Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

Beyond the waves: Unraveling pandemic outcomes with genomic insights and immunity analysis - Evidence from 14 countries.

OBJECTIVE: Although the World Health Organization and many governments have recategorized COVID-19 as a generally mild to moderately severe disease, consecutive pandemic waves driven by immune escape variants have underscored the need for timely and accurate prediction of the next outbreak. Nevertheless, little attention has been paid to translating genomic data and infection- and vaccine-induced immunity into direct estimates. METHODS: We retrieved epidemiologic and genomic data shortly before pandemic waves across 14 developed countries from late 2021 to mid-2022 and examined associations between early-stage variant competition, infection- and vaccine-induced immunity, and the time intervals between wave peaks. We applied regression analysis and the generalized estimating equation method to construct an inferential model. RESULTS: Each per cent increase in the proportion of a new variant was associated with a 1.0% reduction in interpeak intervals on average. Curvilinear associations between vaccine-induced immunity and outcome variables were observed, suggesting that reaching a critical vaccine distribution rate may decrease the caseload of the upcoming wave. CONCLUSIONS: By leveraging readily accessible pre-outbreak genomic and epidemiologic data, our results not only substantiate the predictive potential of early variant fractions but also propose that immunity acquired through infection alone may not sufficiently mitigate transmission. Conversely, a rapid and widespread vaccination initiative appears to be correlated with a decrease in disease incidence.

Patients with first-episode psychosis in northern Taiwan: neurocognitive performance and niacin response profile in comparison with schizophrenia patients of different familial loadings and relationship with clinical features.

BACKGROUND: Examining patients with first-episode psychosis (FEP) provides opportunities to better understand the mechanism underlying these illnesses. By incorporating quantitative measures in FEP patients, we aimed to (1) determine the baseline distribution of clinical features; (2) examine the impairment magnitude of the quantitative measures by comparing with external controls and then the counterparts of schizophrenia patients of different familial loadings; and (3) evaluate whether these quantitative measures were associated with the baseline clinical features. METHODS: Patients with FEP were recruited from one medical center, two regional psychiatric centers, and two private clinics in northern Taiwan with clinical features rated using the Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale. Quantitative measurements included the Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), niacin response abnormality (NRA), and minor physical anomalies and craniofacial features (MPAs). To evaluate the relative performance of the quantitative measures in our FEP patients, four external comparison groups from previous studies were used, including three independent healthy controls for the CPT, WCST, and NRA, respectively, and one group of treatment-resistant schizophrenia patients for the MPAs. Additionally, patients from simplex families and patients from multiplex families were used to assess the magnitude of FEP patients' impairment on the CPT, WCST, and NRA. RESULTS: Among the 80 patients with FEP recruited in this study (58% female, mean age = 25.6 years, mean duration of untreated psychosis = 132 days), the clinical severity was mild to moderate (mean PANSS score = 67.3; mean PSP score = 61.8). Patients exhibited both neurocognitive and niacin response impairments (mean Z-scores: -1.24 for NRA, - 1.06 for undegraded d', - 0.70 for degraded d', - 0.32 for categories achieved, and 0.44 for perseverative errors) but did not show MPAs indicative of treatment resistance. Among these quantitative measures, three of the four neurocognitive indices were correlated with the baseline clinical features, whereas NRA did not show such correlation. CONCLUSIONS: This FEP study of Taiwanese patients revealed the presence of neurocognitive performance and niacin response and their different relationships with clinical features, rendering this sample useful for future follow-up and incorporation of multiomics investigation.

COVID-19 control measures unexpectedly increased the duration of stay at High Speed Rail stations during the first community outbreak in Taiwan.

