Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure.

Although the evolutionary history of the X chromosome indicates its specialization in male fitness, its role in spermatogenesis has largely been unexplored. Currently only three X chromosome genes are considered of moderate-definitive diagnostic value. We aimed to provide a comprehensive analysis of all X chromosome-linked protein-coding genes in 2,354 azoospermic/cryptozoospermic men from four independent cohorts. Genomic data were analyzed and compared with data in normozoospermic control individuals and gnomAD. While updating the clinical significance of known genes, we propose 21 recurrently mutated genes strongly associated with and 34 moderately associated with azoospermia/cryptozoospermia not previously linked to male infertility (novel). The most frequently affected prioritized gene, RBBP7, was found mutated in ten men across all cohorts, and our functional studies in Drosophila support its role in germ stem cell maintenance. Collectively, our study represents a significant step towards the definition of the missing genetic etiology in idiopathic severe spermatogenic failure and significantly reduces the knowledge gap of X-linked genetic causes of azoospermia/cryptozoospermia contributing to the development of future diagnostic gene panels.

The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans.

Infertility affects around 7% of the male population and can be due to severe spermatogenic failure (SPGF), resulting in no or very few sperm in the ejaculate. We initially identified a homozygous frameshift variant in FKBP6 in a man with extreme oligozoospermia. Subsequently, we screened a total of 2,699 men with SPGF and detected rare bi-allelic loss-of-function variants in FKBP6 in five additional persons. All six individuals had no or extremely few sperm in the ejaculate, which were not suitable for medically assisted reproduction. Evaluation of testicular tissue revealed an arrest at the stage of round spermatids. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining. In mice, Fkbp6 is essential for spermatogenesis and has been described as being involved in piRNA biogenesis and formation of the synaptonemal complex (SC). We did not detect FKBP6 as part of the SC in normal human spermatocytes, but small RNA sequencing revealed that loss of FKBP6 severely impacted piRNA levels, supporting a role for FKBP6 in piRNA biogenesis in humans. In contrast to findings in piRNA-pathway mouse models, we did not detect an increase in LINE-1 expression in men with pathogenic FKBP6 variants. Based on our findings, FKBP6 reaches a "strong" level of evidence for being associated with male infertility according to the ClinGen criteria, making it directly applicable for clinical diagnostics. This will improve patient care by providing a causal diagnosis and will help to predict chances for successful surgical sperm retrieval.

Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility.

Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.

From mouth to gut: microfluidic in vitro simulation of human gastro-intestinal digestion and intestinal permeability.

Reproducible in vitro studies of bioaccessibility, intestinal absorption, and bioavailability are key to the successful development of novel food ingredients or drugs intended for oral administration. There is currently a lack of methods that offer the finesse required to study these parameters for valuable molecules typically found in small volumes - as is the case of nanomaterials, which are often used to carry and protect bioactives. Here, we describe a modular microfluidic-based platform for total simulation of the human gastro-intestinal tract. Digestion-chips and cell-based gut-chips were fabricated from PDMS by soft lithography. On-chip digestion was validated using a fluorescently labelled casein derivative, which followed typical Michaelis-Menten kinetics and showed temporal resolution and good agreement with well-established bench-top protocols. Irreversible inhibition of serine proteases using Pefabloc® SC and a 1 : 6 dilution was sufficient to mitigate the cytotoxicity of simulated digestion fluids. Caco-2/HT29-MTX co-cultures were grown on-chip under a continuous flow for 7 days to obtain a differentiated cell monolayer forming a 3D villi-like epithelium with clear tight junction formation, and with an apparent permeability (Papp) of Lucifer Yellow closely approximating values reported ex vivo (3.7 × 10-6 ± 1.4 × 10-6vs. 4.0 × 10-6 ± 2.2 × 10-6). Digesta from the digestion-chips were flowed through the gut-chip, demonstrating the capacity to study sample digestion and intestinal permeability in a single microfluidic platform holding great promise for use in pharmacokinetic studies.

Phasing of de novo mutations using a scaled-up multiple amplicon long-read sequencing approach.

