Concomitant use of antidepressants and benzodiazepines during pregnancy and associated risk of congenital malformations: a population-based cohort study in Taiwan.

BACKGROUND: Despite the frequent co-administration of antidepressants and benzodiazepines, the association between such concomitant use during pregnancy and the risk of congenital malformations remains inadequately explored. This study aims to examine the association between concomitant use of antidepressants and benzodiazepines during the first trimester and organ-specific congenital malformations. METHODS: We conducted a population-based cohort study using Taiwan's National Birth Certificate Application database, the Maternal and Child Health database, and Taiwan's National Health Insurance database. Pregnant people aged 15-50 years with singleton births between Jan 1, 2004, and Dec 31, 2018, were included. Use of antidepressants and benzodiazepines was defined as at least one prescription during the first trimester, and concomitant use was defined as the overlapping prescription of both drugs with an overlapping prescription period. The primary outcomes were overall congenital malformations and eight organ-specific malformations, consisting of the nervous system, heart, respiratory system, oral cleft, digestive system, urinary system, genital system, and limb malformations. Logistic regression models with propensity score fine stratification weighting approach were used to control for measured confounders. Analyses controlling for confounding by indication and sibling comparison analyses were done to address unmeasured confounders. No individuals with lived experience participated in the research or writing process. FINDINGS: The cohort included 2 634 021 singleton pregnancies, and 8599 (0·3%) individuals were concomitant users of antidepressants and benzodiazepines during the first trimester (mean age at delivery was 31·8 years [SD 5·2] for pregnancies with exposure to antidepressants and benzodiazepines vs 30·7 years [SD 4·9] for pregnancies without exposure). All study participants were female, and information about ethnicity was not available. Absolute risk of overall malformations was 3·81 per 100 pregnancies with exposure, compared with 2·87 per 100 pregnancies without exposure. The propensity score-weighted odds ratios (weighted ORs) did not suggest an increased risk for overall malformations (weighted OR 1·10, 95% CI 0·94-1·28), heart defects (1·01, 0·83-1·23), or any of the other organ-specific malformations, except for digestive system malformations, for which the weighted OR remained statistically significant after adjustment (1·63, 1·06-2·51). The absence of an increased risk for overall congenital malformations associated with concomitant use of antidepressants and benzodiazepines was supported by the analyses controlling for confounding by indication and sibling-matched comparisons. INTERPRETATION: The findings of this study suggest that the concomitant use of antidepressants and benzodiazepines during the first trimester is not associated with a substantial increase in risk for most malformation subtypes. However, considering other potential adverse effects of using both medications concomitantly, a thorough assessment of the risks and benefits is crucial for clinical decision making. FUNDING: National Science and Technology Council.

Prescription Patterns and Predisposing Factors of Benzodiazepine and Z-Hypnotic Use During Pregnancy: A Nationwide Cohort Study.

