was not an independent risk factor for the composite outcome. The isolation of Enterococcus from IAIs may not warrant an alternative treatment approach but larger studies are needed to validate these findings.

Exposure to violence during adolescence is associated with increased risk behaviors and mental health problems in adulthood. Friendship attachment during adolescence may, however, mitigate the negative effects of exposure to violence on trajectories of depression and anxiety in young adulthood. In this study, we used growth curve modeling to examine associations between exposure to violence and mental health outcomes, followed by multi-group analyses with friendship attachment as the moderator. The sample was drawn from a longitudinal study (12 waves; 1994–2012) of 676 (54% female) urban high school students. We found strong positive associations between exposure to violence during adolescence and later self-reported depressive and anxiety symptoms. Notably, securely attached adolescents reported faster decreases in mental health symptoms as a function of violence relative to their insecurely attached peers as they transitioned into adulthood.

Background We previously demonstrated a gene-by-prenatal-environment interaction whereby the monoamine oxidase A gene (MAOA) modified the impact of prenatal tobacco exposure (PTE) on adolescent disruptive behavior (DB), with the MAOA risk genotype varying by sex. We extend this work by examining whether this mechanism is evident with another common adversity, prenatal stress exposure (PSE), and whether sex differences are present earlier in development in closer proximity to exposure. Methods Participants were 281 mothers and their 285 children derived from a prenatal cohort with in-depth prospective measures of PSE and PTE. We assessed DB at age 5 via dimensional developmentally-sensitive measurement. Analyses were stratified by sex based on prior evidence for sex differences. Results Concurrent stress exposure predicted DB in children (β = 0.310, p = 0.001), while main effects of prenatal exposures were seen only in boys. We found a three-way interaction of MAOA × PSE × sex on DB (β = 0.813, p = 0.022). Boys with MAOA-H had more DB as a function of PSE, controlling for PTE (β = 0.774, p = 0.015), and as a function of PTE, controlling for PSE (β = 0.362, p = 0.037). Boys with MAOA-L did not show this susceptibility. MAOA did not interact with PSE (β = − 0.133, p = 0.561) nor PTE (β = − 0.144; p = 0.505) in predicting DB in girls. Examination of gene-environment correlation (rGE) showed a correlation between paternal MAOA-L and daughters' concurrent stress exposure (r = − 0.240, p = 0.013). Discussion Findings underscore complex mechanisms linking genetic susceptibility and early adverse exposures. Replication in larger cohorts followed from the pregnancy through adolescence is suggested to elucidate mechanisms that appear to have varying developmental expression.

Age has been shown to play a significant role in the etiology of complicated intra-abdominal infections (cIAIs), but the correlation between age and outcomes after therapy was not investigated in the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial.Data were obtained by post hoc analysis of the STOP-IT trial database. Patients were stratified by age65 or ≥65 years. Primary outcomes were surgical site infection (SSI), recurrent IAI (recIAI), and death. Multivariable analysis was performed to identify independent predictors of outcomes.There were 398 subjects65 and 120 ≥ 65 years. Overall baseline characteristics of the two groups were similar. The site of infection was similar between groups except: Colon or rectum (48.3% vs. 29.9%, p = 0.0002) and biliary tree (16.7% vs. 9.1%, p = 0.02), which were more common in the older group, whereas small intestine (6.7% vs. 16.3%, p = 0.008) and appendix (4.2% vs.17.1%, p = 0.0004) were more common in the younger group. Among the primary outcomes, only death was significantly different between the age groups and was more prevalent in the ≥65 years group (4 [3.3%] vs. 1 [0.3%], p = 0.01). Surgical site infection (9.2% vs. 7.3%, p = 0.50), recIAI (15.8% vs. 14.4%, p = 0.69), and a composite outcome (26.7% vs. 20.4%, p = 0.14) were statistically similar between the age groups, and this remained true when controlling for other co-variables. Multivariable analyses did not reveal age as an independent predictor of the composite or individual outcomes.Patients with a more advanced age demonstrated variable sources of infection relative to the younger cohort, yet received similar treatments. Patient age was not an independent predictor of the undesired cIAI outcomes. These findings suggest that advanced age itself does not play a significant role in predicting these adverse outcomes for cIAIs and does not necessitate an altered treatment tactic.

