Novel mutations in RASGRP2 encoding for CalDAG-GEFI abrogate Rap1 activation causing platelet dysfunction

In addition to mutations in ITG2B or ITGB3 genes that cause defective α(IIb)β(3) expression and/or function in Glanzmann’s thrombasthenia patients, platelet dysfunction can be a result of genetic variability in proteins that mediate inside-out activation of α(IIb)β(3). The RASGRP2 gene is strongly expressed in platelets and neutrophils, where its encoded protein CalDAG-GEFI facilitates the activation of Rap1 and subsequent activation of integrins. We used next-generation sequencing (NGS) and whole-exome sequencing (WES) to identify 2 novel function-disrupting mutations in RASGRP2 that account for bleeding diathesis and platelet dysfunction in 2 unrelated families. By using a panel of 71 genes, we identified a homozygous change (c.1142C>T) in exon 10 of RASGRP2 in a 9-year-old child of Chinese origin (family 1). This variant led to a p.Ser381Phe substitution in the CDC25 catalytic domain of CalDAG-GEFI. In 2 Spanish siblings from family 2, WES identified a nonsense homozygous variation (c.337C>T) (p.Arg113X) in exon 5 of RASGRP2. CalDAG-GEFI expression was markedly reduced in platelets from all patients, and by using a novel in vitro assay, we found that the nucleotide exchange activity was dramatically reduced in CalDAG-GEFI p.Ser381Phe. Platelets from homozygous patients exhibited agonist-specific defects in α(IIb)β(3) integrin activation and aggregation. In contrast, α- and δ-granule secretion, platelet spreading, and clot retraction were not markedly affected. Integrin activation in the patients’ neutrophils was also impaired. These patients are the first cases of a CalDAG-GEFI deficiency due to homozygous RASGRP2 mutations that are linked to defects in both leukocyte and platelet integrin activation

Barriers of mental health treatment utilization among first-year college students: First cross-national results from the WHO World Mental Health International College Student Initiative.

BACKGROUND: Although mental disorders and suicidal thoughts-behaviors (suicidal thoughts and behaviors) are common among university students, the majority of students with these problems remain untreated. It is unclear what the barriers are to these students seeking treatment. AIMS: The aim of this study is to examine the barriers to future help-seeking and the associations of clinical characteristics with these barriers in a cross-national sample of first-year college students. METHOD: As part of the World Mental Health International College Student (WMH-ICS) initiative, web-based self-report surveys were obtained from 13,984 first-year students in eight countries across the world. Clinical characteristics examined included screens for common mental disorders and reports about suicidal thoughts and behaviors. Multivariate regression models adjusted for socio-demographic, college-, and treatment-related variables were used to examine correlates of help-seeking intention and barriers to seeking treatment. RESULTS: Only 24.6% of students reported that they would definitely seek treatment if they had a future emotional problem. The most commonly reported reasons not to seek treatment among students who failed to report that they would definitely seek help were the preference to handle the problem alone (56.4%) and wanting to talk with friends or relatives instead (48.0%). Preference to handle the problem alone and feeling too embarrassed were also associated with significantly reduced odds of having at least some intention to seek help among students who failed to report that they would definitely seek help. Having 12-month major depression, alcohol use disorder, and suicidal thoughts and behaviors were also associated with significantly reduced reported odds of the latter outcome. CONCLUSIONS: The majority of first-year college students in the WMH-ICS surveys report that they would be hesitant to seek help in case of future emotional problems. Attitudinal barriers and not structural barriers were found to be the most important reported reasons for this hesitation. Experimental research is needed to determine whether intention to seek help and, more importantly, actual help-seeking behavior could be increased with the extent to which intervention strategies need to be tailored to particular student characteristics. Given that the preference to handle problems alone and stigma and appear to be critical, there could be value in determining if internet-based psychological treatments, which can be accessed privately and are often build as self-help approaches, would be more acceptable than other types of treatments to student who report hesitation about seeking treatment.status: publishe

WHO World Mental Health Surveys International College Student Project: Prevalence and Distribution of Mental Disorders

