Search

Traumatic brain injury (TBI) in children

OBJECTIVE: Acetaminophen is a common cause of intentional and inadvertent overdoses among children and adolescents worldwide. Little is known about characteristics and clinical outcomes of these youths. The primary goal of this naturalistic study was to describe the psychiatric characteristics, medical management, outcomes, and dispositions of children and adolescents evaluated for excessive acetaminophen exposure. METHODS: The Rochester Epidemiology Project database was searched for all patients ages 0–18 treated for excessive acetaminophen exposure in Olmsted County, Minnesota, during a 7-year period (2004–2010). Demographic factors, overdose intentionality, medical and psychiatric treatment, mental health and addiction history, and disposition from the emergency department (ED) were documented. RESULTS: Of 110 cases of acetaminophen overdose (89 female patients and 21 male patients), 97 (88%) were intentional and 13 (12%) were unintentional. Fifteen patients (14%) were discharged from the ED, and 69 (63%) required admission to a medical unit. Sixty-four (59%) received N-acetylcysteine. Ninety-eight (89%) were evaluated by psychiatry, and 80 (73%) were admitted for psychiatric hospitalization. Most had at least one psychiatric diagnosis, most commonly depression (55%); 22 (20%) had a prior suicide attempt. Substance use was common, notably alcohol dependence (N=16, 15%), alcohol abuse (N=18, 16%), and cannabis abuse (N=18, 16%). All survived and recovered without liver transplant. CONCLUSIONS: Among pediatric patients with acetaminophen overdoses, psychiatric comorbidities and substance use were common. Most received both inpatient medical and psychiatric treatment. Interventions that restrict acetaminophen access are needed for this population, as are suicide risk reduction interventions for delivery in emergency settings.

A benzo[6]annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC(90) = 1.45 μM and viral titer reduction (VTR) of 2.5 log at 10 μM with no observed cytotoxicity (CC(50) = 169 μM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity (EC(90) = 270 nM and VTR of 4.5 log at 10 μM) and improved liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage pathway.

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.

Lung fibrosis and tissue remodeling are features of chronic diseases such as severe asthma, idiopathic pulmonary fibrosis, and systemic sclerosis. However, fibrosis-targeted therapies are currently limited. We demonstrate in mouse models of allergen- and bleomycin-driven airway inflammation that neutralization of the TNF family cytokine TL1A through Ab blocking or genetic deletion of its receptor DR3 restricted increases in peribronchial smooth muscle mass and accumulation of lung collagen, primary features of remodeling. TL1A was found as a soluble molecule in the airways and expressed on the surface of alveolar macrophages, dendritic cells, innate lymphoid type 2 cells, and subpopulations of lung structural cells. DR3 was found on CD4 T cells, innate lymphoid type 2 cells, macrophages, fibroblasts, and some epithelial cells. Suggesting in part a direct activity on lung structural cells, administration of recombinant TL1A into the naive mouse airways drove remodeling in the absence of other inflammatory stimuli, innate lymphoid cells, and adaptive immunity. Correspondingly, human lung fibroblasts and bronchial epithelial cells were found to express DR3 and responded to TL1A by proliferating and/or producing fibrotic molecules such as collagen and periostin. Reagents that disrupt the interaction of TL1A with DR3 then have the potential to prevent deregulated tissue cell activity in lung diseases that involve fibrosis and remodeling.

What is known and objective Metabolic syndrome is a well-documented adverse effect of second-generation antipsychotics (SGAs). Patients with metabolic syndrome are at an increased risk of potentially fatal cardiovascular events, including myocardial infarction and stroke. This elevated risk prompted the creation of a national guideline on metabolic monitoring for patients on SGAs in 2004. However, monitoring practices remained low at our clinic. To address this concern, a clinical decision support system was developed to alert providers of monitoring requirements. The purpose of this study is to determine the effect of the best practice alert (BPA), and to assess the impact of provider and patient characteristics on metabolic laboratory (lab) order rates. Methods A retrospective chart review was conducted at a large outpatient psychiatric clinic. Data were collected from all adult patients who were prescribed an SGA and triggered the BPA (indicating lab monitoring is needed for the patient). Data collection included a variety of patient, provider and alert variables. The primary outcome was a composite of fasting blood glucose (FBG), haemoglobin A1c (HbA1c) and/or fasting lipid panel order rates. Secondary outcomes included the rate of valid response, which considered appropriate reasons for not ordering labs (ie monitoring already completed during recent primary care visit), as well as order rates of individual labs. Results and discussion Data from 1112 patients were collected and analysed. Patients with a thought disorder diagnosis had significantly more labs ordered than those without. No other patient factors affected order rates. Resident psychiatrists and nurse practitioners ordered significantly more labs and had significantly more valid responses than attending psychiatrists. An active alert, which fired during medication order entry, was associated with a higher rate of lab ordering and valid response compared to a passive alert, which fired whenever a prescribing healthcare provider opened the chart. What is new and conclusion Prescribers may associate metabolic syndrome with schizophrenia or with use of SGAs specifically in thought disorders, even though these medications pose a risk for all indications. Higher rates of monitoring by resident physicians may have been due to spending more time with patients during the encounter and in documentation. Lastly, the active BPA was an effective tool to increase metabolic monitoring in patients taking SGAs. Continued education on the importance of regular metabolic monitoring should be implemented for all providers.

Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.

Pulmonary fibrosis is one of the important causes of morbidity and mortality in fibroproliferative disorders such as systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding protein-5 (IGFBP-5) is a conserved member of the IGFBP family of proteins that is overexpressed in SSc and IPF lung tissues. In this study, we investigated the functional role of IGFBP-5 in the development of fibrosis in vivo using a transgenic model. We generated transgenic mice ubiquitously expressing human IGFBP-5 using CRISPR/Cas9 knock-in. Our data show that the heterozygous and homozygous mice are viable and express human IGFBP-5 (hIGFBP-5). Transgenic mice had increased expression of extracellular matrix (ECM) genes, especially Col3a1, Fn, and Lox in lung and skin tissues of mice expressing higher transgene levels. Histologic analysis of the skin tissues showed increased dermal thickness, and the lung histology showed subtle changes in the heterozygous and homozygous mice as compared with the wild-type mice. These changes were more pronounced in animals expressing higher levels of hIGFBP-5. Bleomycin increased ECM gene expression in wild-type mice and accentuated an increase in ECM gene expression in transgenic mice, suggesting that transgene expression exacerbated bleomycin-induced pulmonary fibrosis. Primary lung fibroblasts cultured from lung tissues of homozygous transgenic mice showed significant increases in ECM gene expression and protein levels, further supporting the observation that IGFBP-5 resulted in a fibrotic phenotype in fibroblasts. In summary, transgenic mice expressing human IGFBP-5 could serve as a useful animal model for examining the function of IGFBP-5 in vivo.