PURPOSE: The use of benzodiazepines and Z-hypnotics during pregnancy has raised significant concerns in recent years. However, there are limited data that capture the prescription patterns and predisposing factors in use of these drugs, particularly among women who have been long-term users of benzodiazepines and Z-hypnotics before pregnancy. METHODS: This population-based cohort study comprised 2 930 988 pregnancies between 2004 and 2018 in Taiwan. Women who were dispensed benzodiazepines or Z-hypnotics during pregnancy were identified and further stratified into groups based on their status before pregnancy: long-term users (with a supply of more than 180 days within a year), short-term users (with a supply of less than 180 days within a year), and nonusers. Trends in the use of benzodiazepines or Z-hypnotics and concomitant use with antidepressants or opioids were assessed. Logistic regression models were utilized to identify factors associated with use of these drugs during pregnancy, and interrupted time series analyses (ITSA) were employed to evaluate utilization patterns of these drugs across different pregnancy-related periods. RESULTS: The overall prevalence of benzodiazepine and Z-hypnotic use was 3.5% during pregnancy. Among prepregnancy long-term users, an upward trend was observed. The concomitant use of antidepressants or opioids among exposed women increased threefold (from 8.6% to 23.1%) and sixfold (from 0.3% to 1.7%) from 2004 to 2018, respectively. Women with unhealthy lifestyle behaviors, such as alcohol abuse (OR 2.48; 95% CI, 2.02-3.03), drug abuse (OR 10.34; 95% CI, 8.46-12.64), and tobacco use (OR 2.19; 95% CI, 1.96-2.45), as well as those with psychiatric disorders like anxiety (OR 6.99; 95% CI, 6.77-7.22), insomnia (OR 15.99; 95% CI, 15.55-16.45), depression (OR 9.43; 95% CI, 9.07-9.80), and schizophrenia (OR 21.08; 95% CI, 18.76-23.69), and higher healthcare utilization, were more likely to use benzodiazepines or Z-hypnotics during pregnancy. ITSA revealed a sudden decrease in use of benzodiazepines and Z-hypnotics after recognition of pregnancy (level change -0.55 percentage point; 95% CI, -0.59 to -0.51). In contrast, exposures to benzodiazepines and Z-hypnotics increased significantly after delivery (level change 0.12 percentage point; 95% CI, 0.09 to 0.16). CONCLUSIONS: In this cohort study, an increased trend of benzodiazepine and Z-hypnotic use during pregnancy among prepregnancy long-term users, as well as concomitant use with antidepressants or opioids were found. The findings have highlighted the existence of various risk factors associated with the use of these drugs during pregnancy. Utilization patterns varied across different stages of pregnancy, highlighting the need for prescription guidelines and educational services for women using these drugs during pregnancy.

Mothering and mother-child interactions in the unaffected siblings of autistic children.

AIM: To investigate parenting and mother-child interactions in unaffected siblings of autistic children. METHOD: This cross-sectional study enrolled 274 probands with a DSM-5 diagnosis of autism spectrum disorder (ASD) (87.4% male; mean [SD] age = 11 years 4 months [3 years 2 months]), their unaffected siblings (n = 274, 46.72% male; mean [SD] age = 11 years 3 months [3 years 4 months]), and 296 age-balanced and sex-balanced typically developing children (82.77% male; mean [SD] age = 11 years 3 months [2 years 8 months]). Maternal parenting styles and mother-child interactions were assessed using maternal reporting. RESULTS: Regardless of the child's age, maternal educational level, or presence of attention-deficit/hyperactivity disorder, autistic children received more overprotective and controlling parental behaviour than unaffected children. Correlates for parenting, mother-child interactions, and behavioural problems in the home setting in children with ASD and typically developing children were autistic traits, maternal anxiety and depressive symptoms, and maternal autistic characteristics; those in unaffected siblings were age, autistic traits, maternal educational level, and maternal autistic characteristics. INTERPRETATION: The diagnosis of ASD in a child can significantly influence maternal parenting behaviours, mother-child interactions, and the child's behavioural problems in the home setting. Furthermore, maternal anxiety or depressive symptoms, along with autistic characteristics in both mother and child, might shape parenting practices and exacerbate behavioural difficulties in autistic children.

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.

Association between maternal benzodiazepine or Z-hypnotic use in early pregnancy and the risk of stillbirth, preterm birth, and small for gestational age: a nationwide, population-based cohort study in Taiwan.

