Buildup from birth onward of short telomeres in human hematopoietic cells.

Telomere length (TL) limits somatic cell replication. However, the shortest among the telomeres in each nucleus, not mean TL, is thought to induce replicative senescence. Researchers have relied on Southern blotting (SB), and techniques calibrated by SB, for precise measurements of TL in epidemiological studies. However, SB provides little information on the shortest telomeres among the 92 telomeres in the nucleus of human somatic cells. Therefore, little is known about the accumulation of short telomeres with age, or whether it limits the human lifespan. To fill this knowledge void, we used the Telomere-Shortest-Length-Assay (TeSLA), a method that tallies and measures single telomeres of all chromosomes. We charted the age-dependent buildup of short telomeres (<3 kb) in human hematopoietic cells from 334 individuals (birth-89 years) from the general population, and 18 patients with dyskeratosis congenita-telomere biology disorders (DC/TBDs), whose hematopoietic cells have presumably reached or are close to their replicative limit. For comparison, we also measured TL with SB. We found that in hematopoietic cells, the buildup of short telomeres occurs in parallel with the shortening with age of mean TL. However, the proportion of short telomeres was lower in octogenarians from the general population than in patients with DC/TBDs. At any age, mean TL was longer and the proportion of short telomeres lower in females than in males. We conclude that though converging to the TL-mediated replicative limit, hematopoietic cell telomeres are unlikely to reach this limit during the lifespan of most contemporary humans.

Telomere-length dependent T-cell clonal expansion: A model linking ageing to COVID-19 T-cell lymphopenia and mortality.

BACKGROUND: Severe COVID-19 T-cell lymphopenia is more common among older adults and entails poor prognosis. Offsetting the decline in T-cell count during COVID-19 demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. METHODS: We developed a model of TL-dependent T-cell clonal expansion capacity with age and virtually examined the relation of T-cell clonal expansion with COVID-19 mortality in the general population. FINDINGS: The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity rapidly declines by more than 90% over the next ten years. The collapse in the T-cell clonal expansion capacity coincides with the steep increase in COVID-19 mortality with age. INTERPRETATION: Short HCTL might increase vulnerability of many older adults, and some younger individuals with inherently short HCTL, to COVID-19 T-cell lymphopenia and severe disease. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

La salud mental de los trabajadores de salud en Guatemala durante la pandemia de COVID-19: resultados de base del estudio de cohortes HÉROES / Mental health of Guatemalan health care workers during the COVID-19 pandemic: baseline findings from the HEROES cohort study / Saúde mental dos trabalhadores da saúde guatemaltecos durante a pandemia de COVID-19: constatações basais do estudo da coorte HEROES

RESUMEN Objetivos. Evaluar la prevalencia de base de los trastornos de salud mental y exposiciones conexas en una cohorte de trabajadores de salud de Guatemala. Métodos Se analizó la información de base del estudio HÉROES (por COVID-19 HEalth caRe wOrkeRs Study, sobre los trabajadores de salud durante la pandemia) en Guatemala, realizado en línea en el 2020. Las variables de resultado fueron malestar psicológico y síntomas depresivos. Las exposiciones incluyeron experiencias con la COVID-19, características sociodemográficas y características del trabajo. En los análisis se utilizaron modelos de regresión de Poisson brutos y ajustados. Resultados. De los 1801 trabajadores de salud que aceptaron participar, 1522 (84,5%) completaron el cuestionario; 1014 (66,8%) eran mujeres. De los participantes, 59,1% (intervalo de confianza de 95% [IC 95%] = 56,6-61,5) tuvo un tamizaje positivo para malestar psicológico y 23% (IC 95% = 20,9-25,2) para síntomas depresivos de moderados a graves. Las experiencias con la pandemia de COVID-19, las características sociodemográficas y las características del trabajo se correlacionaron con las variables de resultado del estudio. Los participantes que estaban preocupados por el contagio de la COVID-19 tuvieron un mayor riesgo de malestar psicológico (riesgo relativo [RR] = 1,47; IC 95% = 1,30-1,66) y síntomas depresivos (RR = 1,51; IC 95% = 1,17-1,96). Asimismo, los participantes más jóvenes presentaban un riesgo alto de malestar psicológico (RR = 1,80; IC 95% = 1,24-2,63) y síntomas depresivos (razón de posibilidades [OR] = 4,58; IC 95% = 1,51-13,87). Conclusiones. Las afecciones de salud mental tienen una prevalencia sumamente alta en los trabajadores de salud de Guatemala.