Background Everyday experiences with racial (RD) and weight discrimination (WD) are risk factors for chronic pain in ethnically diverse adults with obesity. However, the individual or combined effects of RD and WD on pain in adults with obesity is not well understood. There are gender differences and sexual dimorphisms in nociception and pain, but the effect of gender on relationships between RD, WD, and pain outcomes in ethnically diverse adults with obesity is unclear. Thus, the purposes of this study were to: 1) examine whether RD and WD are associated with pain intensity and interference, and 2) explore gender as a moderator of the associations between RD, WD, and pain. Methods This is a baseline data analysis from a randomized, controlled clinical trial of a lifestyle weight-management intervention. Eligible participants were English or Spanish-speaking (ages 18–69 years) and had either a body mass index of ≥30 kg/m2 or ≥ 25 kg/m2 with weight-related comorbidity. RD and WD were measured using questions derived from the Experiences of Discrimination questionnaire (EOD). Pain interference and intensity were measured using the PROMIS 29 adult profile V2.1. Linear regression models were performed to determine the associations between WD, RD, gender, and pain outcomes. Results Participants (n = 483) reported mild pain interference (T-score: 52.65 ± 10.29) and moderate pain intensity (4.23 ± 3.15). RD was more strongly associated with pain interference in women (b = .47, SE = .08, p b = .14, SE = .07, p = .06). Also, there were no significant interaction effects between RD and gender on pain intensity, or between WD and gender on pain interference or pain intensity. Conclusions Pain is highly prevalent in adults with obesity, and is impacted by the frequencies of experiences with RD and WD. Further, discrimination against adults with obesity and chronic pain could exacerbate existing racial disparities in pain and weight management. Asking ethnically diverse adults with obesity about their pain and their experiences of RD and WD could help clinicians make culturally informed assessment and intervention decisions that address barriers to pain relief and weight loss. Trial registration NCT03006328

Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl(−)/H(+) exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.

Phenotypic changes in lung fibroblasts are believed to contribute to the development of Idiopathic Pulmonary Fibrosis (IPF), a progressive and fatal lung disease. Long intergenic non-coding RNAs (lincRNAs) have been identified as novel regulators of gene expression and protein activity. In non-stimulated cells, we observed reduced proliferation and inflammation but no difference in the fibrotic response of IPF fibroblasts. These functional changes in non-stimulated cells were associated with changes in the expression of the histone marks, H3K4me1, H3K4me3 and H3K27ac indicating a possible involvement of epigenetics. Following activation with TGF-β1 and IL-1β, we demonstrated an increased fibrotic but reduced inflammatory response in IPF fibroblasts. There was no significant difference in proliferation following PDGF exposure. The lincRNAs, LINC00960 and LINC01140 were upregulated in IPF fibroblasts. Knockdown studies showed that LINC00960 and LINC01140 were positive regulators of proliferation in both control and IPF fibroblasts but had no effect upon the fibrotic response. Knockdown of LINC01140 but not LINC00960 increased the inflammatory response, which was greater in IPF compared to control fibroblasts. Overall, these studies demonstrate for the first time that lincRNAs are important regulators of proliferation and inflammation in human lung fibroblasts and that these might mediate the reduced inflammatory response observed in IPF-derived fibroblasts.

Contains fulltext : 202800.pdf (Publisher’s version ) (Open Access) SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.

Despite comprising the largest proportion of the “lesbian, gay, and bisexual (LGB)” population, research focusing on the unique health concerns and needs of bisexual individuals is relatively scarce. While health disparities are increasingly well documented among lesbian, gay, bisexual, and transgender (LGBT) individuals relative to their heterosexual and cisgender counterparts, gaps remain in our basic understanding of how health status, behaviors, and outcomes vary within these groups, especially bisexual individuals. The lack of specified research on bisexual health is even more curious given that, when separated from both heterosexual and gay/lesbian individuals, bisexual individuals consistently report higher rates of a wide range of negative health outcomes, including mood and anxiety disorders, substance use, suicidality, as well as disparities related to healthcare access and utilization. Indeed, in scientific research, mass media, and in public health interventions, bisexual individuals remain relatively invisible. This Special Section represents an effort to shed light on a new generation of quantitative, qualitative, and mixed methods research studies that examine health-related concerns, outcomes, and intervention opportunities specifically among diverse samples of bisexual individuals from a variety of social and cultural contexts. The research herein focuses on intersections of multiple identities, the development of new measures, the use of large national data sets, and diverse groups of self-identified bisexual men (who tend to be least visible in health research). Findings from these studies will significantly advance our knowledge of factors associated with health disparities, as well as health and wellbeing more generally, among bisexual individuals and will help to inform directions for future health promotion research and intervention efforts.

Pericytes are key regulators of the microvasculature through their close interactions with the endothelium. However, pericytes play additional roles in tissue homeostasis and repair, in part by transitioning into myofibroblasts. Accumulation of myofibroblasts is a hallmark of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). To understand the contribution and role of pericytes in human lung fibrosis, we isolated these cells from non-IPF control and IPF lung tissues based on expression of platelet-derived growth factor receptor-β (PDGFR-β), a common marker of pericytes. When cultured in a specialized growth medium, PDGFR-β+ cells retain the morphology and marker profile typical of pericytes. We found that IPF pericytes migrated more rapidly and invaded a basement membrane matrix more readily than control pericytes. Exposure of cells to transforming growth factor-β, a major fibrosis-inducing cytokine, increased expression of α-smooth muscle actin and extracellular matrix genes in both control and IPF pericytes. Given that pericytes are uniquely positioned in vivo to respond to danger signals of both systemic and tissue origin, we stimulated human lung pericytes with agonists having pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Both control and IPF lung pericytes increased expression of proinflammatory chemokines in response to specific PAMPs and DAMPs released from necrotic cells. Our results suggest that control and IPF lung pericytes are poised to react to tissue damage, as well as microbial and fibrotic stimuli. However, IPF pericytes are primed for migration and matrix invasion, features that may contribute to the function of these cells in lung fibrosis.

