Hôpital Fernand-Widal

BACKGROUND: Suicide is a leading cause of death worldwide; however, the prevalence and risk factors for the immediate precursors to suicide - suicidal ideation, plans and attempts - are not wellknown, especially in low- and middle-income countries. AIMS: To report on the prevalence and risk factors for suicidal behaviours across 17 countries. METHOD: A total of 84 850 adults were interviewed regarding suicidal behaviours and socio-demographic and psychiatric risk factors. RESULTS: The cross-national lifetime prevalence of suicidal ideation, plans, and attempts is 9.2% (s.e.=0.1), 3.1% (s.e.=0.1), and 2.7% (s.e.=0.1). Across all countries, 60% of transitions from ideation to plan and attempt occur within the first year after ideation onset. Consistent cross-national risk factors included being female, younger, less educated, unmarried and having a mental disorder. Interestingly, the strongest diagnostic risk factors were mood disorders in high-income countries but impulse control disorders in low- and middle-income countries. CONCLUSION: There is cross-national variability in the prevalence of suicidal behaviours, but strong consistency in the characteristics and risk factors for these behaviours. These findings have significant implications for the prediction and prevention of suicidal behaviours.

BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

BACKGROUND: Considerable research has documented that exposure to traumatic events has negative effects on physical and mental health. Much less research has examined the predictors of traumatic event exposure. Increased understanding of risk factors for exposure to traumatic events could be of considerable value in targeting preventive interventions and anticipating service needs. METHOD: General population surveys in 24 countries with a combined sample of 68 894 adult respondents across six continents assessed exposure to 29 traumatic event types. Differences in prevalence were examined with cross-tabulations. Exploratory factor analysis was conducted to determine whether traumatic event types clustered into interpretable factors. Survival analysis was carried out to examine associations of sociodemographic characteristics and prior traumatic events with subsequent exposure. RESULTS: Over 70% of respondents reported a traumatic event; 30.5% were exposed to four or more. Five types - witnessing death or serious injury, the unexpected death of a loved one, being mugged, being in a life-threatening automobile accident, and experiencing a life-threatening illness or injury - accounted for over half of all exposures. Exposure varied by country, sociodemographics and history of prior traumatic events. Being married was the most consistent protective factor. Exposure to interpersonal violence had the strongest associations with subsequent traumatic events. CONCLUSIONS: Given the near ubiquity of exposure, limited resources may best be dedicated to those that are more likely to be further exposed such as victims of interpersonal violence. Identifying mechanisms that account for the associations of prior interpersonal violence with subsequent trauma is critical to develop interventions to prevent revictimization.

Establishment of a human model of the blood-brain barrier has proven to be a difficult goal. To accomplish this, normal human brain endothelial cells were transduced by lentiviral vectors incorporating human telomerase or SV40 T antigen. Among the many stable immortalized clones obtained by sequential limiting dilution cloning of the transduced cells, one was selected for expression of normal endothelial markers, including CD31, VE cadherin, and von Willebrand factor. This cell line, termed hCMEC/D3, showed a stable normal karyotype, maintained contact-inhibited monolayers in tissue culture, exhibited robust proliferation in response to endothelial growth factors, and formed capillary tubes in matrix but no colonies in soft agar. hCMEC/D3 cells expressed telomerase and grew indefinitely without phenotypic dedifferentiation. These cells expressed chemokine receptors, up-regulated adhesion molecules in response to inflammatory cytokines, and demonstrated blood-brain barrier characteristics, including tight junctional proteins and the capacity to actively exclude drugs. hCMEC/D3 are excellent candidates for studies of blood-brain barrier function, the responses of brain endothelium to inflammatory and infectious stimuli, and the interaction of brain endothelium with lymphocytes or tumor cells. Thus, hCMEC/D3 represents the first stable, fully characterized, well-differentiated human brain endothelial cell line and should serve as a widely usable research tool.