During the COVID-19 pandemic, Taiwan has implemented strict border controls and community spread prevention measures. As part of these efforts, the government also implemented measures for public transportation. In Taiwan, there are two primary public transportation systems: Taiwan Railways (TR) is commonly utilized for local travel, while the Taiwan High-Speed Rail (THSR) is preferred for business trips and long-distance journeys due to its higher speed. In this study, we examined the impact of these disease prevention measures on the number of passengers and duration of stay in two major public transportation systems during the first community outbreak from April 29th to May 29th, 2021. Using data from a local telecommunications company, our study observed an expected decrease in the number of passengers after the cancellation of non-reserved seats at both TR and THSR stations across all 19 cities in the main island of Taiwan. Surprisingly, however, the duration of stay in some of the cities unexpectedly increased, especially at THSR stations. This unanticipated rise in the duration of stay has the potential to elevate contact probability among passengers and, consequently, the transmission rate. Our analysis shows that intervention policies may result in unforeseen outcomes, highlighting the crucial role of human mobility data as a real-time reference for policymakers. It enables them to monitor the impact of disease prevention measures and facilitates informed, data-driven decision-making.

Emergence and Persistent Dominance of SARS-CoV-2 Omicron BA.2.3.7 Variant, Taiwan.

Since April 2022, waves of SARS-CoV-2 Omicron variant cases have surfaced in Taiwan and spread throughout the island. Using high-throughput sequencing of the SARS-CoV-2 genome, we analyzed 2,405 PCR-positive swab samples from 2,339 persons and identified the Omicron BA.2.3.7 variant as a major lineage within recent community outbreaks in Taiwan.

Characterization of clinical features and comorbidities between bipolar affective disorder with and without depressive episodes.

BACKGROUNDS: A proportion of patients with bipolar disorder (BD) manifests with only unipolar mania (UM). This study examined relevant clinical features and psychosocial characteristics in UM compared with depressive-manic (D-M) subgroups. Moreover, comorbidity patterns of physical conditions and psychiatric disorders were evaluated between the UM and D-M groups. METHODS: This clinical retrospective study (N = 1015) analyzed cases with an average of 10 years of illness duration and a nationwide population-based cohort (N = 8343) followed up for 10 years in the Taiwanese population. UM was defined as patients who did not experience depressive episodes and were not prescribed adequate antidepressant treatment during the disease course of BD. Logistic regression models adjusted for relevant covariates were used to evaluate the characteristics and lifetime comorbidities in the two groups. RESULTS: The proportion of UM ranged from 12.91% to 14.87% in the two datasets. Compared with the D-M group, the UM group had more psychotic symptoms, fewer suicidal behaviors, a higher proportion of morningness chronotype, better sleep quality, higher extraversion, lower neuroticism, and less harm avoidance personality traits. Substantially different lifetime comorbidity patterns were observed between the two groups. CONCLUSIONS: Patients with UM exhibited distinct clinical and psychosocial features compared with patients with the D-M subtype. In particular, a higher risk of comorbid cardiovascular diseases and anxiety disorders is apparent in patients with D-M. Further studies are warranted to investigate the underlying mechanisms for diverse presentations in subgroups of BDs.

The use of premixed drugs in commodity packets in the population: prevalence and correlates revealed by the 2018 National Survey of Substance Use in Taiwan.

BACKGROUND: Administering premixed drugs in commodity packets was first reported in Asia in 2015, but there continues to be a dearth of related population-based data. This study aimed at examining (1) the prevalence of drug packet use in the population and (2) the sociodemographic profiles, particularly gender distribution, of drug packet users. METHODS: Data were derived from a survey of 18,626 Taiwanese civilians, aged 12-64 years, using stratified, multi-stage, random sampling in 2018. Participants anonymously completed a computer-assisted self-interview on tablet computers which covered the use and problematic use of illicit drugs/inhalants, prescription drugs and other psychoactive substances, among others. RESULTS: Approximately 1.46% of respondents had a lifetime use of illicit drugs, with drugs in commodity packets (0.18%) being ranked the fifth-most commonly used illicit drugs, higher than nitrous oxide (0.14%) and heroin (0.09%). Ten formats of drug packets were endorsed by users. Approximately 81.6% of persons with drug packet use had a lifetime use of other illicit drugs. The correlates of the use of drugs in commodity packets were similar to those of the exclusive use of other drugs except that there was a lack of gender differences in the use of drugs in commodity packets but not in the exclusive use of other drugs. CONCLUSION: Drugs in commodity packets have become a common way of administering illicit drugs in the population in Taiwan, and there were no gender differences among users. Our findings have implications for more efficient drug testing and culturally appropriate intervention for drug packet use.