ABSTRACT Objectives. To assess the baseline prevalence of mental health conditions and associated exposures in a cohort of health care workers (HCWs) in Guatemala. Methods. We analyzed baseline information from the 2020 Web-based COVID-19 Health Care Workers Study (HEROES)-Guatemala. Outcomes included mental distress and depressive symptoms. Exposures included COVID-19 experiences, sociodemographic characteristics, and job characteristics. We used crude and adjusted Poisson regression models in our analyses. Results. Of the 1801 HCWs who accepted to participate, 1522 (84.5%) completed the questionnaire; 1014 (66.8%) were women. Among the participants, 59.1% (95% confidence interval [CI] = 56.6, 61.5) screened positive for mental distress and 23% (95% CI = 20.9, 25.2) for moderate to severe depressive symptoms. COVID-19 experiences, sociodemographic characteristics, and job characteristics were associated with the study outcomes. Participants who were worried about COVID-19 infection were at higher risk of mental distress (relative risk [RR] = 1.47; 95% CI = 1.30, 1.66) and depressive symptoms (RR = 1.51; 95% CI = 1.17, 1.96). Similarly, the youngest participants were at elevated risk of mental distress (RR = 1.80; 95% CI = 1.24, 2.63) and depressive symptoms (OR = 4.58; 95% CI = 1.51, 13.87). Conclusions. Mental health conditions are highly prevalent among Guatemalan.

RESUMO Objetivos. Avaliar a prevalência basal de condições de saúde mental e exposições associadas em uma coorte de trabalhadores da saúde (TS) na Guatemala. Métodos. Analisamos as informações da linha de base do estudo on-line sobre trabalhadores da saúde e a COVID-19 (HEROES), realizado em 2020 na Guatemala. Os desfechos incluíram angústia debilitante e sintomas de depressão. As exposições incluíram experiências com a COVID-19, características sociodemográficas e características do trabalho. Usamos em nossas análises modelos de regressão bruta e ajustada de Poisson. Resultados. Dos 1801 TS que concordaram em participar, 1522 (84,5%) preencheram o questionário, sendo que 1014 (66,8%) eram mulheres. Dentre esses participantes, 59,1% (intervalo de confiança [IC] de 95%=56,6; 61,5) apresentaram resultado positivo na triagem de angústia debilitante e 23% (IC 95%=20,9, 25,2) apresentaram resultado positivo para sintomas de depressão moderados a graves. Experiências com COVID-19, e características sociodemográficas e de trabalho apresentaram associação com os resultados do estudo. Os participantes que estavam preocupados com infecção por COVID-19 apresentaram maior risco de angústia debilitante (risco relativo [RR]=1,47; IC95%=1,30; 1,66) e sintomas de depressão (RR=1,51; IC 95% =1,17; 1,96). Da mesma maneira, os participantes mais jovens apresentaram alto risco de apresentarem angústia debilitante (RR=1,80; IC 95%=1,24; 2,63) e sintomas de depressão (OR=4,58; IC 95%=1,51; 13,87). Conclusões. Condições de saúde mental são altamente prevalentes entre os guatemaltecos.

Short Telomeres and a T-Cell Shortfall in COVID-19: The Aging Effect.