Researchers posit that negative attitudes, prejudice, and discrimination (i.e., binegativity) from heterosexual and gay/lesbian individuals may contribute to health disparities among bisexual individuals relative to heterosexual and gay/lesbian individuals. Recent studies have focused on gay, lesbian, and heterosexual people’s (e.g., “others”) attitudes toward bisexual people. No studies have investigated how bisexual individuals perceive others’ attitudes toward bisexual people, which are generally known as “meta-perceptions.” As part of the 2015 National Survey of Sexual Health and Behavior (NSSHB), we collected data from a nationally representative probability sample of 2,999 adults, including from a subsample of 33 men and 61 women self-identified as “bisexual.” The Bisexualities: Indiana Attitudes Scale–bisexual (BIAS-b), a modified 5-item scale assessing bisexual people’s perceptions of others’ attitudes toward bisexual individuals, was included and was followed by an open-ended textbox question. Quantitative scale data were analyzed using descriptive and gamma regression methods. Two coders thematically analyzed the open-ended textbox data. The internal consistency of the BIAS-b was high (Cronbach’s α = 0.85). An exploratory factor analysis supported a one-factor solution. Participants responded to statements regarding others’ attitudes toward them as bisexual people, including the domains of confusion, HIV/STD risk, incapability of monogamy, promiscuity, and instability (“just a phase”). Participants’ textbox descriptions largely aligned with these five domains, with the exception of HIV/STD risk. Additionally, some participants reported others’ positive perceptions of them as bisexual individuals. In sum, we observed a range of meta-perceptions, primarily neutral to negative, but also including some relatively positive. These results show the need for interventions to promote acceptance of bisexual individuals among heterosexual and gay/lesbian individuals.

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by overproduction of extracellular matrix (ECM) and multiorgan fibrosis. Animal studies pointed to bone marrow-derived cells as a potential source of pathological ECM-producing cells in immunofibrotic disorders. So far, involvement of monocytes and macrophages in the fibrogenesis of SSc remains poorly understood. Methods and Results Immunohistochemistry analysis showed accumulation of CD14+ monocytes in the collagen-rich areas, as well as increased amount of alpha smooth muscle actin (αSMA)-positive fibroblasts, CD68+ and mannose-R+ macrophages in the heart and lungs of SSc patients. The full genome transcriptomics analyses of CD14+ blood monocytes revealed dysregulation in cytoskeleton rearrangement, ECM remodeling, including elevated FN1 (gene encoding fibronectin) expression and TGF-β signalling pathway in SSc patients. In addition, single cell RNA sequencing analysis of tissue-resident CD14+ pulmonary macrophages demonstrated activated profibrotic signature with the elevated FN1 expression in SSc patients with interstitial lung disease. Peripheral blood CD14+ monocytes obtained from either healthy subjects or SSc patients exposed to profibrotic treatment with profibrotic cytokines TGF-β, IL-4, IL-10, and IL-13 increased production of type I collagen, fibronectin, and αSMA. In addition, CD14+ monocytes co-cultured with dermal fibroblasts obtained from SSc patients or healthy individuals acquired a spindle shape and further enhanced production of profibrotic markers. Pharmacological blockade of the TGF-β signalling pathway with SD208 (TGF-β receptor type I inhibitor), SIS3 (Smad3 inhibitor) or (5Z)-7-oxozeaenol (TGF-β-activated kinase 1 inhibitor) ameliorated fibronectin levels and type I collagen secretion. Conclusions Our findings identified activated profibrotic signature with elevated production of profibrotic fibronectin in CD14+ monocytes and CD14+ pulmonary macrophages in SSc and highlighted the capability of CD14+ monocytes to acquire a profibrotic phenotype. Taking together, tissue-infiltrating CD14+ monocytes/macrophages can be considered as ECM producers in SSc pathogenesis.

Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification.In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months.During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months.In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).

WHAT IS KNOWN ON THE SUBJECT?: Established research from the United States and other Western countries has found that lesbian, gay, bisexual and transgender (LGBT) populations are at an elevated risk for suicide. Suicidality among LGBT individuals is understudied in Thailand and other Asian countries, warranting additional research to better understand risk factors and to create effective treatment and suicide prevention interventions. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: The study examined rates and predictors of suicidality in Thai LGBT adults. Study findings suggest that general (e.g. stress and loneliness) and minority stressors (e.g. discrimination and victimization) played important roles in predicting lifetime and past-year suicidal ideation, while socio-demographic and health-related factors (e.g. living in high poverty area and having chronic diseases) were associated with suicide attempts among LGBT individuals. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Changes in the nursing curriculum and continuing education resources are needed to improve knowledge and core competencies in the mental health and treatment needs of LGBT individuals in Thailand. Among LGBT serving practitioners, routine assessment of suicidality is needed to increase the early identification and treatment of individual at risk for suicidal behaviours. Standardized measures of sexual orientation and gender identity should be included in all patient intake forms. In conducting research on strategies to improve mental health outcomes among LGBT populations, standardized measures of sexual orientation/gender identity and minority-specific stressors should be used. Suicide prevention interventions aimed at reducing general and minority stress among LGBT populations should be a priority in mental health nursing. ABSTRACT INTRODUCTION: A large and rigorous body of research in the United States has demonstrated that lesbian, gay, bisexual and transgender (LGBT) populations are at an elevated risk for suicide. However, scant research aimed at understanding the rates and predictors for suicidality among Thai LGBT individuals exists. AIM To examine rates and predictors of suicidality among Thai LGBT adults (N = 411). METHOD Data collection was conducted via online and in-person surveys. Guided by the Minority Stress Model, standardized measures of demographics, health-related factors, general and minority-specific stressors and suicidality were completed. RESULTS Thirty-nine per cent of participants reported lifetime suicidal ideation, 19.0% past 12-month suicidal ideation and 13.1% lifetime suicide attempts. Lifetime suicidal ideation was associated with higher levels of social discrimination, stress, loneliness and chronic disease (OR = 1.12, 1.16, 2.75, and 1.46, p ≤ .05, R2 = 0.327). Past-year suicidal ideation was associated with victimization, stress, loneliness and being a former smoker (OR = 1.52, 1.20, 2.34, and 4.89, p