BACKGROUND: Benzodiazepines and Z-hypnotics are commonly prescribed for anxiety and insomnia during pregnancy, but the evidence regarding potential adverse neonatal outcomes is insufficient because of poor control for confounding factors in previous studies. We therefore aimed to evaluate the association between the use of benzodiazepines or Z-hypnotics during early pregnancy and adverse neonatal outcomes (stillbirth, preterm birth, and small for gestational age). METHODS: We did a nationwide, population-based cohort study in Taiwan using three data sources: Taiwan's National Birth Certificate Application database, the National Health Insurance database, and the Maternal and Child Health Database. The study cohort included all singleton pregnancies of females aged 15-50 years who gave birth between Jan 1, 2004, and Dec 31, 2018. Pregnancies without valid information were excluded. Benzodiazepine and Z-hypnotic use was defined as at least one benzodiazepine or Z-hypnotic prescription during early pregnancy (the first 20 weeks of pregnancy). The primary outcomes were stillbirth (fetal death at or after 20 weeks' gestation), preterm birth (<37 weeks' gestation), and small for gestational age (birthweight below the 10th percentile for gestational age by sex). Logistic regression models with propensity score fine stratification weighting were used to control for potential confounders and examine the association between benzodiazepines or Z-hypnotics use during early pregnancy and the risk of adverse neonatal outcomes. Odds ratios (ORs) and 95% CIs were reported. We used confounding by indication control analyses, a sibling control study, and a paternal negative control design to account for unmeasured confounders. The risk associated with exposure during late pregnancy was also assessed. FINDINGS: Between Oct 7, 2021, and June 10, 2022, we analysed the study data. The cohort included 2 882 292 singleton pregnancies; of which, 75 655 (2·6%) of the mothers were dispensed one or more benzodiazepines or Z-hypnotics during early pregnancy. Women exposed during pregnancy were older (mean age at delivery was 31·0 years [SD 5·3] for exposed women vs 30·6 years [4·9] for unexposed women), had a higher prevalence of psychiatric disorders, and were more likely to have unhealthy lifestyle behaviours than unexposed women. Information about ethnicity was not available. Early pregnancy exposure was associated with adverse neonatal outcomes compared with non-exposure. The propensity score-weighted OR was 1·19 (95% CI 1·10-1·28) for stillbirth, 1·19 (1·16-1·23) for preterm birth, and 1·16 (1·13-1·19) for small for gestational age. After controlling for confounding by indication, there was no significant association between drug exposure and stillbirth risk; however, this attenuation was not observed for preterm birth and small for gestational age. In models with sibling controls that accounted for familial confounding and genetic factors, early exposure to benzodiazepines or Z-hypnotics was not associated with an increased risk of stillbirth and preterm birth, but it remained significantly associated with small for gestational age. The paternal negative control analyses with point estimates close to the null indicated no strong evidence of unmeasured confounding shared by the mother and the father. Substantially increased risks of stillbirth and preterm birth were observed for late pregnancy exposure. INTERPRETATION: Benzodiazepine or Z-hypnotic use in early pregnancy is not associated with a substantial increase in the risk of stillbirth and preterm birth after accounting for unmeasured confounding factors. Clinicians should be aware of the increased risk of small for gestational age and caution should be taken when prescribing these medications during late pregnancy. FUNDING: National Science and Technology Council, Taiwan. TRANSLATION: For the Taiwanese translation of the abstract see Supplementary Materials section.

Population-based prevalence of somatic symptom disorder and comorbid depression and anxiety in Taiwan.

OBJECTIVE: The nationwide prevalence of somatic symptom disorder (SSD) has not yet been investigated in Asia. SSD is often comorbid with depression and anxiety, and the effects of these conditions on medical utilization await clarification. We hence performed a study in Taiwan to explore these issues. METHODS: Using telephone-based sampling and interview, we obtained data for 3161 participants whose age, gender and living area were compatible with the Taiwan population. We gathered scores of the Patient Health Questionnaire-15 (PHQ-15), Health Anxiety Questionnaire (HAQ) and Patient Health Questionnaire-4 (PHQ-4). Individuals with a PHQ-15 score of at least 4 and a HAQ score of at least 17 were considered to have SSD. Descriptive statistics were used to clarify the prevalence and normative data of the questionnaires. We used multiple logistic regression analyses to investigate the relation between diagnoses and medical utilization. RESULTS: The prevalence of SSD was 5.00% and women had a higher SSD prevalence than men; participants aged 40-49 years had the highest SSD prevalence. In SSD patients, 33.58% had depression or anxiety. After correcting for demographics, SSD and anxiety (but not depression) were associated with a significantly high level of outpatient/emergency department attendance. Comorbid depression or anxiety did not significantly increase the medical utilization of SSD patients. CONCLUSION: The nationwide SSD prevalence in Taiwan is compatible with the description in the DSM-5. The comorbidity of SSD and depression/anxiety is common, but depression or anxiety does not significantly increase the SSD patients' medical utilization.

A Counting Stroop Functional Magnetic Resonance Imaging Study on the Effects of ORADUR-Methylphenidate in Drug-Naive Children with Attention-Deficit/Hyperactivity Disorder.