Management of complicated intra-abdominal infections (cIAIs) includes broad-spectrum antimicrobial coverage and commonly includes vancomycin for the empiric coverage of methicillin-resistant Staphylococcus aureus (MRSA). Ideally, culture-guided de-escalation follows to promote robust antimicrobial stewardship. This study assessed the impact and necessity of vancomycin in cIAI treatment regimens.A post hoc analysis of the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial was performed. Patients receiving piperacillin-tazobactam (P/T) and/or a carbapenem were included with categorization based on use of vancomycin. Univariate and multivariable analyses evaluated effects of including vancomycin on individual and the composite of undesirable outcomes (recurrent IAI, surgical site infection [SSI], or death).The study cohort included 344 patients with 110 (32%) patients receiving vancomycin. Isolation of MRSA occurred in only eight (2.3%) patients. Vancomycin use was associated with a similar composite outcome, 29.1%, vs. no vancomycin, 22.2% (p = 0.17). Patients receiving vancomycin had (mean [standard deviation]) higher Acute Physiology and Chronic Health Evaluation II scores (13.1 [6.6] vs. 9.4 [5.7], p 0.0001), extended length of stay (12.6 [10.2] vs. 8.6 [8.0] d, p 0.001), and prolonged antibiotic courses (9.1 [8.0] vs. 7.1 [4.9] d, p = 0.02). After risk adjustment in a multivariate model, no significant difference existed for the measured outcomes.This post hoc analysis reveals that addition of vancomycin occurred in nearly one third of patients and more often in sicker patients. Despite this selection bias, no appreciable differences in undesired outcomes were demonstrated, suggesting limited utility for adding vancomycin to cIAI treatment regimens.

This study examines how romantic relationship cognitions are associated with changes of condomless anal sex among emerging adult gay and bisexual men. The sample was drawn from four waves of a prospective cohort study ( N = 598; Mage = 18.2). Results suggest that condomless anal sex increased over the emerging adulthood period. Romantic relationship fear was associated with increased receptive condomless anal sex. Perceptions of greater romantic relationship control increased the likelihood of having insertive and receptive condomless anal sex. Findings suggest that romantic relationship cognitions are important to consider when understanding longitudinal changes in condomless anal sex in this population.

Background Exposure to sexual orientation-related discrimination among sexual minorities may lead to elevated levels of C-reactive protein (CRP) as compared to their heterosexual counterparts. However, little is known about factors that may buffer the association between discrimination and CRP among sexual minorities versus heterosexuals. The current study examined if the association between discrimination, sexual orientation, and CRP differed across levels of social support from one's father/father-figure or mother/mother-figure between sexual minorities and heterosexuals. Methods Data came from Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health). The sample sizes for father support and mother support was 3167 and 3575, respectively. Participants ranged in age from 24 to 33 years. Stratified linear regression models examined if father and mother support moderated the association between discrimination and CRP among sexual minorities and heterosexuals. Results Father support significantly moderated the association between discrimination and CRP among sexual minorities but not heterosexuals. Sexual minorities with higher father support and who experienced discrimination had lower CRP as compared to those with lower father support and who experienced discrimination. Mother support did not moderate the association between discrimination and CRP among either sexual minorities or heterosexuals. Conclusion Father support may mitigate the negative effects of stress from discrimination on CRP among sexual minorities. Future research should further examine the potential differential role that father support may play in reducing cardiovascular risk among sexual minorities versus heterosexuals who experience discrimination.

Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium - Collaborators (162): Anney RJL, Ripke S, Anttila V, Grove J, Holmans P, Huang H, Klei L, Lee PH, Medland SE, Neale B, Robinson E, Weiss LA, Zwaigenbaum L, Yu TW, Wittemeyer K, Willsey AJ, Wijsman EM, Werge T, Wassink TH, Waltes R, Walsh CA, Wallace S, Vorstman JAS, Vieland VJ, Vicente AM, vanEngeland H, Tsang K, Thompson AP, Szatmari P, Svantesson O, Steinberg S, Stefansson K, Stefansson H, State MW, Soorya L, Silagadze T, Scherer SW, Schellenberg GD, Sandin S, Sanders SJ, Saemundsen E, Rouleau GA, Rogé B, Roeder K, Roberts W, Reichert J, Reichenberg A, Rehnström K, Regan R, Poustka F, Poultney CS, Piven J, Pinto D, Pericak-Vance MA, Pejovic-Milovancevic M, Pedersen MG, Pedersen CB, Paterson AD, Parr JR, Pagnamenta AT, Oliveira G, Nurnberger JI, Nordentoft M, Murtha MT, Mouga S, Mortensen PB, Mors O, Morrow EM, Moreno-De-Luca D, Monaco AP, Minshew N, Merikangas A, McMahon WM, McGrew SG, Mattheisen M, Martsenkovsky I, Martin DM, Mane SM, Magnusson P, Magalhaes T, Maestrini E, Lowe JK, Lord C, Levitt P, Martin CL, Ledbetter DH, Leboyer M, LeCouteur AS, Ladd-Acosta C, Kolevzon A, Klauck SM, Jacob S, Iliadou B, Hultman CM, Hougaard DM, Hertz-Picciotto I, Hendren R, Hansen CS, Haines JL, Guter SJ, Grice DE, Green JM, Green A, Goldberg AP, Gillberg C, Gilbert J, Gallagher L, Freitag CM, Fombonne E, Folstein SE, Fernandez B, Fallin MD, Ercan-Sencicek AG, Ennis S, Duque F, Duketis E, Delorme R, DeRubeis S, DeJonge MV, Dawson G, Cuccaro ML, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Celestino-Soper PBS, Casey J, Cantor RM, Café C, Bybjerg-Grauholm J, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bolshakova N, Betancur C, Bernier R, Beaudet AL, Battaglia A, Bal VH, Baird G, Bailey AJ, Bækvad-Hansen M, Bader JS, Bacchelli E, Anagnostou E, Amaral D, Almeida J, Børglum AD, Buxbaum JD, Chakravarti A, Cook EH, Coon H, Geschwind DH, Gill M, Hallmayer J, Palotie A, Santangelo S, Sutcliffe JS, Arking DE, Devlin B, Daly MJ. Astrid M. Vicente .- Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA. PMS free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441062/ Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR)

Purpose Forming secure friendship attachments during adolescence are important for mental health; few, however, have specifically examined the ways in which the transitions in attachment during adolescence may influence future mental health outcomes among African Americans. Methods The present study examines how transitions in attachment in adolescence predicted changes in depression symptoms from late adolescents through adulthood in an African-American sample. We used growth curve modeling to examine the association between transitions in friendship attachment and changes in depression symptoms in adulthood. Results At age 16 years, 346 (64.0%) adolescents reported secure attachment with 195 (36.0%) reporting either avoidant or resistant attachment. At age 17 years, 340 (62.9%) reported secure attachment and 201 (37.2%) reported avoidant or resistant attachment. The largest percentage of participants (46.2%) reported stable-secure attachment across the two time points. Results of the growth model indicated that adolescents who reported a stable-secure attachment style had lower levels of depression symptoms during adulthood than those individuals who transitioned from secure-to-insecure, from insecure-to-secure, or were in the stable-insecure group. Interestingly enough, individuals in both the attachment transition groups had a faster declining rate of depression symptoms over time compared to the two stability groups. Conclusions Data support existing research showing an association between transitions in attachment during adolescence and depression through adulthood. Furthermore, these study findings suggest there may be protective features associated with transitioning between attachment styles during adolescence on later depression, compared to African Americans who remain stable in their attachment style.

The measurement of aggression in its different forms (e.g., physical and verbal) and functions (e.g., impulsive and instrumental) is given little attention in subjects with developmental disabilities (DD). In this study, we confirm the factor structure of the Children's Scale for Hostility and Aggression: Reactive/Proactive (C-SHARP) and demonstrate measurement invariance (consistent performance across clinical groups) between clinic-referred groups with and without autism spectrum disorder (ASD). We also provide evidence of the construct validity of the C-SHARP.Caregivers provided C-SHARP, Child Behavior Checklist (CBCL), and Proactive/Reactive Rating Scale (PRRS) ratings for 644 children, adolescents, and young adults 2-21 years of age. Five types of measurement invariance were evaluated within a confirmatory factor analytic framework. Associations among the C-SHARP, CBCL, and PRRS were explored.The factor structure of the C-SHARP had a good fit to the data from both groups, and strict measurement invariance between ASD and non-ASD groups was demonstrated (i.e., equivalent structure, factor loadings, item intercepts and residuals, and latent variance/covariance between groups). The C-SHARP Problem Scale was more strongly associated with CBCL Externalizing than with CBCL Internalizing, supporting its construct validity. Subjects classified with the PRRS as both Reactive and Proactive had significantly higher C-SHARP Proactive Scores than those classified as Reactive only, who were rated significantly higher than those classified by the PRRS as Neither Reactive nor Proactive. A similar pattern was observed for the C-SHARP Reactive Score.This study provided evidence of the validity of the C-SHARP through confirmation of its factor structure and its relationship with more established scales. The demonstration of measurement invariance demonstrates that differences in C-SHARP factor scores were the result of differences in the construct rather than to error or unmeasured/nuisance variables. These data suggest that the C-SHARP is useful for quantifying subtypes of aggressive behavior in children, adolescents, and young adults with DD.