Polyunsaturated fatty acids (PUFAs) are critical for brain development and have been linked with neurodevelopmental outcomes. We conducted a population-based case-control study in California to examine the association between PUFAs measured in midpregnancy serum samples and autism spectrum disorder (ASD) in offspring. ASD cases (n = 499) were identified through the California Department of Developmental Services and matched to live-birth population controls (n = 502) on birth month, year (2010 or 2011), and sex. Logistic regression models were used to examine crude and adjusted associations. In secondary analyses, we examined ASD with and without co-occurring intellectual disability (ID; n = 67 and n = 432, respectively) and effect modification by sex and ethnicity. No clear patterns emerged, though there was a modest inverse association with the top quartile of linoleic acid level (highest quartile vs. lowest: adjusted odds ratio = 0.74, 95% confidence interval: 0.49, 1.11; P for trend = 0.10). Lower levels of total and ω-3 PUFAs were associated with ASD with ID (lowest decile of total PUFAs vs. deciles 4–7: adjusted odds ratio = 2.78, 95% confidence interval: 1.13, 6.82) but not ASD without ID. We did not observe evidence of effect modification by the factors examined. These findings do not suggest a strong association between midpregnancy PUFA levels and ASD. In further work, researchers should consider associations with ASD with ID and in other time windows.

We conducted a population-based case-control study to examine newborn polyunsaturated fatty acid (PUFA) levels in association with autism spectrum disorder (ASD) and assess PUFA correlation across two time points. ASD cases (n = 200) were identified through the Department of Developmental Services and matched to live-birth population controls (n = 200) on birth month, year (2010-2011), and sex. Nonesterified PUFAs were measured by isotope dilution liquid chromatography-high resolution mass spectrometry from archived newborn dried blood spots and maternal mid-pregnancy serum samples. Crude and adjusted conditional logistic regression models were used to examine the association between neonatal PUFA levels, categorized in quartiles and according to distributional extremes, and ASD. Cubic splines were utilized to examine nonlinear relationships between continuous neonatal PUFAs and ASD. The correlation between neonatal and maternal levels was examined using Pearson correlation coefficients. In adjusted analyses of neonatal PUFA levels, no clear trends emerged, though there was an elevated odds ratio of ASD for the third quartile of linoleic acid, relative to the first (adjusted odds ratio = 2.49, 95% confidence interval: 1.31, 4.70). Cubic spline analysis suggested a nonlinear association between linoleic acid and ASD, though this was not robust to sensitivity analyses. While individual PUFAs were significantly correlated with one another within a given time point, aside from docohexaseanoic acid, PUFAs were not correlated across maternal and neonatal samples. Overall, our findings do not support an association between neonatal PUFA levels and ASD. Future work should confirm and expand these findings by examining associations with phenotypic subgroups and considering PUFAs in other time points. LAY SUMMARY: In this study, we examined whether levels of fats known as polyunsaturated fatty acids, measured in newborns, were related to later child diagnosis of autism spectrum disorder (ASD). Overall, we did not find strong evidence for hypothesized reduction in risk of ASD based on newborn levels of these fats. Future studies in larger samples and considering other time points may be useful to explain whether these fats are important in brain development related to ASD. Autism Res 2020, 13: 1601-1613. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Background Prenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD). This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results. Methods To provide an orthogonal measure of fetal exposure, this study used meconium, the first stool of a newborn, to measure prenatal androgen exposure from infants in the Early Autism Risk Longitudinal Investigation (EARLI). EARLI is a familial-enriched risk cohort that enrolled pregnant mothers who already had a child with an ASD diagnosis. In the younger child, we investigated the association between meconium unconjugated (u) and total (t) concentrations of major androgens testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4), and ASD-related traits at 12 and 36 months of age. Traits were measured at 12 months with Autism Observation Scale for Infants (AOSI) and at 36 months with total score on the Social Responsiveness Scale (SRS). One hundred and seventy children had meconium and AOSI, 140 had meconium and SRS, and 137 had meconium and both AOSI and SRS. Results Separate robust linear regressions between each of the log-transformed androgens and log-transformed SRS scores revealed three-way interaction between sex of the child, sex of the proband, and testosterone concentration. In the adjusted analyses, t-T, u-A4, and u-DHEA (P ≤ 0.01) were positively associated with AOSI scores, while u-T (P = 0.004) and u-DHEA (P = 0.007) were positively associated with SRS total score among females with female probands (n = 10). Additionally, higher concentrations of u-T (P = 0.01) and t-T (P = 0.01) predicted higher SRS total score in males with male probands (n = 63). Limitations Since we explored three-way interactions, this resulted in a limited sample size for some analyses. This study was from an enriched-risk cohort which may limit generalizability, and this study used ASD-assessment scales as outcomes instead of diagnostic categories. Additionally, the novel use of meconium in this study limits the ability to compare the results in this cohort to others due to the paucity of research on meconium. Conclusions This study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies.

Contains fulltext : 218305.pdf (Publisher’s version ) (Closed access) BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor beta signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.

Schaaf‐Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader‐Willi critical region 15q11‐15q13. SYS is a neurodevelopmental disorder that has clinical overlap with Prader‐Willi Syndrome in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence. Here, we describe the phenotype of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2. This cohort includes 43 individuals that have been reported previously, as well as 35 newly identified individuals with confirmed pathogenic genetic variants. We emphasize that intellectual disability/developmental delay, autism spectrum disorder, neonatal hypotonia, infantile feeding problems, and distal joint contractures are the most consistently shared features of patients with SYS. Our results also indicate that there is a marked prevalence of infantile respiratory distress, gastroesophageal reflux, chronic constipation, skeletal abnormalities, sleep apnea, and temperature instability. While there are many shared features, patients with SYS are characterized by a wide phenotypic spectrum, including a variable degree of intellectual disability, language development, and motor milestones. Our results indicate that the variation in phenotypic severity may depend on the specific location of the truncating mutation, suggestive of a genotype–phenotype association. This evidence may be useful in both prenatal and pediatric genetic counseling.