Objective: Methylphenidate is effective in reducing the clinical symptoms of patients with attention-deficit/hyperactivity disorder (ADHD). ORADUR®-methylphenidate is a new extended-release preparation of methylphenidate. This study aimed at identifying brain regions with activation changes and their correlations with neuropsychological functions after treatment with ORADUR-methylphenidate in children with ADHD. Methods: We recruited drug-naive children with ADHD and age- and sex-matched typically developing (TD) children. They were all scanned with the functional magnetic resonance imaging (fMRI) during the counting Stroop task at baseline, and those with ADHD had the second fMRI assessment after 8-week treatment with ORADUR-methylphenidate. The Rapid Visual Information Processing (RVP) and Conners' Continuous Performance Test (CCPT) were used to assess the attention performance of the ADHD (before and after treatment) and TD groups. Results: ORADUR-methylphenidate significantly decreased inattention (Cohen d = 2.17) and hyperactivity-impulsivity (Cohen d = 0.98) symptoms. We found less activation in the right inferior frontal gyrus (rIFG) in the pre-treatment ADHD children than TD children and greater treatment-induced activation in the dorsal anterior cingulate cortex (dACC) and the right dorsolateral prefrontal cortex (rDLPFC). There was no significant difference between the post-treatment ADHD and TD groups. However, the treatment-related activations in the dACC, rDLPFC, and rIFG were significantly correlated with CCPT and RVP measures. Conclusions: Our findings indicated that ORADUR-methylphenidate increased brain activations in the dACC, rDLPFC, and rIFG in children with ADHD, associated with improved focused attention, reduced impulsivity, and enhanced inhibition control. Activities of these brain regions might be biomarkers for the treatment effectiveness of methylphenidate for ADHD. Clinical Trials Registration: ClinicalTrials.gov number, NCT02450890.

Activation of PGRN/MAPK axis stimulated by the hypoxia-conditioned mesenchymal stem cell-derived HIF-1α facilitates osteosarcoma progression.

BACKGROUND: Progranulin (PGRN) is an important survival factor in the progression of multiple cancers. PURPOSE: To explore the effects and mechanisms of PGRN on malignant biological behavior of osteosarcoma (OS) cells and the effects of mesenchymal stem cells (MSCs) and the hypoxic microenvironment on PGRN alteration. MATERIAL AND METHODS: The expression pattern of PGRN in OS were evaluated in OS tissues and cell lines. Next, a loss-of-function assay investigated the function of PGRN on the proliferation, migration and cell death of OS cells. The activation of MAPK signaling in the process was examined by western blot and functional experiments accompanied by skatole. Additionally, we internally silenced hypoxia-inducible factor-1α (HIF-1α) in MSCs along with exogenously added HIF-1α (exo-HIF-1α) to explore how MSCs affect PGRN alteration and the malignant behavior of OS cells. RESULTS: An aberrantly high expression of PGRN was observed in OS and associated with the poor prognosis of OS patients. PGRN knockdown repressed the proliferation, migration and induced cell death of OS cells, and activating MAPK pathway reversed these effects. Further evidence showed that MSCs regulated PGRN to mediate the malignant biological behavior of OS cells. Hypoxia enhanced HIF-1α expression in MSCs. HIF-1α silencing in MSCs under hypoxia suppressed the oncogenic effects of MSCs and reduced PGRN expression in OS cells, while the treatment of exo-HIF-1α reversed the depressive effects of HIF1α silencing on OS progression. CONCLUSION: Overall, we concluded that PGRN, which was activated by the increase of hypoxic-MSCs-derived HIF-1α, promoted OS progression through the activation of MAPK signaling.

Neurodevelopmental model of schizophrenia revisited: similarity in individual deviation and idiosyncrasy from the normative model of whole-brain white matter tracts and shared brain-cognition covariation with ADHD and ASD.