De novo mutations (DNMs) play an important role in severe genetic disorders that reduce fitness. To better understand their role in disease, it is important to determine the parent-of-origin and timing of mutational events that give rise to these mutations, especially in sex-specific developmental disorders such as male infertility. However, currently available short-read sequencing approaches are not ideally suited for phasing, as this requires long continuous DNA strands that span both the DNM and one or more informative single-nucleotide polymorphisms. To overcome these challenges, we optimized and implemented a multiplexed long-read sequencing approach using Oxford Nanopore technologies MinION platform. We focused on improving target amplification, integrating long-read sequenced data with high-quality short-read sequence data, and developing an anchored phasing computational method. This approach handled the inherent phasing challenges of long-range target amplification and the normal accumulation of sequencing error associated with long-read sequencing. In total, 77 of 109 DNMs (71%) were successfully phased and parent-of-origin identified. The majority of phased DNMs were prezygotic (90%), the accuracy of which is highlighted by an average mutant allele frequency of 49.6% and standard error of 0.84%. This study demonstrates the benefits of employing an integrated short-read and long-read sequencing approach for large-scale DNM phasing.

Transdiagnostic development of internalizing psychopathology throughout the life course up to age 45: a World Mental Health Surveys report.

BACKGROUND: Depressive and anxiety disorders are highly comorbid, which has been theorized to be due to an underlying internalizing vulnerability. We aimed to identify groups of participants with differing vulnerabilities by examining the course of internalizing psychopathology up to age 45. METHODS: We used data from 24158 participants (aged 45+) in 23 population-based cross-sectional World Mental Health Surveys. Internalizing disorders were assessed with the Composite International Diagnostic Interview (CIDI). We applied latent class growth analysis (LCGA) and investigated the characteristics of identified classes using logistic or linear regression. RESULTS: The best-fitting LCGA solution identified eight classes: a healthy class (81.9%), three childhood-onset classes with mild (3.7%), moderate (2.0%), or severe (1.1%) internalizing comorbidity, two puberty-onset classes with mild (4.0%) or moderate (1.4%) comorbidity, and two adult-onset classes with mild comorbidity (2.7% and 3.2%). The childhood-onset severe class had particularly unfavorable sociodemographic outcomes compared to the healthy class, with increased risks of being never or previously married (OR = 2.2 and 2.0, p < 0.001), not being employed (OR = 3.5, p < 0.001), and having a low/low-average income (OR = 2.2, p < 0.001). Moderate or severe (v. mild) comorbidity was associated with 12-month internalizing disorders (OR = 1.9 and 4.8, p < 0.001), disability (B = 1.1-2.3, p < 0.001), and suicidal ideation (OR = 4.2, p < 0.001 for severe comorbidity only). Adult (v. childhood) onset was associated with lower rates of 12-month internalizing disorders (OR = 0.2, p < 0.001). CONCLUSIONS: We identified eight transdiagnostic trajectories of internalizing psychopathology. Unfavorable outcomes were concentrated in the 1% of participants with childhood onset and severe comorbidity. Early identification of this group may offer opportunities for preventive interventions.

Perceived helpfulness of treatment for social anxiety disorder: findings from the WHO World Mental Health Surveys.

PURPOSE: To investigate the prevalence and predictors of perceived helpfulness of treatment in persons with a history of DSM-IV social anxiety disorder (SAD), using a worldwide population-based sample. METHODS: The World Health Organization World Mental Health Surveys is a coordinated series of community epidemiological surveys of non-institutionalized adults; 27 surveys in 24 countries (16 in high-income; 11 in low/middle-income countries; N = 117,856) included people with a lifetime history of treated SAD. RESULTS: In respondents with lifetime SAD, approximately one in five ever obtained treatment. Among these (n = 1322), cumulative probability of receiving treatment they regarded as helpful after seeing up to seven professionals was 92.2%. However, only 30.2% persisted this long, resulting in 65.1% ever receiving treatment perceived as helpful. Perceiving treatment as helpful was more common in female respondents, those currently married, more highly educated, and treated in non-formal health-care settings. Persistence in seeking treatment for SAD was higher among those with shorter delays in seeking treatment, in those receiving medication from a mental health specialist, and those with more than two lifetime anxiety disorders. CONCLUSIONS: The vast majority of individuals with SAD do not receive any treatment. Among those who do, the probability that people treated for SAD obtain treatment they consider helpful increases considerably if they persisted in help-seeking after earlier unhelpful treatments.