Numerous studies have demonstrated microorganism interaction through signaling molecules, some of which are recognized by other bacterial species. This interspecies synergy can prove detrimental to the human host in polymicrobial infections. We hypothesized that polymicrobial intra-abdominal infections (IAI) have worse outcomes than monomicrobial infections.Data from the Study to Optimize Peritoneal Infection Therapy (STOP-IT), a prospective, multicenter, randomized controlled trial, were reviewed for all occurrences of IAI having culture results available. Patients in STOP-IT had been randomized to receive four days of antibiotics vs. antibiotics until two days after clinical symptom resolution. Patients with polymicrobial and monomicrobial infections were compared by univariable analysis using the Wilcoxon rank sum, χ(2), and Fisher exact tests.Culture results were available for 336 of 518 patients (65%). The durations of antibiotic therapy in polymicrobial (n = 225) and monomicrobial IAI (n = 111) were equal (p = 0.78). Univariable analysis demonstrated similar demographics in the two populations. The 37 patients (11%) with inflammatory bowel disease were more likely to have polymicrobial IAI (p = 0.05). Polymicrobial infections were not associated with a higher risk of surgical site infection, recurrent IAI, or death.Contrary to our hypothesis, polymicrobial IAI do not have worse outcomes than monomicrobial infections. These results suggest polymicrobial IAI can be treated the same as monomicrobial IAI.

Selective serotonin reuptake inhibitors such as escitalopram are commonly used to treat patients with autism spectrum disorder (ASD), but there are individual differences in treatment response and tolerability. CYP2C19 encodes the primary enzyme responsible for escitalopram metabolism and we investigated whether polymorphisms in CYP2C19 were related to symptoms and dosing in a pharmacogenetic study of ASD.Participants completed the Aberrant Behavior Checklist--Community Version (ABC-CV) weekly for 6 weeks. Escitalopram was initiated at a dose of 2.5 mg per day, with weekly increases to 20 mg unless intolerable side-effects occurred. Three CYP2C19 metabolizer groups, including ultrarapid, extensive, and reduced metabolizers, were examined in relation to symptom improvement and tolerated dose.ABC-CV scores improved over the course of treatment (P0.0001). No differences were identified in the rate of improvement across metabolizer groups for the ABC-CV irritability subscale, which was the primary outcome for clinical symptoms. There was a trend for a metabolizer group by time interaction with respect to dose (P=0.10). This interaction was driven by the linear rate of change from week 1 to study endpoint between the reduced metabolizers and ultrarapid metabolizer groups (P=0.05). Post-hoc analyses identified significant differences in the rate of dose escalation between ultrarapid metabolizers and extensive metabolizers and for ultrarapid metabolizers compared with reduced metabolizers (P's0.04), whereby ultrarapid metabolizers showed a slower rate of change in dose over time.CYP2C19 ultrarapid metabolizers were associated with reduced tolerance to a fixed titration schedule of open-label escitalopram in this ASD study sample. Possible explanations may involve the altered kinetics of faster metabolizers or previously unknown activities of escitalopram metabolites.

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1). Through analysis of de novo mutations in autism spectrum disorder (ASD), Sanders et al. find that small deletions, but not large deletions/duplications, contain one critical gene. Combining CNV and sequencing data, they identify 6 loci and 65 genes associated with ASD.