The neurodevelopmental model of schizophrenia is supported by multi-level impairments shared among schizophrenia and neurodevelopmental disorders. Despite schizophrenia and typical neurodevelopmental disorders, i.e., autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), as disorders of brain dysconnectivity, no study has ever elucidated whether whole-brain white matter (WM) tracts integrity alterations overlap or diverge between these three disorders. Moreover, whether the linked dimensions of cognition and brain metrics per the Research Domain Criteria framework cut across diagnostic boundaries remains unknown. We aimed to map deviations from normative ranges of whole-brain major WM tracts for individual patients to investigate the similarity and differences among schizophrenia (281 patients subgrouped into the first-episode, subchronic and chronic phases), ASD (175 patients), and ADHD (279 patients). Sex-specific WM tract normative development was modeled from diffusion spectrum imaging of 626 typically developing controls (5-40 years). There were three significant findings. First, the patterns of deviation and idiosyncrasy of WM tracts were similar between schizophrenia and ADHD alongside ASD, particularly at the earlier stages of schizophrenia relative to chronic stages. Second, using the WM deviation patterns as features, schizophrenia cannot be separated from neurodevelopmental disorders in the unsupervised machine learning algorithm. Lastly, the canonical correlation analysis showed schizophrenia, ADHD, and ASD shared linked cognitive dimensions driven by WM deviations. Together, our results provide new insights into the neurodevelopmental facet of schizophrenia and its brain basis. Individual's WM deviations may contribute to diverse arrays of cognitive function along a continuum with phenotypic expressions from typical neurodevelopmental disorders to schizophrenia.

Men's decrease and women's increase in harmful alcohol use from the 2014 to 2018 national surveys in Taiwan: A harbinger for an emerging national trend in East Asia?

BACKGROUND: Gender differences in alcohol use have narrowed in Western societies, but that in Asia has been less investigated. By comparing the 2014 and 2018 waves of the national survey in Taiwan, we aimed to examine the gender differences in population trends in past-month alcohol use, binge drinking, and harmful alcohol use. METHODS: The national survey enrolled 17,837 participants in 2014 and 18,626 participants in 2018. Binge drinking was defined as having ≥5 drinks on one occasion in the past month, and harmful alcohol use as having an Alcohol Use Disorders Identification Test score of ≥8. RESULTS: There were significant decreases from 2014 to 2018 in the population's prevalence of past-month alcohol use, binge drinking, and harmful alcohol use. However, males and females had different trends: males showed significant reductions in all three alcohol use behaviours (a decrease of 3.79%, 1.59%, and 2.60%, respectively), while females exhibited a significant rise in harmful alcohol use (from 1.32% to 1.72%), particularly among those aged 18-29 years. CONCLUSION: There was gender convergence in alcohol use in Taiwan, mainly due to men's decrease and women's increase in harmful alcohol use. Our findings have important implications for the intervention and prevention of the problematic use of alcohol in East Asia.

Neural substrates underpinning intra-individual variability in children with ADHD: A voxel-based morphometry study.

BACKGROUND/PURPOSE: Increased intra-individual variability (IIV) in reaction time (RT) is a key feature of attention-deficit/hyperactivity disorder (ADHD). However, little is known about neurobiology underpinnings of IIV in ADHD. METHODS: We assessed 55 youths with ADHD, and 55 individually-matched typically developing control (TDC) with the MRI and Conners' Continuous Performance Test. The ex-Gaussian distribution of RT was estimated to capture IIV with the parameters σ (sigma) and τ (tau). The regional brain volumes, analyzed by voxel-based morphometry, were correlated with IIV parameters. RESULTS: We found both distinct and shared correlations among ADHD and TDC. For grey matter, there were significant σ-by-group interactions in the cingulate cortex and thalamus and also a τ-by-group interaction in the right inferior frontal gyrus. There was also shared negative associations between σ and regional volumes of the right posterior cerebellum and a positive association between τ and the right anterior insula. For white matter, there was a significant σ-by-group interaction in the genu of the corpus callosum and significant τ-by-group interactions in the right anterior corona radiata, the left splenium of the corpus callosum, and bilateral posterior cerebellum. There were also shared patterns that increased τ was associated with increased regional volumes of the right anterior corona radiata and decreased regional volumes of the right posterior limb of the internal capsule. CONCLUSION: This study highlights that brain regions responsible for the motor, salience processing and multimodal information integration are associated with increased IIV in youths with ADHD.

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.

Effect of Eriocitrin on Cell Proliferation, Apoptosis, Migration, and Scar Formation-Related Genes Expression in Tendon Stem Cells.