BACKGROUND: Little is known about the epidemiology of adult attention-deficit hyperactivity disorder (ADHD). AIMS: To estimate the prevalence and correlates of DSM-IV adult ADHD in the World Health Organization World Mental Health Survey Initiative. METHOD: An ADHD screen was administered to respondents aged 18-44 years in ten countries in the Americas, Europe and the Middle East (n=11422). Masked clinical reappraisal interviews were administered to 154 US respondents to calibrate the screen. Multiple imputation was used to estimate prevalence and correlates based on the assumption of cross-national calibration comparability. RESULTS: Estimates of ADHD prevalence averaged 3.4% (range 1.2-7.3%), with lower prevalence in lower-income countries (1.9%) compared with higher-income countries (4.2%). Adult ADHD often co-occurs with other DSM-IV disorders and is associated with considerable role disability. Few cases are treated for ADHD, but in many cases treatment is given for comorbid disorders. CONCLUSIONS: Adult ADHD should be considered more seriously in future epidemiological and clinical studies than is currently the case.

The DSM-IV diagnoses generated by the fully structured lay-administered Composite International Diagnostic Interview Version 3.0 (CIDI 3.0) in the WHO World Mental Health (WMH) surveys were compared to diagnoses based on follow-up interviews with the clinician-administered non-patient edition of the Structured Clinical Interview for DSM-IV (SCID) in probability subsamples of the WMH surveys in France, Italy, Spain, and the US. CIDI cases were oversampled. The clinical reappraisal samples were weighted to adjust for this oversampling. Separate samples were assessed for lifetime and 12-month prevalence. Moderate to good individual-level CIDI-SCID concordance was found for lifetime prevalence estimates of most disorders. The area under the ROC curve (AUC, a measure of classification accuracy that is not influenced by disorder prevalence) was 0.76 for the dichotomous classification of having any of the lifetime DSM-IV anxiety, mood and substance disorders assessed in the surveys and in the range 0.62-0.93 for individual disorders, with an inter-quartile range (IQR) of 0.71-0.86. Concordance increased when CIDI symptom-level data were added to predict SCID diagnoses in logistic regression equations. AUC for individual disorders in these equations was in the range 0.74-0.99, with an IQR of 0.87-0.96. CIDI lifetime prevalence estimates were generally conservative relative to SCID estimates. CIDI-SCID concordance for 12-month prevalence estimates could be studied powerfully only for two disorder classes, any anxiety disorder (AUC = 0.88) and any mood disorder (AUC = 0.83). As with lifetime prevalence, 12-month concordance improved when CIDI symptom-level data were added to predict SCID diagnoses. CIDI 12-month prevalence estimates were unbiased relative to SCID estimates. The validity of the CIDI is likely to be under-estimated in these comparisons due to the fact that the reliability of the SCID diagnoses, which is presumably less than perfect, sets a ceiling on maximum CIDI-SCID concordance.

Abstract Objectives Genome‐wide association studies (GWAS) have become increasingly popular to identify associations between single nucleotide polymorphisms (SNPs) and phenotypic traits. The GWAS method is commonly applied within the social sciences. However, statistical analyses will need to be carefully conducted and the use of dedicated genetics software will be required. This tutorial aims to provide a guideline for conducting genetic analyses. Methods We discuss and explain key concepts and illustrate how to conduct GWAS using example scripts provided through GitHub ( https://github.com/MareesAT/GWA_tutorial/ ) . In addition to the illustration of standard GWAS, we will also show how to apply polygenic risk score (PRS) analysis. PRS does not aim to identify individual SNPs but aggregates information from SNPs across the genome in order to provide individual‐level scores of genetic risk. Results The simulated data and scripts that will be illustrated in the current tutorial provide hands‐on practice with genetic analyses. The scripts are based on PLINK, PRSice, and R, which are commonly used, freely available software tools that are accessible for novice users. Conclusions By providing theoretical background and hands‐on experience, we aim to make GWAS more accessible to researchers without formal training in the field.