The purpose of this study was to determine whether polymorphisms in the serotonin transporter (SLC6A4) and serotonin-2A receptor (HTR2A) genes are associated with response to escitalopram in patients with autism spectrum disorder (ASD).Forty-four participants with ASD were enrolled in a 6 week, forced titration, open label examination of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Doses increased at weekly intervals starting at 2.5mg daily with a maximum possible dose of 20 mg daily achieved by the end of the study. If adverse events were experienced, participants subsequently received the previously tolerated dose for the duration of study. SLC6A4 (5-HTTLPR) and HTR2A (rs7997012) genotype groups were assessed in relation to treatment outcomes and drug doses.Insistence on sameness and irritability symptoms significantly improved over the course of the 6 week treatment period (p0.0001) in this open-label trial. There were no significant differences observed in the rate of symptom improvement over time across genotype groups. Similarly, dosing trajectory was not significantly associated with genotype groups.Previous studies have identified SLC6A4 and HTR2A associations with SSRI response in patients with depression and 5-HTTLPR (SLC6A4) associations with escitalopram response in ASD. We did not observe evidence for similar relationships in this ASD study.

Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.

Introduction: The present study sought to identify time-dependent within-participant effects of CYP2A6 genotypes on smoking frequency and nicotine dependence in young smokers. Methods: Predicted nicotine metabolic rate based on CYP2A6 diplotypes (CYP2A6 diplotype predicted rate [CDPR]) was partitioned into Normal, Intermediate, and Slow categories using a metabolism metric. Growth-curve models characterized baseline and longitudinal CDPR effects with data from eight longitudinal assessments during a 6-year period (from approximately age 16–22) in young smokers of European descent (N = 296, 57% female) who had smoked less than 100 cigarettes lifetime at baseline and more than that amount by Year 6. Phenotypes were number of days smoked during the previous 30 days and a youth version of the Nicotine Dependence Syndrome Scale (NDSS). A zero-inflated Poisson growth-curve model was used to account for the preponderance of zero days smoked. Results: At baseline, Intermediate CDPR was a risk factor relative to both Normal and Slow CDPR for smoking frequency and the NDSS. Slow CDPR was associated with the highest probability of smoking discontinuation at baseline. However, due to CDPR time trend differences, by young adulthood these baseline effects had been reordered such that the greatest risks for smoking frequency and the NDSS were associated with Normal CDPR. Conclusions: Reduced metabolism CYP2A6 genotypes are associated with both risk and protective effects in novice smokers. However, differences in the time-by-CDPR effects result in a reordering of genotype effects such that normal metabolism becomes the risk variant by young adulthood, as has been reliably reported in older smokers.

Background: Religious themes are commonly encountered in delusions and hallucinations associated with major mental disorders, and the form and content of presentation are significant in relation to both diagnosis and management. Aims: This study aimed to establish what is known about the frequency of occurrence of religious delusions (RD) and religious hallucinations (RH) and their inter-relationship. Methods: A review was undertaken of the quantitative empirical English literature on RD and RH. Results: A total of 55 relevant publications were identified. The lack of critical criteria for defining and classifying RD and RH makes comparisons between studies difficult, but prevalence clearly varies with time and place, and probably also according to personal religiosity. In particular, little is known about the content and frequency of RH and the relationship between RH and RD. Conclusion: Clearer research criteria are needed to facilitate future study of RD and RH, and more research is needed on the relationship between RD and RH.

Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the ‘sub-phenotypes' of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder.

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Background Inhibitory control deficits are common in autism spectrum disorder (ASD) and associated with more severe repetitive behaviors. Inhibitory control deficits may reflect slower execution of stopping processes, or a reduced ability to delay the onset of behavioral responses in contexts of uncertainty. Previous studies have documented relatively spared stopping processes in ASD, but whether inhibitory control deficits in ASD reflect failures to delay response onset has not been systematically assessed. Further, while improvements in stopping abilities and response slowing are seen through adolescence/early adulthood in health, their development in ASD is less clear. Methods A stop-signal test (SST) was administered to 121 individuals with ASD and 76 age and IQ-matched healthy controls (ages 5–28). This test included ‘GO trials’ in which participants pressed a button when a peripheral target appeared and interleaved ‘STOP trials’ in which they were cued to inhibit button-presses when a stop-signal appeared at variable times following the GO cue. STOP trial accuracy, RT of the stopping process (SSRT), and reaction time (RT) slowing during GO trials were examined. Results Relative to controls, individuals with ASD had reduced accuracy on STOP trials. SSRTs were similar across control and ASD participants, but RT slowing was reduced in patients compared to controls. Age-related increases in stopping ability and RT slowing were attenuated in ASD. Reduced stopping accuracy and RT slowing were associated with more severe repetitive behaviors in ASD. Discussion Our findings show that inhibitory control deficits in ASD involve failures to strategically delay behavioral response onset. These results suggest that reduced preparatory behavioral control may underpin inhibitory control deficits as well as repetitive behaviors in ASD. Typical age-related improvements in inhibitory control during late childhood/early adolescence are reduced in ASD, highlighting an important developmental window during which treatments may mitigate cognitive alterations contributing to repetitive behaviors.