Associations between lifetime mental disorders and suicidal behaviors: findings from the Taiwan psychiatry morbidity survey.

BACKGROUND: East Asia has high suicide rates but low prevalence of mental disorders. We examined the associations between prior lifetime mental disorders (mood disorders, anxiety disorders, substance use disorders, and impulse control disorders) and subsequent suicidal behaviors (suicidal ideation and attempts in the general population and suicide plans, planned attempts, and unplanned attempts in suicidal ideators) in Taiwan. METHODS: This survey applied the World Mental Health Survey Composite International Diagnostic Interview to a population representative sample of noninstitutionalized adults between 2003 and 2005. Odds ratios (ORs) obtained using discrete-time survival analysis were used to estimate population attributable fractions (PAFs) of suicidal behaviors due to lifetime mental disorders. RESULTS: Lifetime mental illness was a significant risk factor for subsequent suicidal behaviors (except unplanned attempts among ideators) despite the relatively low prevalence of mental disorders in people with suicidality (16.1%-35.0%). Each diagnosis increased the odds of suicidal ideation. In terms of acting on suicidal ideation, mood disorders were most strongly associated with having plans (OR = 10.0; 95% confidence interval, CI 4.3-21.1), whereas substance use disorders most strongly with either planned (OR = 27.3; 95% CI 6.3-118.5) or unplanned attempts (OR = 14.5; 95% CI 1.7-121.5). PAFs of all mental disorders on suicidality lay between 20 and 30% (except 11% of unplanned attempts among ideators). Mood, anxiety, and substance use disorders had higher PAFs than impulse control disorders. CONCLUSIONS: In addition to mood disorders, considering anxiety and substance use disorders is essential in devising population-based suicide prevention strategies.

Prevalence and correlates of suicidal behaviors in the Taiwan Psychiatric Morbidity Survey.

BACKGROUND/PURPOSE: Suicide is a huge global health burden. High suicide rates with a low prevalence of major depressive disorder were reported in East Asia. This study aimed to investigate the prevalence of suicidal behaviors in relation to the demographic characteristics and major depressive disorder in Taiwan. METHODS: This study was based on the Taiwan Psychiatric Morbidity Survey, conducted between 2003 and 2005, a survey of common psychiatric disorders in a nationally representative sample of non-institutionalized civilians aged 18 or above. Demographic data, major depressive disorder, and suicidal behaviors were ascertained by a face-to-face interview using the paper version of the World Mental Health Survey Composite International Diagnostic Interview. RESULTS: According to the total sample of 10,135 participants, the lifetime prevalence of suicidal ideation, plans and attempts was 7.52% (S.E = 0.46%), 1.31% (S.E. = 0.16%) and 1.29% (S.E. = 0.16%), respectively. Among suicide ideators, the conditional probability of making a suicide plan was 17.39% (S.E. = 1.92%), and a suicide attempt 17.16% (S.E. = 2.15%). Age ≤ 40, female sex, and major depressive disorder were related to a higher risk of suicidal behaviors in the general population; the former two were associated with further developing suicide attempts and the latter one developing plans among ideators. CONCLUSION: Despite low prevalence, major depressive disorder remained a significant risk factor for suicidal behaviors in Taiwan.

Nonpolio Enterovirus Activity during the COVID-19 Pandemic, Taiwan, 2020.

In Taiwan, lower nonpolio enterovirus activity during the coronavirus disease pandemic in 2020 compared with 2014-2019 might be attributable to adherence to nonpharmaceutical interventions. The preventable fraction among unexposed persons indicated that 90% of nonpolio enterovirus activity might have been prevented during 2014-2019 by adopting the same measures enforced in 2020.

The impact of Taiwan's implementation of a nationwide harm reduction program in 2006 on the use of various illicit drugs: trend analysis of first-time offenders from 2001 to 2017.