BACKGROUND: Alcohol, tobacco, and illegal drug use cause considerable morbidity and mortality, but good cross-national epidemiological data are limited. This paper describes such data from the first 17 countries participating in the World Health Organization's (WHO's) World Mental Health (WMH) Survey Initiative. METHODS AND FINDINGS: Household surveys with a combined sample size of 85,052 were carried out in the Americas (Colombia, Mexico, United States), Europe (Belgium, France, Germany, Italy, Netherlands, Spain, Ukraine), Middle East and Africa (Israel, Lebanon, Nigeria, South Africa), Asia (Japan, People's Republic of China), and Oceania (New Zealand). The WHO Composite International Diagnostic Interview (CIDI) was used to assess the prevalence and correlates of a wide variety of mental and substance disorders. This paper focuses on lifetime use and age of initiation of tobacco, alcohol, cannabis, and cocaine. Alcohol had been used by most in the Americas, Europe, Japan, and New Zealand, with smaller proportions in the Middle East, Africa, and China. Cannabis use in the US and New Zealand (both 42%) was far higher than in any other country. The US was also an outlier in cocaine use (16%). Males were more likely than females to have used drugs; and a sex-cohort interaction was observed, whereby not only were younger cohorts more likely to use all drugs, but the male-female gap was closing in more recent cohorts. The period of risk for drug initiation also appears to be lengthening longer into adulthood among more recent cohorts. Associations with sociodemographic variables were consistent across countries, as were the curves of incidence of lifetime use. CONCLUSIONS: Globally, drug use is not distributed evenly and is not simply related to drug policy, since countries with stringent user-level illegal drug policies did not have lower levels of use than countries with liberal ones. Sex differences were consistently documented, but are decreasing in more recent cohorts, who also have higher levels of illegal drug use and extensions in the period of risk for initiation.

BACKGROUND: A quantitative scale of intubation difficulty would be useful for objectively comparing the complexity of endotracheal intubations. The authors have developed a quantitative score that can be used to evaluate intubating conditions and techniques with the aim of determining the relative values of predictive factors of intubation difficulty and of the techniques used to decrease such difficulties. METHODS: An Intubation Difficulty Scale (IDS) was developed, based on parameters known to be associated with difficult intubation. It was then evaluated prospectively in a group of 311 consecutive prehospital intubations and 315 intubations in an operating room. In the operating room, the IDS was compared with two other parameters: the time to completion of intubation and the visual analog scale (VAS). Time was measured by an independent observer. Operators in both groups completed a checklist regarding the conditions of intubation. RESULTS: There is a good correlation between the IDS scale and the VAS assessment of difficulty and time to completion of intubation. VAS and time to completion have a significant but lesser correlation to each other. Comparison of IDS with operator-assessed subjective categorical impression of difficulty by Kruskall-Wallis was statistically significant. CONCLUSIONS: The IDS correlates with but is less subjective than the VAS and categorical classification. IDS correlates with time to intubation, but it offers details regarding the difficulty encountered that time alone does not. This score may not only aid in evaluation of factors linked to difficult intubations, but it may provide a uniform approach to comparing studies related to this subject.

Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The transcytotic pathways present at the BBB and its morphological and enzymatic properties provide the means for movement of the molecules through the endothelial cytoplasm. AMT-based drug delivery to the brain was performed using cationic proteins and cell-penetrating peptides (CPPs). Protein cationization using either synthetic or natural polyamines is discussed and some examples of diamine/polyamine modified proteins that cross BBB are described. Two main families of CPPs belonging to the Tat-derived peptides and Syn-B vectors have been extensively used in CPP vector-mediated strategies allowing delivery of a large variety of small molecules as well as proteins across cell membranes in vitro and the BBB in vivo. CPP strategy suffers from several limitations such as toxicity and immunogenicity--like the cationization strategy--as well as the instability of peptide vectors in biological media. The review concludes by stressing the need to improve the understanding of AMT mechanisms at BBB and the effectiveness of cationized proteins and CPP-vectorized proteins as neurotherapeutics.