Barriers and facilitators to implementing a continuing medical education intervention in a primary health care setting.

BACKGROUND: Continuing medical education (CME), as a systematic attempt to facilitate change in General Practitioners' (GPs) practices, is considered crucial, assuming that if physicians are up-to-date, they will change and improve their practice, resulting in better performance and ultimately better patient care. However, studies continue to demonstrate considerable gaps between the real and ideal performance and patient-related outcomes. The objective of this study was to explore GP's perception of the factors affecting the implementation of a CME digital platform in a primary health care setting in Portugal. METHODS: Our work is framed in a larger effectiveness-implementation hybrid type 1 study, where a Digital Behaviour Change Intervention (DBCI), called ePrimaPrescribe, was developed and implemented with the aim of changing benzodiazepines (BZD) prescribing patterns. Our design used mixed methodologies to obtain an enriched knowledge on GPs' perspectives on the facilitators and barriers to implementing a Digital Behaviour Change Intervention (DBCI) applied to CME. To do so, we used data coming from an onsite questionnaire, an adapted version of the Barriers and Facilitators Assessment Instrument (BaFAI) and in-depth interviews. RESULTS: From the 47 GPs successfully included in the intervention arm of our cluster-randomized effectiveness study, we collected 37 onsite questionnaires, 24 BaFAIs, and performed 12 in-depth interviews. GPs reported as the main barriers to CME a lack of time, a perception of work overload, a lack of digital competence, a lack of digital infrastructure, and motivational and emotional factors. They reported as facilitators to CME delivered through a DBCI the convenience of the delivery method, the practical and pragmatic characteristics of the content, and the possibility for CME to be mandatory. CONCLUSIONS: The perceptions of the barriers and facilitators reported by GPs represent an important contribution to improving knowledge regarding the factors influencing the implementation of CME in primary health care settings. We consider that our study might bring useful insights to other countries where primary health care plays a central role in the provision of care. TRIAL REGISTRATION: ClinicalTrials.gov number NCT04925596 .

Advances in Microfluidics for the Implementation of Liquid Biopsy in Clinical Routine.

In recent years, we have seen major advances in the field of liquid biopsy and its implementation in the clinic, mainly driven by breakthrough developments in the area of molecular biology. New developments have seen an integration of microfluidics and also biosensors in liquid biopsy systems, bringing advantages in terms of cost, sensitivity and automation. Without a doubt, the next decade will bring the clinical validation and approval of these combined solutions, which is expected to be crucial for the wide implementation of liquid biopsy systems in clinical routine.

Barriers to mental health services utilisation in Portugal - results from the National Mental Health Survey.

BACKGROUND: The treatment gap for mental disorders remains a challenge worldwide. Identifying reasons for nontreatment may contribute to reducing this gap. AIMS: To evaluate sociodemographic and clinical factors associated with use and barriers to treatment in Portugal. METHOD: Data from the 2009 National Mental Health Survey were used. Participants reported 12-month treatment and reasons for nontreatment. Logistic regression models analysed the association between sociodemographic (education; employment; income; marital status) and clinical variables (mental disorder diagnosis; disability) with treatment and type of barriers (low perceived need; structural; attitudinal). RESULTS: The majority of participants with a mental disorder was not treated. Treatment was more common among participants with mood disorders (OR = 4.19; 95% CI: 2.72-6.46), and disability (OR = 2.43; 95% CI: 1.33-4.46), and less common among single participants (OR = 0.38; 95% CI: 0.20-0.70) and those with basic/secondary education (OR = 0.42; 95% CI: 0.24-0.73). Attitudinal barriers were more likely among participants with none/primary (OR = 2.90; 95% CI: 1.42-5.90) and basic/secondary education (OR = 1.70; 95% CI: 1.01-2.85), and less likely among those with substance use disorders (OR = 0.27; 95% CI: 0.10-0.70). Low perceived need was higher among single people (OR = 1.77; 95% CI: 1.01-3.08), and lower among those with anxiety (OR = 0.50; 95% CI: 0.28-0.90) and mood disorders (OR = 0.16; 95% CI: 0.09-0.30). Unemployed participants had higher odds of reporting structural barriers (OR = 3.76; 95% CI: 1.29-10.92). CONCLUSIONS: This study identifies factors associated with nontreatment, providing useful evidence to develop policies and effective interventions.

Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure.

Male infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n = 176) did not reveal known gene-candidates but identified a potentially significant single-nucleotide variant (SNV) in X-linked germ-cell nuclear antigen (GCNA). Together with a larger follow-up study (n = 2049), 7 likely clinically relevant GCNA variants were identified. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-seq and immunohistochemistry confirm human GCNA expression from spermatogonia to elongated spermatids. Five identified SNVs were located in key functional regions, including N-terminal SUMO-interacting motif and C-terminal Spartan-like protease domain. Notably, variant p.Ala115ProfsTer7 results in an early frameshift, while Spartan-like domain missense variants p.Ser659Trp and p.Arg664Cys change conserved residues, likely affecting 3D structure. For variants within GCNA's intrinsically disordered region, we performed computational modeling for consensus motifs. Two SNVs were predicted to impact the structure of these consensus motifs. All identified variants have an extremely low minor allele frequency in the general population and 6 of 7 were not detected in > 5000 biological fathers. Considering evidence from animal models, germ-cell-specific expression, 3D modeling, and computational predictions for SNVs, we propose that identified GCNA variants disrupt structure and function of the respective protein domains, ultimately arresting germ-cell division. To our knowledge, this is the first study implicating GCNA, a key genome integrity factor, in human male infertility.

Patterns of care and dropout rates from outpatient mental healthcare in low-, middle- and high-income countries from the World Health Organization's World Mental Health Survey Initiative.

BACKGROUND: There is a substantial proportion of patients who drop out of treatment before they receive minimally adequate care. They tend to have worse health outcomes than those who complete treatment. Our main goal is to describe the frequency and determinants of dropout from treatment for mental disorders in low-, middle-, and high-income countries. METHODS: Respondents from 13 low- or middle-income countries (N = 60 224) and 15 in high-income countries (N = 77 303) were screened for mental and substance use disorders. Cross-tabulations were used to examine the distribution of treatment and dropout rates for those who screened positive. The timing of dropout was examined using Kaplan-Meier curves. Predictors of dropout were examined with survival analysis using a logistic link function. RESULTS: Dropout rates are high, both in high-income (30%) and low/middle-income (45%) countries. Dropout mostly occurs during the first two visits. It is higher in general medical rather than in specialist settings (nearly 60% v. 20% in lower income settings). It is also higher for mild and moderate than for severe presentations. The lack of financial protection for mental health services is associated with overall increased dropout from care. CONCLUSIONS: Extending financial protection and coverage for mental disorders may reduce dropout. Efficiency can be improved by managing the milder clinical presentations at the entry point to the mental health system, providing adequate training, support and specialist supervision for non-specialists, and streamlining referral to psychiatrists for more severe cases.

Perceived helpfulness of treatment for generalized anxiety disorder: a World Mental Health Surveys report.

BACKGROUND: Treatment guidelines for generalized anxiety disorder (GAD) are based on a relatively small number of randomized controlled trials and do not consider patient-centered perceptions of treatment helpfulness. We investigated the prevalence and predictors of patient-reported treatment helpfulness for DSM-5 GAD and its two main treatment pathways: encounter-level treatment helpfulness and persistence in help-seeking after prior unhelpful treatment. METHODS: Data came from community epidemiologic surveys in 23 countries in the WHO World Mental Health surveys. DSM-5 GAD was assessed with the fully structured WHO Composite International Diagnostic Interview Version 3.0. Respondents with a history of GAD were asked whether they ever received treatment and, if so, whether they ever considered this treatment helpful. Number of professionals seen before obtaining helpful treatment was also assessed. Parallel survival models estimated probability and predictors of a given treatment being perceived as helpful and of persisting in help-seeking after prior unhelpful treatment. RESULTS: The overall prevalence rate of GAD was 4.5%, with lower prevalence in low/middle-income countries (2.8%) than high-income countries (5.3%); 34.6% of respondents with lifetime GAD reported ever obtaining treatment for their GAD, with lower proportions in low/middle-income countries (19.2%) than high-income countries (38.4%); 3) 70% of those who received treatment perceived the treatment to be helpful, with prevalence comparable in low/middle-income countries and high-income countries. Survival analysis suggested that virtually all patients would have obtained helpful treatment if they had persisted in help-seeking with up to 10 professionals. However, we estimated that only 29.7% of patients would have persisted that long. Obtaining helpful treatment at the person-level was associated with treatment type, comorbid panic/agoraphobia, and childhood adversities, but most of these predictors were important because they predicted persistence rather than encounter-level treatment helpfulness. CONCLUSIONS: The majority of individuals with GAD do not receive treatment. Most of those who receive treatment regard it as helpful, but receiving helpful treatment typically requires persistence in help-seeking. Future research should focus on ensuring that helpfulness is included as part of the evaluation. Clinicians need to emphasize the importance of persistence to patients beginning treatment.