This report describes the development and evaluation of an interprofessional pilot course aimed at health science students. The course was developed through collaboration of three health professions: Dentistry, Kinesiology, and Pharmacy. The coursework comprised of traditional lecture-based learning, interprofessional experiential education through four on-site visits at two area clinics that participate in team-based care, four student self-reflections following each site visit, and demonstration of interprofessional education and collaboration (IPEC) competencies through student evaluation of current interprofessional care at those existing clinics with a component for key improvement intervention. The study aims include evaluating both the course's effectiveness and quality in increasing student preparedness for interprofessional practice and its ability to enhance collaboration between health professions at two area clinics. Methods of evaluation include the Interprofessional Collaborative Competency Attainment Survey (ICCAS) instrument, pre- and post- course surveys, and course evaluation survey. The results show that students felt their knowledge and skills increased across the four IPEC core competency domains: interprofessional communication, values and ethics, roles and responsibilities, and team and teamwork. We suggest that using an integrated course framework is an effective measure in enhancing interprofessional education (IPE) outcomes.

Mental health inequities among bisexual and lesbian women are well-documented. Compared to heterosexual women, both bisexual and lesbian women are more likely to report lifetime depressive disorders, with bisexual women often faring the worst on mental health outcomes. Risk factors for depression, such as victimization in childhood and adulthood, are also more prevalent among bisexual women. Less is known about the intersection of racial/ethnic and sexual minority identities, and how depression and victimization may differ across these multiple, co-occurring identities. Data were from Wave 3 of the Chicago Health and Life Experiences of Women study, an 18-year, community-based longitudinal study of sexual minority women's health. We constructed a six-category "intersection" variable based on sexual identity and race/ethnicity to examine group differences in lifetime depression and victimization. We tested childhood and adult victimization as moderators of lifetime depression (n = 600). A majority (58.2%) of the total sample met criteria for lifetime depression. When considering the intersection of race/ethnicity and sexual identity, Black bisexual and Black lesbian women had significantly lower odds of depression than White lesbian women, despite their higher reports of victimization. Latina bisexual and lesbian women did not differ from White lesbians on depression. Victimization did not moderate the association between the intersection variable and depression. More research is needed to better understand risk and protective factors for depression among racially/ethnically diverse sexual minority women (SWM). We highlight the need to deliberately oversample SWM of color to accomplish this goal.

BACKGROUND: Pediatric use of second-generation antipsychotics, or neuroleptics, has increased over the past decade. Neuroleptic use can have significant and lasting adverse neurologic, metabolic, and cardiovascular effects. In the current literature, neuroleptic prescribing and monitoring is described in outpatient settings, with little description of inpatient pediatric practice. In this study, we are the first to explore prescribing and monitoring in inpatient pediatrics, highlighting similarities and differences in practice between pediatric medicine and psychiatry. METHODS: This retrospective study included patients RESULTS: Factors associated with improved neuroleptic monitoring included longer length of stay and evidence of an adverse drug effect. Clearly specified indication for use was associated with improved neuroleptic monitoring. Although neuroleptic initiation during admission had improved indication documentation and monitoring practices compared with initiation before admission, a significant gap exists between inpatient psychiatry and medical settings in adverse drug effect monitoring, particularly extrapyramidal symptom monitoring and lipid collection. CONCLUSIONS: In our study, we describe current practice in the use and monitoring of neuroleptics in inpatient pediatric medical and psychiatric settings. In this study, we suggest that the use of neuroleptics in inpatient pediatrics, particularly inpatient medical settings, is conducted with suboptimal monitoring and, at times, without clear documented indication.

Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-β1 (TGF-β1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF.We aimed to define an association between mtDNA and fibroblast responses in IPF.We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-β1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects.Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-β1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival.These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.

Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblast phenotype has prevented the development of targeted therapies for IPF. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 (CD44 variant containing exon 6), which enhances the TGFβ1 autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. NADPH oxidase 4 (NOX4) enzyme, which catalyzes the reduction of O2 to hydrogen peroxide (H2O2), has been implicated in the cardiac and lung myofibroblast phenotype. However, whether CD44V6 regulates NOX4 to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how TGF-β-1-induced CD44V6 regulates the NOX4/reactive oxygen species (ROS) signaling that mediates the myofibroblast differentiation. Specifically, we found that NOX4/ROS regulates hyaluronan synthesis and the transcription of CD44V6 via an effect upon AP-1 activity. Further, CD44V6 is part of a positive-feedback loop with TGFβ1/TGFβRI signaling that acts to increase NOX4/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both NOX4 and CD44v6 are up-regulated in the lungs of mice subjected to experimental lung injury and in cases of human IPF. Genetic (CD44v6 shRNA) or a small molecule inhibitor (CD44v6 peptide) targeting of CD44v6 abrogates fibrogenesis in murine models of lung injury. These studies support a function for CD44V6 in lung fibrosis and offer proof of concept for therapeutic targeting of CD44V6 in lung fibrosis disorders.

Patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) continue to have an unacceptably high mortality rate despite the progress achieved with pulmonary arterial vasodilator therapies.We sought to determine whether SSc-PAH is a clinically distinct pulmonary vascular disease phenotype when compared with idiopathic pulmonary arterial hypertension (IPAH) on the basis of progression of echocardiographic right ventricular (RV) dysfunction.Retrospective analysis of echocardiographic data in 13 patients with SSc-PAH and 11 patients with IPAH was used to delineate the progression of RV dysfunction during single or combination pulmonary arterial vasodilator therapy. All patients had right heart catheterization-confirmed pulmonary arterial hypertension as well as complete baseline (at the time of diagnosis) and follow-up (most recent) echocardiograms. We excluded patients with significant scleroderma-associated interstitial lung disease. Adjusting for time of follow-up and disease duration, we performed mixed model regression analyses comparing the changes between the two groups for different echocardiographic variables: tricuspid annular plane systolic excursion, tricuspid regurgitation jet velocity, right atrial area, and RV diameter.The mean ages for the SSc-PAH and IPAH groups were 60.8 and 48.2 years, respectively. The mean follow-up periods for the two groups were 3.8 and 1.95 years, respectively. Tricuspid annular plane systolic excursion did not improve in patients with SSc-PAH, whereas it increased in the patients with IPAH (-0.38 mm, P = 0.87; vs. +5.6 mm, P = 0.02). The other echocardiographic variables showed a trend toward worsening in the SSc-PAH group and improvement in the IPAH group.Our results indicate that, in patients with SSc-PAH, echocardiographic RV function does not improve over time compared with that of patients with IPAH, despite institution of pulmonary artery vasodilator therapies.