BackgroundRecent studies have suggested the length of treatment of intra-abdominal infections (IAIs) can be shortened without detrimental effects on patient outcomes. However, data from high-risk patient populations are lacking. We hypothesized that patients at high risk for treatment failure will benefit from a longer course of antimicrobial therapy.MethodsPatients enrolled in the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial were evaluated retrospectively to identify risk factors associated with treatment failure, which was defined as the composite outcome of recurrent IAI, surgical site infection, or death. Variables were considered risk factors if there was a positive statistical association with treatment failure. Patients were then stratified according to the presence and number of these risk factors. Univariable analyses were performed using the Kruskal-Wallis, χ2, and Fisher exact tests. Logistic regression controlling for risk factors and original randomization group, either a fixed four-day antimicrobial regimen (experimental) or a longer course based on clinical response (control), also was performed.ResultsWe identified corticosteroid use, Acute Physiology and Chronic Health Evaluation II score ≥5, hospital-acquired infection, or a colonic source of IAI as risk factors associated with treatment failure. Of the 517 patients enrolled, 263 (50.9%) had one or two risk factors and 16 (3.1%) had three or four risk factors. The rate of treatment failure rose as the number of risk factors increased. When controlling for randomization group, the presence and number of risk factors were independently associated with treatment failure, but the duration of antimicrobial therapy was not.ConclusionsWe were able to identify patients at high risk for treatment failure in the STOP-IT trial. Such patients did not benefit from a longer course of antibiotic administration. Further study is needed to determine the optimum duration of antimicrobial therapy in high-risk patients.

Childhood poverty is hypothesized to increase risk for mental and physical health problems at least in part through dysregulation of the hypothalamic-pituitary-adrenal axis. However, less is known about the specific psychosocial stressors associated with cortisol reactivity and regulation for children living in poverty. The current study investigates negative life events, household chaos, and family conflict in preschool and middle childhood as potential predictors of cortisol regulation in low-income 7-10 year olds (N = 242; M age = 7.9 years). Participants were assessed in preschool and participated in a follow-up assessment in middle childhood, during which diurnal free cortisol and free cortisol reactivity to the Trier Social Stress Test for Children (TSST-C) were assessed. Household chaos during preschool predicted a more blunted diurnal cortisol slope in middle childhood. Greater negative life events during preschool and greater concurrent family conflict were associated with increased free cortisol reactivity in middle childhood.

Background: Since 2001, a policy of positive mental health recovery has been promoted in the UK, with service user involvement. This has not been easy to implement in the clinical setting.\ud \ud Aims: To develop and validate a brief self-report, service user-designed, outcome measure (Mini-SeRvE), for clinical use, including spiritual and religious issues.\ud \ud Methods: From the previously developed Service user Recovery Evaluation scale (SeRvE), 15 questions were selected for Mini-SeRvE which was self-completed by 207 people; 100 service users and, for comparison, 107 staff. Results were analysed using SPSS software (SPSS Inc., Chicago, IL).\ud \ud Results: Mini-SeRvE is reliable, Cronbach’s alpha 0.852. Correlation with another recovery scale, Mental Health Recovery Measure, was high, r = 0.819. Three reliable subscales emerged; existential well-being (EWB), mental ill-being (MIB) and religious well-being (RWB). Scores of the EWB and MIB subscales were higher for staff, consistent with higher mental well-being. Religious well-being scores were higher in service users, who also rated religion as more important to them.\ud \ud Conclusions: Mini-SeRvE is a valid measure of service user recovery. The importance of religion/spiritual belief for our users is highlighted, this being reflected in the subject matter of Mini-SeRvE. Mini-SeRvE assessments could show individual priorities, evaluate therapy and aid clinical decision-making.

Background Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. Methods In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. Results Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-β pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. Conclusions Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. Electronic supplementary material The online version of this article (doi:10.1186/s13229-017-0130-3) contains supplementary material, which is available to authorized users.