A multicentric study on stigma towards people with mental illness in health sciences students.

BACKGROUND: There is evidence of negative attitudes among health professionals towards people with mental illness but there is also a knowledge gap on what training must be given to these health professionals during their education. The purpose of this study is to compare the attitudes of students of health sciences: nursing, medical, occupational therapy, and psychology. METHODS: A comparative and cross-sectional study in which 927 final-year students from health sciences university programmes were evaluated using the Mental Illness: Clinicians' Attitudes (both MICA-2 and MICA-4) scale. The sample was taken in six universities from Chile and Spain. RESULTS: We found consistent results indicating that stigma varies across university programmes. Medical and nursing students showed more negative attitudes than psychology and occupational therapy students in several stigma-related themes: recovery, dangerousness, uncomfortability, disclosure, and discriminatory behaviour. CONCLUSIONS: Our study presents a relevant description of the attitudes of each university programme for education against stigma in the formative years. Results show that the biomedical understanding of mental disorders can have negative effects on attitudes, and that education based on the psychosocial model allows a more holistic view of the person over the diagnosis.

How did the use of psychotropic drugs change during the Great Recession in Portugal? A follow-up to the National Mental Health Survey.

BACKGROUND: Research suggests that economic recessions might be associated with a higher use of psychotropic drugs, but literature is scarce and contradictory in identifying the most vulnerable groups. This study aims to assess possible changes in the use of psychotropic drugs due to the economic recession in Portugal, by comparing self-reported consumption in 2008/09 and 2015/16. METHODS: Data from the World Mental Health Survey Initiative Portugal (2008/09) and the National Mental Health Survey Follow-Up (2015/16) were used (n = 911). McNemar's tests were performed to estimate changes in consumption of any psychotropic drug and of antidepressants, anxiolytics, and hypnotics/sedatives. Multiple Generalised Estimating Equations models with interaction effects were used to estimate the population odds of consuming psychotropic drugs according to year, gender and age. RESULTS: An increase of 6.74% was estimated in the consumption of psychotropic drugs from 2008/09 to 2015/16. Population odds of consuming any psychotropic drugs in 2015/16 were estimated to be 1.5 times higher than in 2008/09 (OR = 1.50;95%CI:1.13-2.01), particularly for hypnotics/sedatives (OR = 1.60;95%CI:1.14-2.25). Women and older individuals presented higher odds of consuming any psychotropic drugs (OR = 2.79;95%CI:2.03-3.84, and OR = 1.80;95%CI:1.28-2.54), after adjusting for year of assessment and education. However, when evaluating the interaction effect of the year with gender and age, men and younger individuals reported higher odds of consuming any psychotropic drugs in 2015/16, when compared to 2008/09 (OR = 1.85;95%CI:1.08-3.17, and OR = 1.95;95%CI:1.32-2.90, respectively). CONCLUSIONS: The findings indicate that the period of economic recession was associated with an increased risk of psychotropic drugs use in Portugal. Consumption of psychotropic drugs remained higher among women and older individuals, but the results suggest that the economic crisis had a disproportionate impact on men and younger individuals. This identification of the most vulnerable population groups is useful to design effective and targeted public health interventions aimed at alleviating the effects of economic recessions.

FASTEN IIoT: An Open Real-Time Platform for Vertical, Horizontal and End-To-End Integration.