The slow pace of global vaccination and the rapid emergence of SARS-CoV-2 variants suggest recurrent waves of COVID-19 in coming years. Therefore, understanding why deaths from COVID-19 are highly concentrated among older adults is essential for global health. Severe COVID-19 T-cell lymphopenia is more common among older adults, and it entails poor prognosis. Much about the primary etiology of this form of lymphopenia remains unknown, but regardless of its causes, offsetting the decline in T-cell count during SARS-CoV-2 infection demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. We have built a model that captures the effect of age-dependent TL shortening in hematopoietic cells and its effect on T-cell clonal expansion capacity. The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity plummets by more than 90% over the next ten years. The collapse coincides with the steep increase in COVID-19 mortality with age. HCTL metrics may thus explain the vulnerability of older adults to COVID-19. That said, the wide inter-individual variation in HCTL across the general population means that some younger adults with inherently short HCTL might be at risk of severe COVID-19 lymphopenia and mortality from the disease. SIGNIFICANCE STATEMENT: Declining immunity with advancing age is a general explanation for the increased mortality from COVID-19 among older adults. This mortality far exceeds that from viral illnesses such as the seasonal influenza, and it thus requires specific explanations. One of these might be diminished ability with age to offset the development of severe T-cell lymphopenia (a low T-cell count in the blood) that often complicates COVID-19. We constructed a model showing that age-dependent shortening of telomeres might constrain the ability of T-cells of some older COVID-19 patients to undertake the massive proliferation required to clear the virus that causes the infection. The model predicts that individuals with short telomeres, principally seniors, might be at a higher risk of death from COVID-19.

Explaining the Black-white depression paradox: Interrogating the Environmental Affordances Model.

The Environmental Affordances (EA) model posits that Black Americans' engagement with unhealthy behaviors (i.e. smoking, alcohol use, eating calorie-dense foods) to cope with stressor exposure may simultaneously account for their observed greater risk of chronic physical illness, and their observed equal or lesser prevalence of depression, relative to white Americans - the so-called "Black-white depression paradox." However, the specific mechanisms through which such effects might arise have been theorized and analyzed inconsistently across studies, raising concerns regarding the appropriateness of existing empirical tests of the model as well as the validity of the conclusions. We specify the two mechanisms most consistent with the EA model - 'Mediation-only' and 'Mediation and Modification' - and derive a priori predictions based on each. We systematically test these pathways using a subset of 559 participants of the Child Health and Development Study who were included in an adult follow-up study between 2010 and 2012 and self-identified as Black or white. Results failed to support either of the two mechanisms derived from the EA model, challenging the validity and utility of the model for explaining racial differences in depression; efforts to develop alternative hypotheses to explain the paradox are needed.

The age pattern of the male-to-female ratio in mortality from COVID-19 mirrors that of cardiovascular disease in the general population.

Males are at a higher risk of dying from COVID-19 than females. Older age and cardiovascular disease are also associated with COVID-19 mortality. To better understand how age and sex interact in contributing to COVID-19 mortality, we stratified the male-to-female (sex) ratios in mortality by age group. We then compared the age-stratified sex ratios with those of cardiovascular mortality and cancer mortality in the general population. Data were obtained from official government sources in the US and five European countries: Italy, Spain, France, Germany, and the Netherlands. The sex ratio of deaths from COVID-19 exceeded one throughout adult life, increasing up to a peak in midlife, and declining markedly in later life. This pattern was also observed for the sex ratio of deaths from cardiovascular disease, but not cancer, in the general populations of the US and European countries. Therefore, the sex ratios of deaths from COVID-19 and from cardiovascular disease share similar patterns across the adult life course. The underlying mechanisms are poorly understood and warrant further investigation.

Racial differences in alcohol and tobacco use in adolescence and mid-adulthood in a community-based sample.