Objectives Studies are conflicting regarding the association of the North American pulsed-field gel electrophoresis type 1 (NAP1) strain in Clostridium difficile infection (CDI) and outcomes. We evaluated the association of NAP1 with healthcare-associated CDI disease severity, mortality, and recurrence at our academic medical center. Methods Healthcare-associated CDI cases were identified from November 1, 2011 through January 31, 2013. Multivariable regression models were used to evaluate the associations of NAP1 with severe disease (based on the Hines VA severity score index), mortality, and recurrence. Results Among 5424 stool specimens submitted to the Clinical Microbiology Laboratory, 292 (5.4%) were positive for C. difficile by polymerase chain reaction (PCR) on or after hospital day 4; 70 (24%) of these specimens also tested positive for NAP1. During the study period, 247 (85%) patients had non-severe disease and 45 (15%) patients had severe disease. Among patients with non-severe disease, 65 (26%) had NAP1 and among patients with severe disease, 5 (11%) had NAP1. After controlling for potential confounders, NAP1 was not associated with an increased likelihood of severe disease (adjusted odds ratio [aOR] = 0.35; 95% confidence interval [CI], 0.13–0.93), in-hospital mortality (aOR = 1.02; 95% CI, 0.53–1.96), or recurrence (aOR = 1.16, 95% CI, 0.36–3.77). Conclusions The NAP1 strain did not increase disease severity, mortality, or recurrence in this study, although the incidence of NAP1-positive healthcare associated-CDI was low. The role of strain typing in outcomes and treatment selection in patients with healthcare-associated CDI remains uncertain.

Background Although studies demonstrate techniques to limit hypoglycaemia in critically ill patients, there are limited data supporting methods to improve management of existing hypoglycaemia. Objective Assess the impact and sustainability of a computerised, three tiered, nurse driven protocol for hypoglycaemia treatment. Design Retrospective pre and post protocol study. Setting Neurosciences and surgical intensive care units at a tertiary academic medical centre. Measurements Patients with a hypoglycaemic episode were included during a pre-protocol or post-protocol implementation period. An additional six-month cohort was evaluated to assess sustainability. Results Fifty-four patients were included for evaluation (35 pre- and 19 post-protocol); 122 patients were included in the sustainability cohort. Hypoglycaemia treatment significantly improved in the post-protocol cohort (20% vs. 52.6%, p = 0.014); with additional improvement to 79.5% in the sustainability cohort. Time to follow-up blood glucose was decreased after treatment from 122 [Q1–Q3: 46–242] minutes pre-protocol to 25 [Q1–Q3: 9–48] minutes post protocol (p Conclusion Implementation of a nurse-driven, three-tiered protocol for treatment of hypoglyacemia significantly improved treatment rates, as well as reduced time to recheck blood glucose measurement. These benefits were sustained during a six-month period after protocol implementation.

Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases.

Amygdala and insula hyper-reactivity to threat is implicated in social anxiety disorder (SAD) yet inconsistencies in activation have been reported. One source of variance are individual differences in 5-HTTLPR genotype where the short (S), relative to long (L) allele, corresponds with greater amygdala activation. However, the impact of genotype on insula to threat in SAD is not known. During functional MRI, 34 SAD patients and 28 healthy controls completed a perceptual assessment task comprising angry, fear, and happy faces. Results showed no diagnostic group differences in limbic/paralimbic regions but within SAD, greater insula, but not amygdala, activation to fearful faces was observed in patients with SS genotype compared with LaLa genotype. Findings indicate genotype influenced insula activation to threat in SAD.