BACKGROUND: After implementing a nationwide harm reduction program in 2006, a dramatic decline in the incidence of human immunodeficiency virus (HIV) infection among people with injection drug use (IDU) was observed in Taiwan. The harm reduction program might have sent out the message discouraging the choice of IDU among illicit drug users in early stage. Based on the yearly first-time offense rates from 2001 to 2017, this study aimed to examine (1) whether the nationwide implementation of the harm reduction program in 2006 led to changes in first-time offenders' use of heroin; (2) whether the intervention had a similar effect on the use of other illicit drugs; and (3) whether the effect of the intervention was limited to the first-time offenders of young age groups. METHODS: Yearly first-time illicit-drug offense rates from 2001 to 2017 in Taiwan were derived from two national databases for drug arrests that were verified using urine tests: the Criminal Record Processing System on Schedule I/II Drugs and the Administrative Penalty System for Schedule III/IV Substances. A hierarchy of mutually exclusive categories of drug uses was defined by the drug with the highest schedule level among those tested positive in an arrest. Segmented regression analyses of interrupted time series were used to test for the impact of the 2006 intervention. RESULTS: There was a decrease of 22.37 per 100,000 in the rate for heroin but no detectable level changes in that for methamphetamine or ecstasy after the 2006 intervention in Taiwan. There were baseline decreasing trends in the first-time offense rate from 2001 to 2017 for heroin and ecstasy and an increasing trend for methamphetamine, with the slopes not altered by the 2006 intervention. The postintervention decrease in the first-time offense rate for heroin was detectable among offenders less than 40 years old. CONCLUSIONS: Our results indicate a diffusion effect of the 2006 intervention on decreasing heroin use among young offenders and have policy implications for better prevention and treatment for different age groups.

Investigation of early and lifetime clinical features and comorbidities for the risk of developing treatment-resistant depression in a 13-year nationwide cohort study.

BACKGROUND: To investigate the risk of treatment-resistant depression (TRD) in patients with depression by examining their clinical features, early prescription patterns, and early and lifetime comorbidities. METHODS: In total, 31,422 depressive inpatients were followed-up from diagnostic onset for more than 10-years. Patients were diagnosed with TRD if their antidepressant treatment regimen was altered ≥two times or if they were admitted after at least two different antidepressant treatments. Multiple Cox regression model were used to determine whether physical and psychiatric comorbidities, psychosis, and prescription patterns increased the risk of TRD by controlling for relevant demographic covariates. Survival analyses were performed for important TRD-associated clinical variables. RESULTS: Females with depression (21.24%) were more likely to suffer from TRD than males (14.02%). Early anxiety disorders were more commonly observed in the TRD group than in the non-TRD group (81.48 vs. 58.96%, p < 0.0001). Lifetime anxiety disorders had the highest population attributable fraction (42.87%). Seventy percent of patients with multiple psychiatric comorbidities developed TRD during follow-up. Cox regression analysis further identified that functional gastrointestinal disorders significantly increased TRD risk (aHR = 1.19). Higher doses of antidepressants and benzodiazepines and Z drugs in the early course of major depressive disorder increased TRD risk (p < 0.0001). CONCLUSION: Our findings indicate the need to monitor early comorbidities and polypharmacy patterns in patients with depression associated with elevated TRD risk.

Abnormally low prolactin levels in schizophrenia patients after switching to aripiprazole in a randomized trial: a biomarker for rebound in psychotic symptoms?

BACKGROUND: Switching to aripiprazole from other antipsychotics can avoid antipsychotic-induced hyperprolactinemia but may result in an abnormally low prolactin level. This study aimed to assess whether the aripiprazole-induced abnormally low prolactin level was a biomarker for subsequent rebound of positive symptoms in schizophrenia patients. METHODS: Participants were 63 patients in an 8-week trial of switching to aripiprazole, in which preswitching antipsychotics were maintained for the first 2 weeks and aripiprazole was fixed at 15 mg orally throughout the trial. A prolactin level of < 3.7 ng/ml was defined as abnormally low, and an increase of two or more points in the positive subscore of the Positive and Negative Syndrome Scale at two adjacent ratings was defined as a psychotic rebound. RESULTS: Among 63 patients, 25 (39.7%) had an abnormally low prolactin level and 21 (33.3%) had a psychotic rebound after switching to aripiprazole. In patients with abnormally low prolactin levels, 48.0% of them had a rebound in psychotic symptoms, whereas in those without abnormally low prolactin levels 23.7% did so. Multivariable logistic regression analysis with adjustment for sex, early age at onset, and preswitching medications revealed that abnormally low prolactin levels were associated with psychotic rebound (adjusted odds ratio = 3.55, 95% confidence interval = 1.02, 12.5). Furthermore, there was concurrency between the trend of the cumulative proportion of patients having an abnormally low prolactin level and that of the cumulative proportion of patients having a rebound in psychotic symptoms. CONCLUSIONS: An abnormally low prolactin level after switching to aripiprazole in schizophrenia patients was a potential warning sign of a psychotic rebound. Hence, monitoring of prolactin levels after switching to aripiprazole may help avoid such rebound in schizophrenia. TRIAL REGISTRATION: NCT00545467 ; Date of registration: 17/10/2007.