Tendinopathy is a common disease in elite and recreational athletes, and Eriocitrin is a flavonoid compound, which has antioxidant properties. The present study was undertaken to investigate the effect of Eriocitrin on tendon stem cells in vitro. Different concentrations of Eriocitrin (0, 25, 50, 75 µM) were used to treat tendon stem cells, cell proliferation was determined by CCK8 assay, apoptosis was detected by propidium iodide (PI) staining assays and caspase-3 activity assessment, wound-healing assaywas selected to detect the migration, and RT-PCR was chosen to detect the expression levels of scar formation-related gene markers (COMP, Fibronectin, and Biglycan). Eriocitrin treatment promoted cell proliferation of tendon stem cells in dose-dependent manner, and it reduced the apoptotic activities and improved the migration of tendon stem cells. It inhibited COMP, Biglycan, and Fibronectin expression. In summary, eriocitrin promoted cell proliferation of tendon stem cells, improved the migration of tendon stem cells, and inhibited the expression levels of some scar formation-related gene markers.

Use of Charlson Comorbidity Index and Nomogram to Predict Mortality in Elderly Patients with Late-Life Schizophrenia.

Objectives: Comorbid illness burden signifies a poor prognosis in schizophrenia. The aims of this study were to estimate the severity of comorbidities in elderly patients with schizophrenia, determine risk factors associated with mortality, and establish a reliable nomogram for predicting 1-, 3- and 5-year mortality and survival. Methods: This population-based study rigorously selected schizophrenia patients (≥65 years) having their first admission due to schizophrenia during the study period (2000-2013). Comorbidity was scored using the updated Charlson Comorbidity Index (CCI). Results: This study comprised 3827 subjects. The mean stay of first admission due to schizophrenia was 26 days. Mean numbers of schizophrenia and non-schizophrenia-related hospitalization (not including the first admission) were 1.80 and 3.58, respectively. Mean ages at death were 73.50, 82.14 and 89.32 years old, and the mean times from first admission to death were 4.24, 3.33, and 1.87 years in three different age groups, respectively. Nearly 30% were diagnosed with ≥3 comorbidities. The most frequent comorbidities were dementia, chronic pulmonary disease and diabetes. The estimated 1-, 3- and 5-year survival rates were 90%, 70%, and 64%, respectively. Schizophrenia patients with comorbid diseases are at increased risk of hospitalization and mortality (p < 0.05). Conclusion: The nomogram, composed of age, sex, the severity of comorbidity burden, and working type could be applied to predict mortality risk in the extremely fragile patients.

Differential Treatment Effects of Methylphenidate and Atomoxetine on Executive Functions in Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: This study aimed to compare the efficacy of methylphenidate and atomoxetine on improving executive functions among children with attention-deficit/hyperactivity disorder (ADHD). Methods: This was an open-label, head-to-head, 3-month, randomized clinical trial with two-arm parallel-treatment groups: osmotic-release oral system methylphenidate (OROS-MPH; n = 79) and atomoxetine once daily (n = 78). Three major domains of executive functions were assessed, including response selection/inhibition, flexibility, and planning/working memory. The neuropsychological measures included the Conners' continuous performance test and the Cambridge Neuropsychological Test Automated Battery. Results: We found that both treatment groups showed improvement in executive functions (p-value <0.05 for the major indices of each domain). In addition, OROS-MPH was associated with a greater magnitude of improvement in the response selection/inhibition; the slope for detectability improvement in the Conners' continuous performance test was 0.06 for atomoxetine and 0.15 for OROS-MPH (p-value <0.01); the slope in rapid visual information processing was 2.22 for atomoxetine and 3.45 for OROS-MPH (p-value <0.05). Conclusion: Both OROS-MPH and atomoxetine improved various domains of executive functions in children with ADHD. There is greater improvement in response selection/inhibition among patients treated with OROS-MPH than those with atomoxetine. This trial was registered with ClinicalTrials.gov (no. NCT00916786).

Farrerol ameliorate adjuvant-induced ankle injury via alteration of PPAR-γ signal pathway.