Among polyunsaturated omega-3 fatty acids, ALA (alpha-linolenic acid) provided the first coherent multidisciplinary experimental demonstration of the effect of diet (one of its major macronutrient) on the structure, the biochemistry, the physiology and thus the function of the brain. In fact, DHA (docosahexaenoic acid) is one for the major building structures of membrane phospholipids of brain and absolute necessary of neuronal function. It was first demonstrated that the differentiation and functioning of cultured brain cells requires not only ALA, but also the very long polyunsaturated omega-3 (DHA) and omega-6 carbon chains. Then, it was found that ALA acid deficiency alters the course of brain development, perturbs the composition of brain cell membranes, neurones, oligodendrocytes and astrocytes, as well as sub cellular particles such as myelin, nerve endings (synaptosomes) and mitochondria. These alterations induce physicochemical modifications in membranes, lead to biochemical and physiological perturbations, and results in neurosensory and behavioural upset. Consequently, the nature of polyunsaturated fatty acids (in particular omega-3, ALA and DHA) present in formula milks for infants (premature and term) conditions the visual, neurological and cerebral abilities, including intellectual. Dietary omega-3 fatty acids are involved in the prevention of some aspects of ischemic cardiovascular disease (including at the level of cerebral vascularization), and in some neuropsychiatric disorders, particularly depression, as well as in dementia, including Alzheimer's disease and vascular dementia. The implication of omega-3 fatty acids in major depression and bipolar disorder (manic-depressive illness) is under evaluation. Their dietary deficiency (and altered hepatic metabolism) can prevent the renewal of membranes and consequently accelerate cerebral ageing; nonetheless, the respective roles of the vascular component on one hand and the cerebral parenchyma itself on the other have not yet been clearly elucidated. Low fat diet may have adverse effects on mood. The nature of the amino acid composition of dietary proteins contributes to cerebral function; taking into account that tryptophan plays a special role. In fact, some indispensable amino acids present in dietary proteins participate to elaborate neurotransmitters (and neuromodulators). The regulation of glycaemia (thanks to the ingestion of food with a low glycaemic index ensuring a low insulin level) improves the quality and duration of intellectual performance, if only because at rest the brain consumes more than 50% of dietary carbohydrates, approximately 80% of which are used only for energy purpose. In infants, adults and aged, as well as in diabetes, poorer glycaemic control is associated with lower performances, for instance on tests of memory. At all ages, and more specifically in aged people, some cognitive functions appear sensitive to short term variations in glucose availability. The presence of dietary fibbers is associated with higher alertness ratings and ensures less perceived stress. Although an increasing number of genetic factors that may affect the risk of neurodegenerative disorders are being identified, number of findings show that dietary factors play major roles in determining whether the brain age successfully of experiences neurodegenerative disorders. Effects of micronutrients have been examined in the accompanying paper.

Importance: Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. Objective: To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. Design, Setting, and Participants: This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer's and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD. Main Outcomes and Measures: Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. Results: A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean [SD], 185.1 [93.5] pg/mL, Aβ-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aβ-negative mean [SD], 121.9 [42.4] pg/mL, Aβ-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aβ-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aβ-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aβ-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aβ-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology. Conclusions and Relevance: This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD.

Sleep dysregulation is a feature of dementia but it remains unclear whether sleep duration prior to old age is associated with dementia incidence. Using data from 7959 participants of the Whitehall II study, we examined the association between sleep duration and incidence of dementia (521 diagnosed cases) using a 25-year follow-up. Here we report higher dementia risk associated with a sleep duration of six hours or less at age 50 and 60, compared with a normal (7 h) sleep duration, although this was imprecisely estimated for sleep duration at age 70 (hazard ratios (HR) 1.22 (95% confidence interval 1.01-1.48), 1.37 (1.10-1.72), and 1.24 (0.98-1.57), respectively). Persistent short sleep duration at age 50, 60, and 70 compared to persistent normal sleep duration was also associated with a 30% increased dementia risk independently of sociodemographic, behavioural, cardiometabolic, and mental health factors. These findings suggest that short sleep duration in midlife is associated with an increased risk of late-onset dementia.