PURPOSE: Smoking and alcohol use have been posited as possible contributors to racial health disparities, despite higher smoking and alcohol use among non-Hispanic White youth and young adults compared to Blacks. To further investigate this claim, we aim to assess variation in alcohol and cigarette use across two distinct points of the life course. METHOD: Data are from a subset of 559 (279 male, 280 female) self-identified Black and White participants of the Child Health and Development study. Self-report alcohol and cigarette use were collected between age 15-17 and at mean age 50. Logistic regressions were estimated; supplementary analyses adjusted for maternal age, prenatal smoking, household income, childhood SES, and education. RESULTS: White participants were more likely to drink regularly (Odds ratio (OR) 2.2; 95%CI 1.2, 4.0) and be intoxicated (OR 2.0; 95%CI 1.2, 3.2) in adolescence compared with Blacks. In mid-adulthood, Whites remained more likely to currently drink (OR 2.3; 95%CI 1.6, 3.4) but among drinkers, less likely to binge drink (OR 0.4; 95%CI 0.2, 0.8). White participants were less likely to smoke in mid-adulthood (OR 0.4; 95%CI 0.3, 0.6), but among smokers, were more likely to smoke ≥ ½ a pack per day (OR 3.4; 95%CI 1.5, 7.8). CONCLUSIONS: Blacks were less likely to engage in drinking across the life course, but, among drinkers, more likely to binge drink in mid-adulthood. Blacks were more likely to smoke in mid-adulthood, but smoked infrequently compared with Whites. These patterns suggest that a reframing of disparities mechanisms to focus on broader structural and social factors may benefit progress in understanding and ameliorating inequities.

Implementing the protocol of a pilot randomized controlled trial for the recovery-oriented intervention to people with psychoses in two Latin American cities / Implementação de um protocolo para um estudo piloto randomizado e controlado sobre uma intervenção voltada para a recuperação em pessoas com psicoses em duas cidades latino-americanas / Implementando un protocolo para una prueba piloto controlada aleatorizada en una intervención orientada a la recuperación de personas con psicosis en dos ciudades latinoamericanas

Several Latin American countries have made remarkable strides towards offering community mental health care for people with psychoses. Nonetheless, mental health clinics generally have a very limited outreach in the community, tending to have weaker links to primary health care; rarely engaging patients in providing care; and usually not providing recovery-oriented services. This paper describes a pilot randomized controlled trial (RCT) of Critical Time Intervention-Task Shifting (CTI-TS) aimed at addressing such limitations. The pilot RCT was conducted in Santiago (Chile) and Rio de Janeiro (Brazil). We included 110 people with psychosis in the study, who were recruited at the time of entry into community mental health clinics. Trial participants were randomly divided into CTI-TS intervention and usual care. Those allocated to the intervention group received usual care and, in addition, CTI-TS services over a 9-month period. Primary outcomes include quality of life (WHO Quality of Life Scale - Brief Version) and unmet needs (Camberwell Assessment of Needs) at the 18-month follow-up. Primary outcomes at 18 months will be analyzed by Generalized Estimating Equations (GEE), with observations clustered within sites. We will use three-level multilevel models to examine time trends on the primary outcomes. Similar procedures will be used for analyzing secondary outcomes. Our hope is that this trial provides a foundation for planning a large-scale multi-site RCT to establish the efficacy of recovery-oriented interventions such as CTI-TS in Latin America.

Diversos países latino-americanos já alcançaram avanços notáveis na oferta de assistência em saúde mental para pessoas com psicoses. No entanto, as clínicas de saúde mental geralmente realizam atividades de extensão muito limitadas dentro das comunidades, tendem a ter vínculos fracos com a assistência primária, raramente envolvem os próprios pacientes nos cuidados e poucas vezes prestam serviços orientados para a recuperação. O artigo descreve um estudo piloto randomizado e controlado sobre a Critical Time Intervention-Task Shifting (CTI-TS), que teve como objetivo analisar essas limitações. O estudo piloto foi realizado em Santiago (Chile) e no Rio de Janeiro (Brasil). Teve como meta a inclusão de 110 pessoas com psicose, recrutadas no momento da entrada em clínicas comunitárias de saúde mental. Os participantes foram randomizados para o CTI-TS ou para os cuidados usuais. Aqueles alocados ao grupo da intervenção receberam os cuidados usuais e os serviços de CTI-TS ao longo de 9 meses. Os desfechos primários incluíram a qualidade de vida (WHO Quality of Life Scale - Brief Version) e as necessidades não atendidas (Camberwell Assessment of Needs) no acompanhamento aos 18 meses. Os desfechos primários aos 18 meses serão analisados com a técnica de Equações de Estimação Generalizadas (GEE), com as observações agrupadas dentro dos locais do estudo. Serão utilizados modelos em três níveis para examinar as tendências temporais nos desfechos primários. Procedimentos semelhantes serão utilizados para analisar os resultados secundários. Espera-se que o estudo forneça uma base para planejar um estudo randomizado e controlado em grande escala e em múltiplos locais para estabelecer a eficácia da intervenção orientada para a recuperação, a exemplo da CTI-TS, na América Latina.