Early sexual initiation and risky sexual practices among alcohol- and tobacco-using young adults in Taiwan: mediation analysis of preceding-sex use of illicit drugs.

BACKGROUND: As early sexual initiation is increasingly common in East Asia, we examined its relations to risky sexual practices in alcohol- and tobacco-using individuals in Taiwan and evaluated whether the associations were mediated through preceding-sex use of illicit drugs. METHODS: Participants, recruited from alcohol- and tobacco-using adults aged 18 to 50 in Taipei through respondent-driven sampling (N = 1115), completed a computer-assisted self-interview covering questions on substance use and sexual experiences. In a subsample of 916 participants who had had sexual experience (median age 27), we examined the relations of early sexual initiation (< 16 years) to multiple sexual partners, casual sex, group sex, and rare condom use. Causal mediation analyses were conducted to examine whether illicit drug use preceding sex mediated these associations. RESULTS: Around 9.3% reported early sexual initiation and the prevalence of risky sexual practices ranged from 7% (group sex) to 47% (rare condom use). Early initiators had a higher prevalence of regular binge drinking, illicit drug use, and risky sexual practices. In the multivariable analyses, higher odds of multiple sexual partners, casual sex, and group sex were consistently associated with early sexual initiation, gender, and their interaction. Mediation through preceding-sex use of illicit drugs was found between early sexual initiation and the three risky sexual practices, with the proportions mediated ranging from 17 to 19%. CONCLUSIONS: Early sexual initiators were more likely to engage in risky sexual practices and preceding-sex use of illicit drugs partially explained this relationship, calling for more attention to this population's sexual health.

Residential Socioeconomic Environments and Areca Nut Use in Taiwan: A Comparison with Alcohol and Tobacco Use in Multilevel Analysis.

BACKGROUND: While the association between residential socioeconomic environments and the use of globally common substances such as alcohol and tobacco has been well documented in Western countries, it remains little known about regionally important substances, such as areca nut in Asia. Objective: This study was aimed to develop residential environmental indicators in the context of Taiwan and examine their associations with areca nut use, in comparison to alcohol and tobacco use. Methods: Data were drawn from 13,392 adults across 168 townships in the 2014 National Survey on Substance Use in Taiwan. Residential socioeconomic environment variables were derived from the census and analyzed using factor analysis. Multilevel logistic regression models were used to examine the association of individual- and residential-level factors with the use of areca nut (use/nonuse), alcohol (harmful use, low-risk use, or nonuse), and tobacco (nicotine dependence, regular active use, or nonuse). Results: A three-factor structure of socioeconomic environments derived from 16 residential-level variables consisted of Rural Disadvantage, Affluence, and Family Fragmentation. Multilevel analyses showed that areca nut use was associated with both individual-level (male sex, age group 35-44 years, being divorced/widowed/separated, low educational attainment, and the occupational group of labors) and residential-level (Rural Disadvantaged and Family Fragmented) variables; such a profile was most similar to that of nicotine dependence. Conclusions: A three-factor structure could be derived for the residential-level socioeconomic environments in the Taiwanese context. Rural Disadvantaged and Family Fragmented were associated with areca nut use, which have implications for interventions targeted at the community level.

Sex-moderated interactions between IL4/IL13 pathway genes and prenatal environment on cord blood IgE levels.