Diversity initiatives in U.S. medical education, following the passage of the Civil Rights Act of 1964, were geared toward increasing the representation of African Americans-blacks born in the United States whose ancestors suffered under slavery and Jim Crow laws. Over time, blacks and, subsequently, underrepresented minorities in medicine (URMs), became a proxy for African Americans, Puerto Ricans, Mexican Americans, and Native Americans, thus obscuring efforts to identify and recruit specifically African Americans. Moreover, demographic shifts resulting from the recent immigration of black people from Africa and the Caribbean have both expanded the definition of "African American medical students" and shifted the emphasis from those with a history of suffering under U.S. oppression and poverty to anyone who meets a black phenotype.Increasingly, research indicates that African American patients fare better when their physicians share similar historical and social experiences. While all people of color risk discrimination based on their skin color, not all have the lived experience of U.S.-based, systematic, multigenerational discrimination shared by African Americans. In the high-stakes effort to increase URM representation in medical school classes, admissions committees may fail to look beyond the surface of phenotype, thus missing the original intent of diversity initiatives while simultaneously conflating all people of color, disregarding their divergent historical and social experiences. In this Perspective, the authors contend that medical school admissions committees must show greater discernment in their holistic reviews of black applicants if historical wrongs and continued underrepresentation of African Americans in medicine are to be redressed.

Background: Studies show that sexual minority women (SMW) report more hazardous alcohol use patterns and higher rates of tobacco use than exclusively heterosexual women. Despite the public ...

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

Background Systemic sclerosis (SSc) is a rare autoimmune fibrosing disease with an incompletely understood genetic and non-genetic etiology. Defining its etiology is important to allow the development of effective predictive, preventative, and therapeutic strategies. We conducted this epigenomic study to investigate the contributions of DNA methylation to the etiology of SSc while minimizing confounding due to genetic heterogeneity. Methods Genomic methylation in whole blood from 27 twin pairs discordant for SSc was assayed over 450 K CpG sites. In silico integration with reported differentially methylated cytosines, differentially expressed genes, and regulatory annotation was conducted to validate and interpret the results. Results A total of 153 unique cytosines in limited cutaneous SSc (lcSSc) and 266 distinct sites in diffuse cutaneous SSc (dcSSc) showed suggestive differential methylation levels in affected twins. Integration with available data revealed 76 CpGs that were also differentially methylated in blood cells from lupus patients, suggesting their role as potential epigenetic blood biomarkers of autoimmunity. It also revealed 27 genes with concomitant differential expression in blood from SSc patients, including IFI44L and RSAD2. Regulatory annotation revealed that dcSSc-associated CpGs (but not lcSSc) are enriched at Encyclopedia of DNA Elements-, Roadmap-, and BLUEPRINT-derived regulatory regions, supporting their potential role in disease presentation. Notably, the predominant enrichment of regulatory regions in monocytes and macrophages is consistent with the role of these cells in fibrosis, suggesting that the observed cellular dysregulation might be, at least partly, due to altered epigenetic mechanisms of these cells in dcSSc. Conclusions These data implicate epigenetic changes in the pathogenesis of SSc and suggest functional mechanisms in SSc etiology. Electronic supplementary material The online version of this article (10.1186/s13148-019-0652-y) contains supplementary material, which is available to authorized users.

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment. ispartof: EPILEPSIA vol:60 issue:3 pages:406-418 ispartof: location:United States status: published

OBJECTIVES: To enhance depression care by improving medication information available prior to initial patient consultations. EXPERIMENTAL DESIGN AND SAMPLE: Single-center, with intervention delivered to all new patient referrals at a tertiary care depression clinic. Trained pharmacy students utilizing a standard script prior to the first consultation visit conducted a medication review and depression treatment telephone assessment. RESULTS: From 225 individuals contacted once by phone in the week prior to scheduled initial consultation, 141 (62.7%) were reached and 113 (50.2%) completed the full phone assessment. An average of 4–5 medication discrepancies were identified per respondent, of which one-third were considered potentially clinically significant and more than 96% of patients having at least one reported discrepancy. Individuals who completed the call were also more likely to attend the initial consultation. In the medical record, 55 of the 106 (51.9%) pharmacy notes were incorporated in the clinical assessment note. On survey, clinicians reported that access to the pharmacy note saved clinician time, with all prescribing clinicians indicating the pharmacy note significantly influenced subsequent medication recommendations. CONCLUSIONS: Telephone assessments conducted by pharmacy students prior to an initial depression clinic consultation was associated with higher consultation attendance, identified a large number of medication discrepancies, were successfully reviewed and received by clinicians, potentially saved clinician time, and influenced subsequent medication prescribing.

Importance Electronic cigarettes (e-cigarettes) for smoking cessation remain controversial. Objective To evaluate e-cigarettes with individual counseling for smoking cessation. Design, Setting, and Participants A randomized clinical trial enrolled adults motivated to quit smoking from November 2016 to September 2019 at 17 Canadian sites (801 individuals screened; 274 ineligible and 151 declined). Manufacturing delays resulted in early termination (376/486 participants, 77% of target). Outcomes through 24 weeks (March 2020) are reported. Interventions Randomization to nicotine e-cigarettes (n = 128), nonnicotine e-cigarettes (n = 127), or no e-cigarettes (n = 121) for 12 weeks. All groups received individual counseling. Main Outcomes and Measures The primary end point was point prevalence abstinence (7-day recall, biochemically validated using expired carbon monoxide) at 12 weeks, changed from 52 weeks following early termination. Participants missing data were assumed to be smoking. The 7 secondary end points, examined at multiple follow-ups, were point prevalence abstinence at other follow-ups, continuous abstinence, daily cigarette consumption change, serious adverse events, adverse events, dropouts due to adverse effects, and treatment adherence. Results Among 376 randomized participants (mean age, 52 years; 178 women [47%]), 299 (80%) and 278 (74%) self-reported smoking status at 12 and 24 weeks, respectively. Point prevalence abstinence was significantly greater for nicotine e-cigarettes plus counseling vs counseling alone at 12 weeks (21.9% vs 9.1%; risk difference [RD], 12.8 [95% CI, 4.0 to 21.6]) but not 24 weeks (17.2% vs 9.9%; RD, 7.3 [95% CI, –1.2 to 15.7]). Point prevalence abstinence for nonnicotine e-cigarettes plus counseling was not significantly different from counseling alone at 12 weeks (17.3% vs 9.1%; RD, 8.2 [95% CI, –0.1 to 16.6]), but was significantly greater at 24 weeks (20.5% vs 9.9%; RD, 10.6 [95% CI, 1.8 to 19.4]). Adverse events were common (nicotine e-cigarette with counseling: 120 [94%]; nonnicotine e-cigarette with counseling: 118 [93%]; counseling only: 88 [73%]), with the most common being cough (64%) and dry mouth (53%). Conclusions and Relevance Among adults motivated to quit smoking, nicotine e-cigarettes plus counseling vs counseling alone significantly increased point prevalence abstinence at 12 weeks. However, the difference was no longer significant at 24 weeks, and trial interpretation is limited by early termination and inconsistent findings for nicotine and nonnicotine e-cigarettes, suggesting further research is needed. Trial Registration ClinicalTrials.gov Identifier:NCT02417467