The Industry 4.0 paradigm, since its initial conception in Germany in 2011, has extended its scope and adoption to a broader set of technologies. It is being considered as the most vital mechanism in the production systems lifecycle. It is the key element in the digital transformation of manufacturing industry all over the world. This scenario imposes a set of major unprecedented challenges which require to be overcome. In order to enable integration in horizontal, vertical, and end-to-end formats, one of the most critical aspects of this digital transformation process consists of effectively coupling digital integrated service/products business models with additive manufacturing processes. This integration is based upon advanced AI-based tools for decentralized decision-making and for secure and trusted data sharing in the global value. This paper presents the FASTEN IIoT Platform, which targets to provide a flexible, configurable, and open solution. The platform acts as an interface between the shop floor and the industry 4.0 advanced applications and solutions. Examples of these efforts comprise management, forecasting, optimization, and simulation, by harmonizing the heterogeneous characteristics of the data sources involved while meeting real-time requirements.

Genomic integrity in the male germ line: evidence in support of the disposable soma hypothesis.

The Big Blue λSelect-cII selection system has been employed along with whole-exome sequencing to examine the susceptibility of the male germ line to mutation in two challenging situations (i) exposure to a chemotherapeutic regime including bleomycin, etoposide and cis-platinum (BEP) and (ii) the ageing process. A 3-week exposure to BEP induced complete azoospermia associated with a loss of developing germ cells and extensive vacuolization of Sertoli cell cytoplasm. Following cessation of treatment, spermatozoa first appeared in the caput epididymis after 6 weeks and by 12 weeks motile spermatozoa could be recovered from the cauda, although the count (P < 0.001) and motility (P < 0.01) of these cells were significantly reduced and superoxide generation was significantly elevated (P < 0.001). Despite this increase in free radical generation, no evidence of chromatin instability was detected in these spermatozoa. Furthermore, embryos obtained from females mated at this 12-week time point showed no evidence of an increased mutational load. Similarly, progressive ageing of Big Blue mice had no impact on the quality of the spermatozoa, fertility or mutation frequency in the offspring despite a significant increase in the mutational load carried by somatic tissues such as the liver (P < 0.05). We conclude that the male germ line is highly resistant to mutation in keeping with the disposable soma hypothesis, which posits that genetic integrity in the germ cells will be maintained at the expense of the soma, in light of the former's sentinel position in safeguarding the stability of the genome.

The influence of clerkship on students' stigma towards mental illness: a meta-analysis.

CONTEXT: In university programmes preparing students to work with patients with mental illness, clerkship is proposed as a component that may contribute to the battle against stigma, through bringing students into contact with the patients' reality. Yet, the precise contribution of clerkship remains unclear, perhaps because of the variety of university programmes, clerkship characteristics or types of stigma explored. This is the first systematic meta-analysis of available evidence determining the precise effect size of the influence of clerkship on stigma and the potential moderators. METHODS: We carried out a systematic literature review in Eric, PsycINFO, Pubmed, Scopus, UMI and Proquest dissertations, aiming to identify all the studies exploring health care students' stigma of mental illness (measured as overall stigma or as attitudes, affect and behavioural intentions) before and after a clerkship from 2000 to 2017. Twenty-two studies were included in the meta-analysis, providing data from 22 independent samples. The total sample consisted of 3161 students. The effects of programme (medicine, nursing, occupational therapy, and their combination), study design (paired-unpaired samples), publication year, sex, age and clerkship context, and inclusion of theoretical training and duration, were examined as potential moderators. RESULTS: Our analyses yielded a highly significant medium effect size for overall stigma (Hedge's g = 0.35; p < 0.001; 95% confidence interval [CI], 0.20, 0.42), attitudes (Hedge's g = 0.308; p = 0.003; 95% CI, 0.10, 0.51) and behavioural intentions (Hedge's g = 0.247; p < 0.001; 95% CI, 0.17, 0.33), indicating a considerable change, whereas there was no significant change in the students' affect. Moderator analyses provided evidence for the distinct nature of each stigma outcome, as they were influenced by different clerkship and student characteristics such as clerkship context, theoretical training, age and sex. CONCLUSIONS: The robust effect of clerkship on students' stigma of mental illness established by the present meta-analysis highlights its role as a crucial curriculum component for experiential learning and as a necessary agent for the battle against stigma.