Increasingly, colleges across the world are contending with rising rates of mental disorders, and in many cases, the demand for services on campus far exceeds the available resources. The present study reports initial results from the first stage of the WHO World Mental Health International College Student project, in which a series of surveys in 19 colleges across 8 countries (Australia, Belgium, Germany, Mexico, Northern Ireland, South Africa, Spain, United States) were carried out with the aim of estimating prevalence and basic sociodemographic correlates of common mental disorders among first-year college students. Web-based self-report questionnaires administered to incoming first-year students (45.5% pooled response rate) screened for six common lifetime and 12-month DSM-IV mental disorders: major depression, mania/hypomania, generalized anxiety disorder, panic disorder, alcohol use disorder, and substance use disorder. We focus on the 13,984 respondents who were full-time students: 35% of whom screened positive for at least one of the common lifetime disorders assessed and 31% screened positive for at least one 12-month disorder. Syndromes typically had onsets in early to middle adolescence and persisted into the year of the survey. Although relatively modest, the strongest correlates of screening positive were older age, female sex, unmarried-deceased parents, no religious affiliation, nonheterosexual identification and behavior, low secondary school ranking, and extrinsic motivation for college enrollment. The weakness of these associations means that the syndromes considered are widely distributed with respect to these variables in the student population. Although the extent to which cost-effective treatment would reduce these risks is unclear, the high level of need for mental health services implied by these results represents a major challenge to institutions of higher education and governments. (PsycINFO Database Record (c) 2018 APA, all rights reserved).status: publishe

First-onset and persistence of suicidal ideation in university students: A one-year follow-up study

Background: Longitudinal evidence about risk and protective factors for suicidal ideation among university students is limited. Methods: 12-month first-onset and persistence of suicidal ideation (SI) among Spanish first-year university students were estimated using baseline (T1) and 12-month follow-up (T2) online surveys. Information about STBs, childhood/adolescence adversities, positive relationships, mental disorders, recent stressful experiences, and university sense of membership was assessed. Logistic regression analysis was used to study risk/protective factors of first-onset and persistence of suicidal ideation (SI). Results: A total of 1,248 respondents (58.9% response) were included. Mean age at baseline was 18.7 (SD = 1.3) and 56.0% were female. 7.3% reported 12-month SI at T2. Incidence of new SI cases was 3.4% and, among students with SI at T1, 21.2% also reported SI at T2 (persistence). Risk factors of T2 SI included 12-month mood disorder at T2 both without (aOR = 12.08 95% CI 5.45-26.80) or with (aOR = 7.2 95% CI 2.91-17.80) lifetime mood at T1, past lifetime suicide attempt (aOR = 8.79 95% CI 2.37-32.64) and plan without attempt (aOR = 4.72 95% CI 2.32-9.61), and 12-month physical or sexual assault (aOR = 3.28 95% CI 1.13-9.46). Twelve-month mood at T2 withoutT1 lifetime mood (aOR = 11.27 95% CI 3.02-42.14) and childhood/adolescence emotional abuse or neglect (aOR = 3.41 95% CI 1.10-10.57) or having been bullied (aOR = 3.2 95% CI 1.08-9.53) were associated with first-onset of SI. Twelve-month mood at T2 either without (aOR = 13.92 95% CI 3.76-51.59) or with (aOR = 8.03 95% CI 2.13-30.29) were associated to T2 SI persistence. University sense of membership was protective for overall 12-month SI at T2 (aOR = 0.25 95% CI 0.12-0.53 for middle tertile), first-onset SI (aOR = 0.1 95% 0.02-0.55 for middle tertile) and persistence (aOR = 0.3 95% CI 0.11-0.81 for middle tertile). Limitations: Analysis was based on self-report data focusing on SI only, and conclusions about the direction of the associations are limited. Conclusions: High proportion of SI suggests the need of suicide prevention strategies. The potential role of university sense of membership in reducing suicidal behaviour among university students deserves further investigation

Severe role impairment associated with mental disorders: results of the WHO World Mental Health Surveys International College Student Project

BACKGROUND: College entrance is a stressful period with a high prevalence of mental disorders. AIMS: To assess the role impairment associated with 12-month mental disorders among incoming first-year college students within a large cross-national sample. METHODS: Web-based self-report surveys assessing the prevalence of DSM-IV mental disorders and health-related role impairment (Sheehan Disability Scale) were obtained and analyzed from 13,984 incoming first-year college students (Response = 45.5%), across 19 universities in eight countries. Impairment was assessed in the following domains: home management, work (e.g., college-related problems), close personal relationships, and social life. ESULTS: Mean age of the sample was 19.3 (SD = 0.59) and 54.4% were female. Findings showed that 20.4% of students reported any severe role impairment (10% of those without a mental disorder vs. 42.9% of those with at least one disorder, P < 0.01). In bivariate analyses, panic disorder, and mania were associated most frequently with severe impairment (60.6% and 57.5%, respectively). Students reporting three or more mental disorders had almost fivefold more frequently severe impairment relative to those without mental disorders. Multiple logistic regression showed that major depression (OR = 4.0; 95%CI = 3.3, 4.8), generalized anxiety (OR = 3.9; 95%CI = 3.1, 4.8), and panic disorder (OR = 2.9; 95%CI 2.4, 4.2) were associated with the highest odds of severe impairment. Only minimal deviations from these overall associations were found across countries. CONCLUSION: Mental disorders among first-year college students are associated with substantial role impairment. Providing preventative interventions targeting mental disorders and associated impairments is a critical need for institutions to address