This study evaluated the anti-inflammatory activity against lipopolysaccharide (LPS)-mediated mouse macrophages (in vitro) and assessed the protective effect of farrerol on arthritis caused by complete freund adjuvant (CFA) in rats. For the evaluation of the pharmacological effect of farrerol on the activity of nitric oxide (NO) and cyclooxygenase, pro-inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1ß, RAW 264.7 cells were used. A 0.1 ml CFA was injected subcutaneously for the induction of arthritis. The paw volume, body weight and arthritic score were estimated at regular intervals. Pro-inflammatory cytokines, inflammatory mediators, and antioxidant parameters were also estimated. Farrerol suppressed NO production and COX-catalyzed prostaglandin (PGE2 ) in RAW 264.7. Farrerol also downregulated the p-p65, p-IκBα expression and upregulated the PPAR-γ expression in RAW 264.7 cells. Treatment of farrerol increased body weight substantially, and reduced paw edema and arthritic score. Farrerol treatment also significantly improved the level of hemoglobin (Hb), count of red blood cells (RBC), and decreased the rate of erythrocyte sedimentation (ESR), white blood cell (WBC) parameters, while the generation of pro-inflammatory cytokines inhibited. Together, farrerol also suppressed the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß. Obtained results directed that the farrerol exerted its therapeutic effect against CFA-induced arthritic rats through anti-inflammatory mechanism by regulation of the PPAR-γ. PRACTICAL APPLICATIONS: Increase the arthritis disease worldwide day-by-day. The current research study showed the anti-arthritic effect of farrerol (flavonoid phytoconstituent) of Rhododendron dauricum Linn. In this study, farrerol considerably inhibited the NF-κB to show the anti-arthritic effect. The finding showed the potential effect against acute and chronic inflammation via inhibition of inflammatory mediators and oxidative stress. The result suggests the anti-inflammatory and antioxidant effect of farrerol. On the basis of result, we can say that farrerol can be the beneficial drug to treat the arthritis.

Whole Brain White Matter Tract Deviation and Idiosyncrasy From Normative Development in Autism and ADHD and Unaffected Siblings Link With Dimensions of Psychopathology and Cognition.

OBJECTIVE: The heterogeneity of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) preclude definitive identification of neurobiomarkers and biological risks. High clinical overlap suggests multifaceted circuit-level alterations across diagnoses, which remains elusive. This study investigated whether individuals with ADHD or ASD and their unaffected siblings constitute a spectrum of neurodevelopmental conditions in terms of white matter etiology. METHODS: Sex-specific white matter tract normative development was modeled from diffusion MRI of 626 typically developing control subjects (ages 5-40 years; 376 of them male). Individualized metrics estimating white matter tract deviation from the age norm were derived for 279 probands with ADHD, 175 probands with ASD, and their unaffected siblings (ADHD, N=121; ASD, N=72). RESULTS: ASD and ADHD shared diffuse white matter tract deviations in the commissure and association tracts (rho=0.54; p<0.001), while prefrontal corpus callosum deviated more remarkably in ASD (effect size=-0.36; p<0.001). Highly correlated deviance patterns between probands and unaffected siblings were found in both ASD (rho=0.69; p<0.001) and ADHD (rho=0.51; p<0.001), but only unaffected sisters of ASD probands showed a potential endophenotype in long-range association fibers and projection fibers connecting prefrontal regions. ADHD and ASD shared significant white matter tract idiosyncrasy (rho=0.55; p<0.001), particularly in tracts connecting prefrontal regions, not identified in either sibling group. Canonical correlation analysis identified multiple dimensions of psychopathology/cognition across categorical entities; autistic, visual memory, intelligence/planning/inhibition, nonverbal-intelligence/attention, working memory/attention, and set-shifting/response-variability were associated with distinct sets of white matter tract deviations. CONCLUSIONS: When conceptualizing neurodevelopmental disorders as white matter tract deviations from normative patterns, ASD and ADHD are more alike than different. The modest white matter tract alterations in siblings suggest potential endophenotypes in these at-risk populations. This study further delineates brain-driven dimensions of psychopathology/cognition, which may help clarify within-diagnosis heterogeneity and high between-diagnosis co-occurrence.

Associations of parental and peer cross-substance use with 12-17-year-old adolescents' problematic alcohol use: A parent-child dyadic gender analysis.