IMPORTANCE: Community-based surveys find that many otherwise healthy individuals report histories of hallucinations and delusions. To date, most studies have focused on the overall lifetime prevalence of any of these psychotic experiences (PEs), which might mask important features related to the types and frequencies of PEs. OBJECTIVE: To explore detailed epidemiologic information about PEs in a large multinational sample. DESIGN, SETTING, AND PARTICIPANTS: We obtained data from the World Health Organization World Mental Health Surveys, a coordinated set of community epidemiologic surveys of the prevalence and correlates of mental disorders in representative household samples from 18 countries throughout the world, from 2001 through 2009. Respondents included 31,261 adults (18 years and older) who were asked about lifetime and 12-month prevalence and frequency of 6 types of PEs (2 hallucinatory experiences and 4 delusional experiences). We analyzed the data from March 2014 through January 2015. MAIN OUTCOMES AND MEASURES: Prevalence, frequency, and correlates of PEs. RESULTS: Mean lifetime prevalence (SE) of ever having a PE was 5.8% (0.2%), with hallucinatory experiences (5.2% [0.2%]) much more common than delusional experiences (1.3% [0.1%]). More than two-thirds (72.0%) of respondents with lifetime PEs reported experiencing only 1 type. Psychotic experiences were typically infrequent, with 32.2% of respondents with lifetime PEs reporting only 1 occurrence and 31.8% reporting only 2 to 5 occurrences. We found a significant relationship between having more than 1 type of PE and having more frequent PE episodes (Cochran-Armitage z = -10.0; P < .001). Lifetime prevalence estimates (SEs) were significantly higher among respondents in middle- and high-income countries than among those in low-income countries (7.2% [0.4%], 6.8% [0.3%], and 3.2% [0.3%], respectively; χ²₂ range, 7.1-58.2; P < .001 for each) and among women than among men (6.6% [0.2%] vs 5.0% [0.3%]; χ²₁ = 16.0; P < .001). We found significant associations with lifetime prevalence of PEs in the multivariate model among nonmarried compared with married respondents (χ²₂ = 23.2; P < .001) and among respondents who were not employed (χ²₄= 10.6; P < .001) and who had low family incomes (χ²₃ = 16.9; P < .001). CONCLUSIONS AND RELEVANCE: The epidemiologic features of PEs are more nuanced than previously thought. Research is needed that focuses on similarities and differences in the predictors of the onset, course, and consequences of distinct PEs.

BACKGROUND: There are few cross-national comparisons of the rates of suicide ideation and attempts across diverse countries. Nine independently conducted epidemiological surveys using similar diagnostic assessment and criteria provided an opportunity to obtain that data. METHODS: Suicide ideation and attempts were assessed on the Diagnostic Interview Schedule in over 40000 subjects drawn from the United States, Canada, Puerto Rico, France, West Germany, Lebanon, Taiwan, Korea and New Zealand. RESULTS: The lifetime prevalence rates/100 for suicide ideation ranged from 2.09 (Beirut) to 18.51 (Christchurch, New Zealand). Lifetime prevalence rates/100 for suicide attempts ranged from 0.72 (Beirut) to 5.93 (Puerto Rico). Females as compared to males had only marginally higher rates of suicidal ideation in most countries, reaching a two-fold increase in Taiwan. Females as compared to males had more consistently higher rates for suicide attempts, reaching a two- to three-fold increase in most countries. Suicide ideation and attempts in most countries were associated with being currently divorced/separated as compared to currently married. CONCLUSIONS: While the rates of suicide ideation varied widely by country, the rates of suicide attempts were more consistent across most countries. The variations were only partly explained by variation in rates of psychiatric disorders, divorce or separation among countries and are probably due to cultural features that we do not, as yet, understand.

BACKGROUND: Familial hemiplegic migraine, an autosomal dominant disorder characterized by attacks of transient hemiparesis followed by a migraine headache, is classically divided into pure familial hemiplegic migraine (affecting 80 percent of families) and familial hemiplegic migraine with permanent cerebellar signs (affecting 20 percent of families). Mutations in CACNA1A, which encodes a neuronal calcium channel, are present in 50 percent of families with hemiplegic migraine, including all those with cerebellar signs. We studied the various clinical manifestations associated with mutations in CACNA1A in families with hemiplegic migraine with and without cerebellar signs. METHODS: CACNA1A was analyzed and nine mutations were detected in 15 of 16 probands of families affected by hemiplegic migraine and cerebellar signs, in 2 of 3 subjects with sporadic hemiplegic migraine and cerebellar signs, and in 4 of 12 probands of families affected by pure hemiplegic migraine. Genotyping of probands and relatives identified a total of 117 subjects with mutations whose clinical manifestations were assessed in detail. RESULTS: Eighty-nine percent of the subjects with mutations had attacks of hemiplegic migraine. One third had severe attacks with coma, prolonged hemiplegia, or both, with full recovery. All nine mutations, including five newly identified ones, were missense mutations. Six mutations were associated with hemiplegic migraine and cerebellar signs, and 83 percent of the subjects with these six mutations had nystagmus, ataxia, or both. Three mutations were associated with pure hemiplegic migraine. CONCLUSIONS: Hemiplegic migraine in subjects with mutations in CACNA1A has a broad clinical spectrum. This clinical variability is partially associated with the various types of mutations.