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Association of Prenatal Exposure to Population-Wide Folic Acid Fortification With Altered Cerebral Cortex Maturation in Youths.

Importance: Presently, 81 countries mandate the fortification of grain products with folic acid to lessen the risk of neural tube defects in the developing fetus. Epidemiologic data on severe mental illness suggest potentially broader effects of prenatal folate exposure on postnatal brain development, but this link remains unsubstantiated by biological evidence. Objective: To evaluate associations among fetal folic acid exposure, cortical maturation, and psychiatric risk in youths. Design, Setting, and Participants: A retrospective, observational clinical cohort study was conducted at Massachusetts General Hospital (MGH) among 292 youths 8 to 18 years of age born between January 1993 and December 2001 (inclusive of folic acid fortification rollout ±3.5 years) with normative results of clinical magnetic resonance imaging, divided into 3 age-matched groups based on birthdate and related level of prenatal folic acid fortification exposure (none, partial, or full). Magnetic resonance imaging was performed between January 2005 and March 2015. Two independent, observational, community-based cohorts (Philadelphia Neurodevelopmental Cohort [PNC] and National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development [NIH]) comprising 1078 youths 8 to 18 years of age born throughout (PNC, 1992-2003) or before (NIH, 1983-1995) the rollout of folic acid fortification were studied for replication, clinical extension, and specificity. Statistical analysis was conducted from 2015 to 2018. Exposures: United States-mandated grain product fortification with folic acid, introduced in late 1996 and fully in effect by mid-1997. Main Outcomes and Measures: Differences in cortical thickness among nonexposed, partially exposed, and fully exposed youths (MGH) and underlying associations between age and cortical thickness (all cohorts). Analysis of the PNC cohort also examined the association of age-cortical thickness slopes with the odds of psychotic symptoms. Results: The MGH cohort (139 girls and 153 boys; mean [SD] age, 13.3 [2.3] years) demonstrated exposure-associated cortical thickness increases in bilateral frontal and temporal regions (9.9% to 11.6%; corrected P < .001 to P = .03) and emergence of quadratic (delayed) age-associated thinning in temporal and parietal regions (ß = -11.1 to -13.9; corrected P = .002). The contemporaneous PNC cohort (417 girls and 444 boys; mean [SD] age, 13.5 [2.7] years) also exhibited exposure-associated delays of cortical thinning (ß = -1.59 to -1.73; corrected P < .001 to P = .02), located in similar regions and with similar durations of delay as in the MGH cohort. Flatter thinning profiles in frontal, temporal, and parietal regions were associated with lower odds of psychosis spectrum symptoms in the PNC cohort (odds ratio, 0.37-0.59; corrected P < .05). All identified regions displayed earlier thinning in the nonexposed NIH cohort (118 girls and 99 boys; mean [SD] age, 13.3 [2.6] years). Conclusions and Relevance: The results of this study suggest an association between gestational exposure to fortification of grain products with folic acid and altered cortical development and, in turn, with reduction in the risk of psychosis in youths.

Depressive symptoms and their association with social determinants and chronic diseases in middle-aged and elderly Chinese people.

Depression is one of the most prevalent mental disorders worldwide. Little information is available regarding association of depressive symptoms (DS) with cancer and chronic diseases among middle-aged and elderly Chinese in a population-based setting. In this study we evaluated the prevalence and examined correlates of DS in two population-based cohort studies. Included in the analyses were 103,595 people with a mean age of 61.8 years at the DS assessment. The prevalence of DS was 2.4% in men and 5.6% in women. We found elderly participants, those with lower BMI, or chronic diseases were more likely to experience DS. Having a history of stroke (odds ratio (OR) = 2.2 in men and 1.8 in women), cancer (OR = 3.3 in men and 1.9 in women), or Parkinson's disease (OR = 3.1 in men and 2.7 in women) was associated with high DS. In women, high income and high education levels were inversely related to DS. Being a single woman, long-term or heavy female smoker was associated with high prevalence of DS. High BMI was correlated with low prevalence of depression in men. Our data suggests a low prevalence of DS among middle-aged and elderly people in Shanghai, China. Age, education, income, marital status, smoking, BMI, and certain health conditions were associated with DS.