BACKGROUND: Elevated cord blood IgE (cIgE), a predictor of atopic diseases, is influenced by genetic and environmental factors. However, gene-environment interactions on cIgE elevation and their difference by sex remain largely unexplored. OBJECTIVE: This study aimed to determine whether there are sex-moderated interactions between genetic variants in the IL4/IL13 pathway and prenatal environments on cIgE elevation. METHODS: Comprehensive information on environmental tobacco smoke (ETS), home dampness (indexed by combining mildewy odour, visible mould and water stamp on the wall) and other household environments was obtained using a structured questionnaire during the third trimester of pregnancy in 1107 full-term newborns. The cord blood was collected for measuring cIgE levels, with elevation defined as ≥0.5 IU/mL, and for genotyping of five single nucleotide polymorphisms of three candidate genes (IL-13 rs1800925, rs20541, rs848, IL-4 rs2243250 and STAT6 rs324011). RESULTS: Gene-environment interactions on cIgE elevation were observed in male but not female newborns, including those between ETS and IL13 rs20541, between home dampness and STAT6 rs324011, and between composite environmental exposure (combined ETS and the three home dampness indices) and STAT6 rs324011 (P for interaction = 0.03, 0.006, and 0.001, respectively). Male newborns carrying STAT6 rs324011 CT or TT genotype manifested with a significant dose-response association of the composite environmental exposure with cIgE elevation. CONCLUSION AND CLINICAL RELEVANCE: Sex moderates the gene-environment interactions involving IL4/IL13 pathway genes and prenatal household environments on cIgE elevation. The absence of prenatal exposure to ETS and home dampness in male neonates carrying the STAT6 rs324011 CT or TT genotype is least likely associated with cIgE elevation.

Genetic associations and expression of extra-short isoforms of disrupted-in-schizophrenia 1 in a neurocognitive subgroup of schizophrenia.

Disrupted-in-schizophrenia 1 (DISC1) was reported to be associated with schizophrenia. In a previous study, we found significant association with schizophrenia patients with deficient sustained attention assessed by continuous performance test (CPT). This study aimed to identify risk polymorphisms in this specific neurocognitive subgroup and investigate the expression of different isoforms of DISC1. A total of 83 genetic variants were identified through direct sequencing in 50 controls and 100 schizophrenia patients. Fourteen variants were genotyped in 600 controls and 912 patients. Patients were subgrouped by familial loading (multiplex or simplex) and performance on CPT. The frequency of AA genotype of rs11122324 at the 3'-UTR of Es and Esv1 isoforms and of rs2793091 at intron 4 were significantly higher in multiplex schizophrenia patients than those in controls (corrected p < 0.05). In further subgrouping, the frequency of AA genotype of the two SNPs were significantly higher in multiplex schizophrenia patients with deficient sustained attention than those in controls (corrected p < 0.005). The mRNA expression levels of two extra-short isoforms (Es and Esv1) in the EBV-transformed lymphocytes of schizophrenia were significantly higher than those of controls. Luciferase reporter assays demonstrated that the A-allele of rs11122324 significantly upregulated DISC1 extra-short isoforms transcription compared with the G-allele. We found two SNPs (rs11122324 and rs2793091) of DISC1 may be specifically associated with multiplex schizophrenia patients with deficient sustained attention. The SNP rs11122324 may be a risk polymorphism, which may have functional influence on the transcription of Es and Esv1 through increasing their expression.

Prenatal and childhood exposure to phthalate diesters and neurobehavioral development in a 15-year follow-up birth cohort study.