Unintentionally retained items feature prominently among surgical "never events." Our knowledge of these rare occurrences, including natural history and intraoperative safety omission or variance (SOV) profile, is limited. We sought to bridge existing knowledge gaps by presenting a secondary analysis of a multicenter study focused on these important aspects of retained surgical items (RSIs).This is a post hoc analysis of results from a multicenter retrospective study of RSIs between January 2003 and December 2009. After excluding previously reported intravascular RSIs (n = 13), a total of 71 occurrences were analyzed for (1) item location and type; (2) time to presentation and/or discovery; (3) presenting signs and symptoms; (4) procedure and incision characteristics; (5) pathology reports; and (6) patterns of SOVs abstracted from medical and operative records. These SOV were then grouped into individual vs team errors and single- vs multifactorial occurrences.Among 71 cases, there were 48 women and 23 men. Mean patient age was 49.7 ± 17.5 years (range 19 to 83 years). Mortality was 4 of 71 (5.63%, only 1 attributable to RSI). Twelve cases (16.9%) occurred at nonparticipating referring hospitals. Most RSI procedures (62%) occurred on the day of hospital admission. The median time from index RSI case to retained item removal was 2 days (range1 to3,600 days, n = 63). Abdominal RSIs predominated, and plain radiography was the most common identification method. Most RSIs removed early (24 hours, n = 23) were asymptomatic. The most common clinical/diagnostic findings in the remaining group were focal pain (n = 22), abscess/fluid collection (n = 18), and mass (n = 8). Most common pathology findings included exudative reaction (n = 22), fibrosis (n = 17), and purulence/abscess (n = 15). On detailed review of intraprocedural events, most RSI cases were found to involve team/system errors (50 of 71) and 2 or more SOVs (37 of 71). Isolated human error was seen in less than 10% of cases.The finding that most operations complicated by RSIs were found to involve team/system errors and 2 or more SOVs emphasizes the importance of team safety training. The observation that early RSI removal minimizes patient morbidity and symptoms highlights the need for prompt RSI identification and treatment. The incidence of inflammation-related findings increases significantly with longer retention periods.

International audience; Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

In search of a standardized noninvasive assessment of intravascular volume status, we prospectively compared the sonographic inferior vena cava collapsibility index (IVC-CI) and central venous pressures (CVPs). Our goals included the determination of CVP behavior across clinically relevant IVC-CI ranges, examination of unitary behavior of IVC-CI with changes in CVP, and estimation of the effect of positive end-expiratory pressure (PEEP) on the IVC-CI/CVP relationship.Prospective, observational study was performed in surgical/medical intensive care unit patients between October 2009 and July 2013. Patients underwent repeated sonographic evaluations of IVC-CI. Demographics, illness severity, ventilatory support, CVP, and patient positioning were recorded. Correlations were made between CVP groupings (7, 7-12, 12-18, 19+) and IVC-CI ranges (25, 25-49, 50-74, 75+). Comparison of CVP (2-unit quanta) and IVC-CI (5-unit quanta) was performed, followed by assessment of per-unit ΔIVC-CI/ΔCVP behavior as well as examination of the effect of PEEP on the IVC-CI/CVP relationship.We analyzed 320 IVC-CI/CVP measurement pairs from 79 patients (mean [SD] age, 55.8 [16.8] years; 64.6% male; mean [SD] Acute Physiology and Chronic Health Evaluation II, 11.7 [6.21]). Continuous data for IVC-CI/CVP correlated poorly (R = 0.177, p0.01) and were inversely proportional, with CVP less than 7 noted in approximately 10% of the patients for IVC-CIs less than 25% and CVP less than 7 observed in approximately 85% of patients for IVC-CIs greater than or equal to 75%. Median ΔIVC-CI per unit CVP was 3.25%. Most measurements (361 of 320) were collected in mechanically ventilated patients (mean [SD] PEEP, 7.76 [4.11] cm H2O). PEEP-related CVP increase was approximately 2 mm Hg to 2.5 mm Hg for IVC-CIs greater than 60% and approximately 3 mm Hg to 3.5 mm Hg for IVC-CIs less than 30%. PEEP also resulted in lower IVC-CIs at low CVPs, which reversed with increasing CVPs. When IVC-CI was examined across increasing PEEP ranges, we noted an inverse relationship between the two variables, but this failed to reach statistical significance.IVC-CI and CVP correlate inversely, with each 1 mm Hg of CVP corresponding to 3.3% median ΔIVC-CI. Low IVC-CI (25%) is consistent with euvolemia/hypervolemia, while IVC-CI greater than 75% suggests intravascular volume depletion. The presence of PEEP results in 2 mm Hg to 3.5 mm Hg of CVP increase across the IVC-CI spectrum and lower collapsibility at low CVPs. Although IVC-CI decreased with increasing degrees of PEEP, this failed to reach statistical significance. While this study represents a step forward in the area of intravascular volume estimation using IVC-CI, our findings must be applied with caution owing to some methodologic limitations.Diagnostic study, level III. Prognostic study, level III.