Evaluating the Relationship Between Birth Weight for Gestational Age and Adult Blood Pressure Using Participants From a Cohort of Same-Sex Siblings, Discordant on Birth Weight Percentile.

Many studies have described an inverse relationship between birth weight and blood pressure (BP). Debate continues, however, over the magnitude and validity of the association. This analysis draws on the Early Determinants of Adult Health study (2005-2008), a cohort of 393 US adults (mean age 43 years; 47% male), including 114 same-sex sibling pairs deliberately sampled to be discordant on sex-specific birth weight for gestational age (BW/GA) in order to minimize confounding in studies of fetal growth and midlife health outcomes. Every quintile increment in BW/GA percentile was associated with a 1.04-mm Hg decrement in adult systolic BP (95% confidence interval (CI): -2.14, 0.06) and a 0.63-mm Hg decrement in diastolic BP (95% CI: -1.35, 0.09), controlling for sex, age, site, smoking, and race/ethnicity. The relationship was strongest among those in the lowest decile of BW/GA. Adding adult body mass index to the models attenuated the estimates (e.g., to -0.90 mm Hg (95% CI: -1.94, 0.14) for systolic BP). In the sibling-pair subgroup, associations were slightly stronger but with wider confidence intervals (e.g., -1.22 mm Hg (95% CI: -5.20, 2.75) for systolic BP). In conclusion, we found a small inverse relationship between BW/GA and BP in cohort and sibling-pair analyses, but the clinical or public health significance is likely limited.

Smoking in Pregnancy and Child ADHD.

BACKGROUND AND OBJECTIVE: There is a well-documented association between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD). The degree to which this reflects causal intrauterine effects or is due to unmeasured confounding is not clear. We sought to compare the association between maternal smoking during pregnancy and offspring ADHD with the associations with paternal smoking, grandmother's smoking when pregnant with mother, and maternal smoking in previous pregnancies. Each of these exposures is expected to be influenced by much of the same confounding factors as maternal smoking during pregnancy, but cannot have direct intrauterine effects. A sibling control design was also used. METHODS: The current study used data from the Norwegian Mother and Child Cohort Study (n > 100 000 children). Mothers and fathers reported on smoking during pregnancy, and mothers reported on smoking in previous pregnancies and their mother's smoking when pregnant with them. Mothers reported on child ADHD symptoms at 5 years of age. Information about child ADHD diagnosis was obtained from the Norwegian Patient Registry. RESULTS: Maternal smoking during pregnancy was not more strongly associated with offspring ADHD diagnosis than was paternal smoking, grandmother's smoking when pregnant with mother, or maternal smoking in previous pregnancies. Sibling control analyses showed no association between maternal smoking in pregnancy and child ADHD symptoms among siblings discordant for maternal smoking. CONCLUSIONS: These results suggest that the association between maternal smoking during pregnancy and offspring ADHD is not due to causal intrauterine effects, but reflects unmeasured confounding.

Telomere Length and the Cancer-Atherosclerosis Trade-Off.

Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan.

Substance use and duration of untreated psychosis in KwaZulu-Natal, South Africa.