OBJECTIVE: Longitudinal studies on neurobehavioral development in relation to prenatal and postnatal exposure to phthalates in school-age children and adolescents are limited. We investigated the association of prenatal and childhood phthalate exposure with the development of behavioral syndromes in 8-14-year-old children. METHOD: We recruited 430 pregnant women from 2000 to 2001 and followed their children at the ages of 2, 5, 8, 11, and 14 years, yielding 153 mother-child pairs in total. Urine samples from pregnant women in the third trimester and from children at 2-8 years of age were analyzed for the concentrations of seven urinary phthalate metabolites: monomethyl phthalate, monoethyl phthalate, monobutyl phthalate, monobenzyl phthalate (MBzP), and three di(2-ethylhexyl) phthalate (DEHP) metabolites, namely mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. Behavioral syndromes in children aged 8-14 years were assessed using the Child Behavior Checklist. We constructed mixed models to examine these associations after adjustments for potential covariates. RESULTS: Maternal urinary MEHP levels were associated with higher scores for internalizing problems (ß = 0.028, 95% confidence interval [CI]: 0.0004, 0.055) and externalizing problems (ß = 0.040, 95% CI: 0.013, 0.066). Associations of the maternal urinary sum of DEHP metabolite levels with delinquent behavior scores and externalizing problems scores were positive (ß = 0.035, 95% CI: 0.013, 0.057 for delinquent behavior; ß = 0.026, 95% CI: 0.001, 0.050 for externalizing problems). Furthermore, children's urinary MBzP levels were associated with higher scores for social problems (ß = 0.018, 95% CI: 0.001, 0.035). Similar patterns were observed for borderline and clinical ranges. CONCLUSION: Early-life exposure to phthalates may influence behavioral syndrome development in children. Future studies are needed to replicate these findings, and efforts to reduce exposures to phthalates during critical early life stages may be warranted.

E-Cigarette Use in a Country With Prevalent Tobacco Smoking: A Population-Based Study in Taiwan.

BACKGROUND: The different profiles of e-cigarette users in different age groups have seldom been investigated, particularly in populations facing a high prevalence of cigarette smoking. This study aims to examine the prevalence and correlates of e-cigarette use separately for adolescents and adults in nationally representative samples in Taiwan. METHODS: Among 17,837 participants in the 2014 National Survey of Substance Use in Taiwan, 4445 were aged 12 to 17 years and 13,392 were aged 18 to 64 years. Individuals' lifetime tobacco use was divided into four groups: non-use, exclusive e-cigarette use, exclusive cigarette use, and dual use. Questions on sociodemographic features, use and problematic use of tobacco, alcohol, and other drugs, and psychosocial distress, among others, were administered using a computer-assisted self-interview on tablet computers. RESULTS: Among lifetime users of e-cigarette (2.2% for adults and 0.8% for adolescents), 4.5% for adults and 36.6% for adolescents were exclusive e-cigarette users. From use of exclusive e-cigarettes to use of exclusive cigarettes to dual use, those usage groups were related to an increasing trend of adjusted odds ratios for use of other psychoactive substances, particularly problematic use of alcohol or drugs, and with more depressive symptoms. Two correlates were specific to e-cigarette use: alcohol use had stronger relationships with e-cigarette use among adolescents, and younger adults (18-34) were more likely to try e-cigarettes compared to older adults. CONCLUSIONS: These results provide essential information regarding e-cigarette use in the general population, and future prevention strategies should account for its specific correlates in young people.

Severity in sustained attention impairment and clozapine-resistant schizophrenia: a retrospective study.

BACKGROUND: Among patients with treatment-resistant schizophrenia (TRS), some exhibited further clozapine resistance (CR). This study aimed to investigate whether greater severity of treatment resistance in schizophrenia is associated with greater impairments in sustained attention. METHODS: Patients with a DSM-IV-defined schizophrenia were recruited from a psychiatric center in northern Taiwan (April 2010 to October 2010). Both TRS and CR were determined retrospectively from participants' medical records following the consensus guidelines. The patients were divided into three groups: 102 non-TRS, 48 TRS without CR, and 54 TRS with CR. They underwent both undegraded and degraded Continuous Performance Tests (CPT), and their performance scores (d') were standardized against a community sample to derive age-, sex-, and education-adjusted z scores. RESULTS: The TRS with CR group had significantly lower adjusted z scores of d' on both undegraded and degraded CPTs than the other two groups. Meanwhile, the differences between the TRS without CR group and the non-TRS group were not significant. Multivariable linear regression analyses with adjustment for covariates revealed a trend of gradient impairments on the degraded CPT from non-TRS to TRS without CR and to TRS with CR. The proportions of attentional deficits (an adjusted z score of ≤ - 2.5) on the degraded CPT also exhibited a significant trend, from 36.3% in the non-TRS group to 62.5% in the TRS without CR group and to 83.3% in the TRS with CR group. CONCLUSIONS: Greater severity of treatment resistance in schizophrenia was associated with greater impairments in sustained attention, indicating some common vulnerability.