Suicidal thoughts and behaviors among college students and same-aged peers: results from the World Health Organization World Mental Health Surveys.

PURPOSE: The primary aims are to (1) obtain representative prevalence estimates of suicidal thoughts and behaviors (STB) among college students worldwide and (2) investigate whether STB is related to matriculation to and attrition from college. METHODS: Data from the WHO World Mental Health Surveys were analyzed, which include face-to-face interviews with 5750 young adults aged 18-22 spanning 21 countries (weighted mean response rate = 71.4%). Standardized STB prevalence estimates were calculated for four well-defined groups of same-aged peers: college students, college attriters (i.e., dropouts), secondary school graduates who never entered college, and secondary school non-graduates. Logistic regression assessed the association between STB and college entrance as well as attrition from college. RESULTS: Twelve-month STB in college students was 1.9%, a rate significantly lower than same-aged peers not in college (3.4%; OR 0.5; p < 0.01). Lifetime prevalence of STB with onset prior to age 18 among college entrants (i.e., college students or attriters) was 7.2%, a rate significantly lower than among non-college attenders (i.e., secondary school graduates or non-graduates; 8.2%; OR 0.7; p = 0.03). Pre-matriculation onset STB (but not post-matriculation onset STB) increased the odds of college attrition (OR 1.7; p < 0.01). CONCLUSION: STB with onset prior to age 18 is associated with reduced likelihood of college entrance as well as greater attrition from college. Future prospective research should investigate the causality of these associations and determine whether targeting onset and persistence of childhood-adolescent onset STB leads to improved educational attainment.

The cross-national epidemiology of social anxiety disorder: Data from the World Mental Health Survey Initiative.

BACKGROUND: There is evidence that social anxiety disorder (SAD) is a prevalent and disabling disorder. However, most of the available data on the epidemiology of this condition originate from high income countries in the West. The World Mental Health (WMH) Survey Initiative provides an opportunity to investigate the prevalence, course, impairment, socio-demographic correlates, comorbidity, and treatment of this condition across a range of high, middle, and low income countries in different geographic regions of the world, and to address the question of whether differences in SAD merely reflect differences in threshold for diagnosis. METHODS: Data from 28 community surveys in the WMH Survey Initiative, with 142,405 respondents, were analyzed. We assessed the 30-day, 12-month, and lifetime prevalence of SAD, age of onset, and severity of role impairment associated with SAD, across countries. In addition, we investigated socio-demographic correlates of SAD, comorbidity of SAD with other mental disorders, and treatment of SAD in the combined sample. Cross-tabulations were used to calculate prevalence, impairment, comorbidity, and treatment. Survival analysis was used to estimate age of onset, and logistic regression and survival analyses were used to examine socio-demographic correlates. RESULTS: SAD 30-day, 12-month, and lifetime prevalence estimates are 1.3, 2.4, and 4.0% across all countries. SAD prevalence rates are lowest in low/lower-middle income countries and in the African and Eastern Mediterranean regions, and highest in high income countries and in the Americas and the Western Pacific regions. Age of onset is early across the globe, and persistence is highest in upper-middle income countries, Africa, and the Eastern Mediterranean. There are some differences in domains of severe role impairment by country income level and geographic region, but there are no significant differences across different income level and geographic region in the proportion of respondents with any severe role impairment. Also, across countries SAD is associated with specific socio-demographic features (younger age, female gender, unmarried status, lower education, and lower income) and with similar patterns of comorbidity. Treatment rates for those with any impairment are lowest in low/lower-middle income countries and highest in high income countries. CONCLUSIONS: While differences in SAD prevalence across countries are apparent, we found a number of consistent patterns across the globe, including early age of onset, persistence, impairment in multiple domains, as well as characteristic socio-demographic correlates and associated psychiatric comorbidities. In addition, while there are some differences in the patterns of impairment associated with SAD across the globe, key similarities suggest that the threshold for diagnosis is similar regardless of country income levels or geographic location. Taken together, these cross-national data emphasize the international clinical and public health significance of SAD.