BACKGROUND: Substance use and psychiatric disorders cause significant burden of disease in low- and middle-income countries. Co-morbid psychopathology and longer duration of untreated psychosis (DUP) can negatively affect treatment outcomes. OBJECTIVES: The study assessed substance use amongst adults with severe mental illness receiving services at a regional psychiatric hospital in KwaZulu-Natal (South Africa). We describe the prevalence and correlates of lifetime substance use and examine the association between substance use and DUP. METHODS: A cross-sectional survey recruited adults diagnosed with severe mental illness and assessed lifetime and past 3-month substance use using the World Health Organization Alcohol, Smoking and Substance Involvement Screening Test. Regression analyses were conducted to determine associations between lifetime substance use (other than alcohol and tobacco) and DUP as measured by the World Health Organization Encounter Form. RESULTS: Amongst 87 participants, alcohol (81.6%), tobacco (75.6%) and cannabis (49.4%) were the most common substances reported for lifetime use. Risk of health-related problems (health, social, financial, legal and relationship) of cannabis use was associated with younger age, single marital status and lower education. Adjusted regression analyses indicated that use of amphetamines and methaqualone is associated with longer DUP. CONCLUSIONS: Substance use is prevalent amongst psychiatric patients in KwaZulu-Natal and may contribute to longer DUP. Mental health services in this region should address co-morbid substance use and psychiatric disorders.

Leukocyte Telomere Length in Newborns: Implications for the Role of Telomeres in Human Disease.

BACKGROUND AND OBJECTIVE: In adults, leukocyte telomere length (LTL) is variable, familial, and longer in women and in offspring conceived by older fathers. Although short LTL is associated with atherosclerotic cardiovascular disease, long LTL is associated with major cancers. The prevailing notion is that LTL is a "telomeric clock," whose movement (expressed in LTL attrition) reflects the pace of aging. Accordingly, individuals with short LTL are considered to be biologically older than their peers. Recent studies suggest that LTL is largely determined before adulthood. We examined whether factors that largely characterize LTL in adults also influence LTL in newborns. METHODS: LTL was measured in blood samples from 490 newborns and their parents. RESULTS: LTL (mean ± SD) was longer (9.50 ± 0.70 kb) in newborns than in their mothers (7.92 ± 0.67 kb) and fathers (7.70 ± 0.71 kb) (both P < .0001); there was no difference in the variance of LTL among the 3 groups. Newborn LTL correlated more strongly with age-adjusted LTL in mothers (r = 0.47; P < .01) than in fathers (r = 0.36; P < .01) (P for interaction = .02). Newborn LTL was longer by 0.144 kb in girls than in boys (P = .02), and LTL was longer by 0.175 kb in mothers than in fathers (P < .0001). For each 1-year increase in father's age, newborn LTL increased by 0.016 kb (95% confidence interval: 0.04 to 0.28) (P = .0086). CONCLUSIONS: The large LTL variation across newborns challenges the telomeric clock model. Having inherently short or long LTL may be largely determined at birth, anteceding by decades disease manifestation in adults.

Maternal smoking and offspring inattention and hyperactivity: results from a cross-national European survey.

In utero exposure to tobacco smoke is associated with adverse neonatal outcomes; the association with later childhood mental health outcomes remains controversial. We used a strategy involving comparison of maternal and paternal smoking reports in a sample pooling data from six diverse European countries. Data were drawn from mother (N = 4,517) and teacher (N = 4,611) reported attention deficit and hyperactivity disorder (ADHD) symptoms in school children aged 6-11 in Turkey, Romania, Bulgaria, Lithuania, Germany, and the Netherlands, surveyed in 2010. Mothers report on self and husband's smoking patterns during the pregnancy period. Logistic regression used with control covariates including demographics, maternal distress, live births, region, and post-pregnancy smoking. In unadjusted models, maternal prenatal smoking was associated with probable ADHD based on mother [Odds Ratio (OR) = 1.82, 95 % Confidence Interval (CI) 1.45-2.29], teacher (OR = 1.69, 95 % CI 1.33-2.14) and mother plus teacher (OR = 1.49, 95 % CI 1.03-2.17) report. Paternal prenatal smoking was similarly associated with probable ADHD in unadjusted models. When controlled for relevant confounders, maternal prenatal smoking remained a risk factor for offspring probable ADHD based on mother report (OR = 1.44, 95 % CI 1.06-1.96), whereas the effect of paternal prenatal smoking diminished (e.g., mother report: OR = 1.17, 95 % CI 0.92-1.49). Drawing on data from a diverse set of countries across Europe, we document that the association between maternal smoking and offspring ADHD is stronger than that of paternal smoking during the pregnancy period and offspring ADHD. To the extent that confounding is shared between parents, these results reflect a potential intrauterine influence of smoking on ADHD in children.