This study examines the association between cannabis use and the hospital course of patients admitted to the psychiatric inpatient unit with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder. Many confounding variables potentially contribute to the clinical presentation of hospitalized patients in the psychiatric unit. Illicit drug use, in particular, has been associated with acute agitation, and questions can be raised as to what lasting effects drug use prior to admission may have throughout a patient's hospital stay.Subjects with a discharge diagnosis of bipolar disorder, schizophrenia, schizoaffective disorder, or psychosis not otherwise specified (N = 201) were retrospectively identified, and those with positive results of urine drug screen for cannabis on admission were compared to negative counterparts. Agitation and aggression were measured using an adaptation of the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC). These markers were also quantified by comparing charted episodes of restraint and seclusion and administration of as needed medications, such as benzodiazepines and antipsychotics.Positive urine drug screen results for cannabis was correlated with young (p = .001) males (p = .003) with bipolar disorder (p = .009) exhibiting active manic symptoms (p = .003) at the time of admission. Cannabis use was further associated with a shorter length of stay (p = .008), agitation triggering adapted PANSS-EC nursing assessments (p = .029), and oral medications as needed (p = .002) for agitation.Cannabis use, as defined by positive urine drug screen results, was more common in patients with bipolar disorder and was accompanied by a higher incidence of inpatient agitation. Although these patients also had short hospital lengths of stay, there was no clear relationship between level of agitation and length of stay across all patient groups. One possible explanation for patients with bipolar disorder experiencing short lengths of stay is that their source of agitation may be more closely related to a complex effect of cannabis use rather than a sole etiology of mental illness. Inpatient clinicians should be aware of patient cannabis use proximate to admission.

AIMS AND OBJECTIVES: This study draws on a life course perspective to evaluate in a sample of sexual minority women: (1) the relationship between age at reaching sexual identity milestones and risk of suicidal ideation, (2) developmental stages or stages of sexual identity development that represent greatest risk and (3) the relationship between age of reaching milestones and parental support. BACKGROUND: Research shows higher rates of suicidal ideation among sexual minority women than heterosexual women. Evidence suggests this is partly accounted for by risk factors including sexual identity development and parental support. However, it remains unclear whether there are stages of particularly high risk. DESIGN: This is a cross-sectional study. Data come from a prospective study of sexual minority women that used convenience and respondent-driven sampling methods. METHODS: Using logistic regression, we examined associations among age at sexual identity developmental milestones, parental support and suicidal ideation in a large (N = 820), ethnically diverse sample of sexual minority women. RESULTS: Compared with women who first wondered about their sexual identity in adulthood, those who first wondered in early, middle or late adolescence had greater odds of lifetime suicidal ideation. Younger age at subsequent milestones (first decided or first disclosed) was not associated with heightened risk of suicidal ideation. Parental support was independently associated with suicidal ideation. CONCLUSIONS: Findings suggest that where one is in the process of identifying as a sexual minority may be more important than age in understanding risk of suicidal ideation in this population. As individuals come to accept and integrate their sexual minority identity risks associated with younger age diminish. RELEVANCE TO CLINICAL PRACTICE: Nurses and other healthcare providers who work with youth should routinely ask about sexual orientation and suicidal ideation and be aware that youth in the earliest stages of coming out as sexual minority may be at particularly high risk of suicide.© 2016 John Wiley & Sons Ltd. Language: en

Focal dermal hypoplasia, or Goltz syndrome, is a highly variable X-linked dominant disorder with abnormalities in ectoderm and mesoderm derived tissues. Classic clinical features include patchy hypoplastic skin, split hand/foot deformities, and ocular malformations. We aimed to refine the understanding of the phenotypic spectrum and natural history of this disorder and now present multi-disciplinary clinical description and medical history review for 18 patients with focal dermal hypoplasia. All disease characteristics were analyzed and compiled in aggregate to aid in development of clinical diagnostic criteria. Medical history data unexpectedly revealed that the majority of patients (87%) had undergone tonsillectomy for obstructive sleep apnea, which exposed an important co-morbidity that is not well described in the literature, but managing physicians should be made aware of. Fifteen of the 18 patients underwent molecular sequencing of PORCN to detect heterozygous or mosaic mutations. Where no mutation was detected, we performed exon-targeted chromosomal microarray to evaluate for large deletions of the PORCN gene region. We detected a pathogenic genotype in 14 of 15 patients, including one novel chromosomal deletion and four novel PORCN sequence variants. Here, we provide phenotypic summary analysis of 18 patients with focal dermal hypoplasia and propose clinical diagnostic criteria.

Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are critical regulators of neuronal excitability, but less is known about their possible roles in synaptic plasticity and memory circuits. Here, we characterized the HCN gene organization, channel properties, distribution, and involvement in associative and nonassociative forms of learning in Aplysia californica. Aplysia has only one HCN gene, which codes for a channel that has many similarities to the mammalian HCN channel. The cloned acHCN gene was expressed in Xenopus oocytes, which displayed a hyperpolarization-induced inward current that was enhanced by cGMP as well as cAMP. Similarly to its homologs in other animals, acHCN is permeable to K(+) and Na(+) ions, and is selectively blocked by Cs(+) and ZD7288. We found that acHCN is predominantly expressed in inter- and motor neurons, including LFS siphon motor neurons, and therefore tested whether HCN channels are involved in simple forms of learning of the siphon-withdrawal reflex in a semiintact preparation. ZD7288 (100 μM) significantly reduced an associative form of learning (classical conditioning) but had no effect on two nonassociative forms of learning (intermediate-term sensitization and unpaired training) or baseline responses. The HCN current is enhanced by nitric oxide (NO), which may explain the postsynaptic role of NO during conditioning. HCN current in turn enhances the NMDA-like current in the motor neurons, suggesting that HCN channels contribute to conditioning through this pathway.

To compare the type and frequency of health care visits in the year before suicide between decedents and controls.Cases (n=86) were Olmsted County, Minnesota, residents whose death certificates listed "suicide" as the cause of death from January 1, 2000, through December 31, 2009. Each case had 3 age- and sex-matched controls (n=258). Demographic, diagnostic, and health care usage data were abstracted from medical records. Conditional logistic regression was used to analyze differences in the likelihood of having had psychiatric and nonpsychiatric visits in the year before death, as well as in visit types and frequencies 12 months, 6 months, and 4 weeks before death.Cases and controls did not significantly differ in having had any health care exposure (P=.18). Suicide decedents, however, had a significantly higher number of total visits in the 12 months, 6 months, and 4 weeks before death (all P.001), were more likely to have carried psychiatric diagnoses in the previous year (odds ratio [OR], 8.08; 95% CI, 4.31-15.17; P.001), and were more likely to have had outpatient and inpatient mental health visits (OR, 1.24; 95% CI, 1.05-1.47; P=.01 and OR 6.76; 95% CI, 1.39-32.96; P=.02, respectively). Only cases had had emergency department mental health visits; no control did.Given that suicide decedents did not differ from controls in having had any health care exposure in the year before death, the fact alone that decedents saw a doctor provides no useful information about risk. Compared with controls, however, decedents had more visits of all types including psychiatric ones. Higher frequencies of health care contacts were associated with elevated suicide risk.

Lung adenocarcinoma (LUAD) is the second most common cancer, affecting both men and women. Fibrosis is a hallmark of LUAD occurring throughout progression with excess production of extracellular matrix (ECM) components that lead to metastatic cell processes. Understanding the ECM cues that drive LUAD progression has been limited due to a lack of tools that can access and report on ECM components within the complex tumor microenvironment. Here, we test whether low-grade LUAD can be distinguished from normal lung tissue using a novel ECM imaging mass spectrometry (ECM IMS) approach. ECM IMS analysis of a tissue microarray with 20 low-grade LUAD tissues and 20 normal lung samples from 10 patients revealed 25 peptides that could discriminate between normal and low-grade LUAD using area under the receiver-operating curve (AUC) ≥0.7, P value ≤.001. Principal component analysis demonstrated that 62.4% of the variance could be explained by sample origin from normal or low-grade tumor tissue. Additional work performed on a wedge resection with moderately differentiated LUAD demonstrated that the ECM IMS analytical approach could distinguish LUAD spectral features from spectral features of normal adjacent lung tissue. Conventional liquid chromatography with tandem mass spectrometry (LC-MS/MS) proteomics demonstrated that specific sites of hydroxylation of proline (HYP) were a main collagen post translational modification that was readily detected in LUAD. A distinct peptide from collagen 3A1 modified by HYP was increased 3.5 fold in low-grade LUAD compared with normal lung tissue (AUC 0.914, P value

Background: Within free-standing academic medical centers, women continue to be underrepresented at upper faculty ranks and in leadership positions. A career development program (CDP) at the Medical University of South Carolina (MUSC) was implemented with the goal of improving the number of women in the upper ranks and in leadership positions. The CDP was initiated in 2013 as a 2-day program. Beginning in 2015, a half-day promotion-focused program was offered alternating with the 2-day program. Materials and Methods: The CDP has served ∼200 women from 2013 to 2017 and was evaluated for reaction and learning through postprogram surveys. Promotion success of ∼160 women who attended at least one of the programs through 2016 was assessed through an additional survey. Promotion information for ∼3000 faculty members during the same 2013-2016 period (post-CDP), as well as a 4-year time period before implementation of the CDP (pre-CDP), was collected using university-level personnel data. Results: The majority of CDP attendees (94%) indicated overall satisfaction with the program and would recommend the program to a colleague. Of the 137 CDP attendees still employed at MUSC in 2017, 50 had applied for promotion and 42 (84%) were successfully promoted. Among all the MUSC faculty, overall and rank-sepcific promotion rates for women and men were similar during the post-CDP time period and there was a significant increase in the promotion rate of women to Full Professor from pre-CDP to post-CDP time periods. Conclusions: CDP attendees were overwhelmingly satisfied with the program and were highly successful in being promoted. Since the overall university promotion rates of women and men were similar during the post-CDP time period and women are currently underrepresented at the upper faculty ranks, parity between men and women will likely not be achievable without additional programs to retain and/or recruit women in the upper ranks.

Previous work has established a significant increase in disengagement as students progress through secondary school. This work has also established that rates of disengagement appear to be higher among boys, leading to an increased focus on the underlying causes and factors associated with disengagement within this population. However, less is known about the patterns of disengagement exhibited by girls. Given that disengagement is consistently associated with negative personal and academic outcomes, it is important to more closely examine the disengagement trajectories of girls. Moreover, it critical to identify factors that buffer the effects of disengagement that are the most effective for girls. Classroom interpersonal support from teachers and peers have been identified as factors that are likely to mitigate disengagement among girls. The present investigation examined longitudinal data from Australian adolescent girls (N = 302, age range 12–16 years old). Latent growth modeling was used to examine the extent to which disengagement was increasing among secondary school girls in Australia, as well as the effects of teacher and peer social support in slowing this increase. The results showed that disengagement significantly increased across 3 years and that teacher support (but not peer support) was associated with a reduction in girls’ upward disengagement trajectories. The results of the current study provide much-needed insight about the developmental trajectories of disengagement among adolescent girls and the role of teachers in buffering these problematic trajectories.