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.

DEPRESS (Depression Research in European Society) is the first large pan-European survey of depression in the community. A total of 13359 of the 78463 adults who participated in screening interviews across six countries were identified as suffering from depression, a 6-month prevalence of 17%. Major depression accounted for 6.9% of the cases of depression and minor depression for 1.8%. Depressed subjects in both these categories perceived that their working or social lives were substantially impaired by depressive symptoms. The remaining 8.3% of depressed subjects considered that their functional impairment was not substantial. A significant proportion of sufferers from depression (43%) failed to seek treatment for their depressive symptoms. Of those who did seek help (57%), most consulted a primary care physician, the frequency of consultation increasing with the severity of depression. Sufferers from major depression imposed the greatest demand on healthcare resources, making almost three times as many visits to their GP or family doctor as non-sufferers (4.4 vs 1.5 visits over 6 months). More than two-thirds of depressed subjects (69%) were not prescribed any treatment and when drug therapy was prescribed (31%), only 25% of these subjects were given antidepressant drugs. The number of days of work lost due to illness increased with the severity of depression. Major depression had most impact on productive work, with sufferers losing four times as many working days over 6 months as non-sufferers. The results of the DEPRES survey confirm the high prevalence of depression in the community and the burden imposed on the individual sufferer in terms of impaired quality of life and on society in terms of healthcare utilization and lost productivity.

Importance: Generalized anxiety disorder (GAD) is poorly understood compared with other anxiety disorders, and debates persist about the seriousness of this disorder. Few data exist on GAD outside a small number of affluent, industrialized nations. No population-based data exist on GAD as it is currently defined in DSM-5. Objective: To provide the first epidemiologic data on DSM-5 GAD and explore cross-national differences in its prevalence, course, correlates, and impact. Design, Setting, and Participants: Data come from the World Health Organization World Mental Health Survey Initiative. Cross-sectional general population surveys were carried out in 26 countries using a consistent research protocol and assessment instrument. A total of 147 261 adults from representative household samples were interviewed face-to-face in the community. The surveys were conducted between 2001 and 2012. Data analysis was performed from July 22, 2015, to December 12, 2016. Main Outcomes and Measures: The Composite International Diagnostic Interview was used to assess GAD along with comorbid disorders, role impairment, and help seeking. Results: Respondents were 147 261 adults aged 18 to 99 years. The surveys had a weighted mean response rate of 69.5%. Across surveys, DSM-5 GAD had a combined lifetime prevalence (SE) of 3.7% (0.1%), 12-month prevalence of 1.8% (0.1%), and 30-day prevalence of 0.8% (0). Prevalence estimates varied widely across countries, with lifetime prevalence highest in high-income countries (5.0% [0.1%]), lower in middle-income countries (2.8% [0.1%]), and lowest in low-income countries (1.6% [0.1%]). Generalized anxiety disorder typically begins in adulthood and persists over time, although onset is later and clinical course is more persistent in lower-income countries. Lifetime comorbidity is high (81.9% [0.7%]), particularly with mood (63.0% [0.9%]) and other anxiety (51.7% [0.9%]) disorders. Severe role impairment is common across life domains (50.6% [1.2%]), particularly in high-income countries. Treatment is sought by approximately half of affected individuals (49.2% [1.2%]), especially those with severe role impairment (59.4% [1.8%]) or comorbid disorders (55.8% [1.4%]) and those living in high-income countries (59.0% [1.3%]). Conclusions and Relevance: The findings of this study show that DSM-5 GAD is more prevalent than DSM-IV GAD and is associated with substantial role impairment. The disorder is especially common and impairing in high-income countries despite a negative association between GAD and socioeconomic status within countries. These results underscore the public health significance of GAD across the globe while uncovering cross-national differences in prevalence, course, and impairment that require further investigation.