Maternal bereavement and cryptorchidism in offspring.

BACKGROUND: Cryptorchidism (undescended testis) is a common anomaly with largely unexplained etiology. Animal studies have suggested maternal emotional stress as a potential risk factor, but this has not been studied in humans. We aimed to investigate whether maternal bereavement due to the death of a close relative in the antenatal period increases the occurrence of cryptorchidism in the offspring. METHODS: In a population-based cohort, we studied death of a close relative as the exposure and cryptorchidism entries in nationwide medical registries as the outcome. Danish national registries included 898,961 (23,609 exposed) boys born from 1978 to 2008 with a maximum of 30 years of follow-up. RESULTS: A total of 20,947 boys had cryptorchidism, of whom 13,524 also underwent corrective surgery. We found no increased occurrence of cryptorchidism in the offspring (hazard ratio = 1.02 [95% confidence interval = 0.92-1.14]). Results were similar when the diagnosis was verified with surgery. We adjusted for maternal and paternal age, birth year, and family history of cryptorchidism. CONCLUSION: We observed no association between maternal bereavement before and during pregnancy and the occurrence of cryptorchidism in the offspring.

Identifying children with autism spectrum disorder at 18 months in a general population sample.

BACKGROUND: Previous research on clinical and high-risk samples suggests that signs of autism spectrum disorder (ASD) can be detected between 1 and 2 years of age. We investigated signs of ASD at 18 months in a population-based sample and the association with later ASD diagnosis. METHODS: The study sample includes 52,026 children born 2003 through 2008 and is a subset of children that participated in the Norwegian Mother and Child Cohort (MoBa), a population-based longitudinal study, and the Autism Birth Cohort (ABC), a sub-study on ASD. Parents completed all 23 items from the Modified Checklist for Autism in Toddlers (M-CHAT) at 18 months. RESULTS: The M-CHAT 6-critical-item criterion and the 23-item criterion had a specificity of 97.9% and 92.7% and a sensitivity of 20.8% and 34.1%, respectively. In the 173 children diagnosed with ASD to date, 60 children (34.7%) scored above the cut-off on either of the screening criteria. The items with the highest likelihood ratios were 'interest in other children', 'show objects to others' and 'response to name'. CONCLUSION: Even though one-third of the children who later received an ASD diagnosis were identified through M-CHAT items, the majority scored below cut-off on the screening criteria at 18 months. The results imply that it might not be possible to detect all children with ASD at this age.

Analysis of self-selection bias in a population-based cohort study of autism spectrum disorders.

BACKGROUND: This study examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data. The outcome under study was specialist-confirmed diagnosis of autism spectrum disorders (ASDs). METHODS: The cohort sample (n = 89 836) was derived from the population-based prospective Norwegian Mother and Child Cohort Study and its substudy of ASDs, the Autism Birth Cohort (ABC) study. The nationwide registry data were derived from the Medical Birth Registry of Norway (n = 507 856). The children were born in 1999­2007, and seven prenatal and perinatal exposures were selected for analyses. RESULTS: ASDs were reported for 234 (0.26%) children in the cohort and 2072 (0.41%) in the nationwide population. Compared with the nationwide population, the cohort had an under-representation of the youngest women (<25 years), those who had single status, mothers who smoked during pregnancy, and non-users of prenatal folic acid supplements. The ratios of the adjusted odds ratios (ORs) in the cohort over the adjusted ORs in the nationwide population were as follows; primipara pregnancy: 1.39/1.22, prenatal folic acid use: 0.85/0.86, prenatal smoking: 1.20/1.17, preterm birth (<37 weeks): 1.48/1.42, low birthweight (<2500 g): 1.60/1.58, male sex: 4.39/4.59 (unadjusted only); and caesarean section history: 1.03/1.04. CONCLUSIONS: Associations estimated between ASDs and perinatal and prenatal exposures in the cohort are close to those estimated in the nationwide population. Self-selection does not appear to compromise validity of exposure-outcome associations in the ABC study.