BACKGROUND: Adolescent alcohol use was found to be influenced by parental and peer alcohol use. Drinking behaviors also differed by gender. However, previous studies mainly focused on adolescents' substance use in relation to the same substance use among their salient others. Hence, this study investigated the cross-substance relationships of alcohol and tobacco use of parents and peers with adolescents' problematic alcohol use, separately by gender. METHODS: Data were derived from 4445 adolescents aged 12-17 years from the 2014 National Survey of Substance Use, a nationally representative survey in Taiwan. Problematic alcohol use was assessed using the Alcohol Use Disorders Identification Test (AUDIT). Multivariate multinomial logistic regression was used, stratified by gender. RESULTS: For males, maternal (adjusted odds ratio [aOR] = 1.73) and peer (aOR = 2.57) alcohol use was related to social drinking (AUDIT < 2); paternal (aOR = 3.58), maternal (aOR = 2.18), peer alcohol use (aOR = 5.37), and their own tobacco use (aOR = 4.72) were related to problem drinking (AUDIT ≥ 2). For females, maternal (aOR = 2.26) and peer (aOR = 2.84) alcohol use was related to social drinking; maternal (aOR = 2.35) and peer tobacco use (aOR = 3.48), and paternal (aOR = 4.56) and peer alcohol use (aOR = 3.36) were linked to problem drinking. CONCLUSIONS: Both male and female adolescents' alcohol use was associated with their peer alcohol use, and gender differences were found in relation to their parental and peer substance use. Specifically, the parental role-modeling of smoking was only significant in mother-daughter dyads. These findings could inform multifaceted adolescent alcohol prevention programs, tailoring for males and females and also targeting their parental and peer substance use.

A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Clinical Trial of ORADUR-Methylphenidate for Treating Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

Objective: Methylphenidate (MPH) is efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD), but there are no data about the efficacy and safety of its new formulation (ORADUR®-MPH extended release, ORADUR-MPH) in patients with ADHD, which is the study objective. Method: This was a Phase III, multicenter, randomized, double-blind, placebo-controlled, two-way crossover clinical trial. One hundred children and adolescents with a clinical diagnosis of ADHD (72.7% male) received at least one dose of ORADUR-MPH or a placebo during the 2-week treatment period of each phase. The primary efficacy measure was the Swanson, Nolan, and Pelham-IV-teacher (SNAP-IV-T) form. Secondary efficacy measures included the SNAP-IV-parent form, the Clinical Global Impression: ADHD-Severity score, the Conner's Teacher's Rating Scale score, and the investigator's rating for 18 Diagnostic and Statistical Manual of Mental Disorders, 5th edition ADHD symptoms. In addition, data related to vital signs, body weight, physical examination, laboratory testing, and adverse events (AEs) were also collected. All data were analyzed on an intent-to-treat basis. Results: Without adjusting for differences in demographics and baseline measures, both treatment groups showed significant reductions in ADHD and oppositional defiant disorder symptoms after a 2-week treatment with greater effect sizes (Cohen's d) in the ORADUR-MPH group (Cohen's d ranging from -0.41 to -1.64; placebo, Cohen's d ranging from -0.26 to -1.18), except for oppositional symptoms, regardless of the informants. For the primary efficacy measure, ORADUR-MPH was significantly superior to the placebo, as evidenced by lower values for and greater reductions in the SNAP-IV-T scores at the endpoint (Cohen's d = -0.16, p = 0.005) and from baseline to the endpoint (Cohen's d = -0.19, p = 0.006), respectively. There were no serious AEs during the clinical study period. The most frequently observed AE was decreased appetite (49.1%). Most physical and laboratory test variables remained within the normal range. Conclusions: Once-daily ORADUR-MPH is an effective, well-tolerable, and safe treatment for children and adolescents with ADHD. ClinicalTrials.gov number, NCT02450890.

Effects of the dopamine transporter gene on striatal functional connectivity in youths with attention-deficit/hyperactivity disorder.

BACKGROUND: The dopamine transporter gene (DAT1), striatal network dysfunction, and visual memory deficits have been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). This study aimed to examine the effects of the DAT1 rs27048 (C)/rs429699 (T) haplotype on striatal functional connectivity and visual memory performance in youths with ADHD. METHOD: After excluding those who had excessive head motion, a total of 96 drug-naïve youths with ADHD and 114 typically developing (TD) youths were assessed with the resting-state functional magnetic resonance imaging and the delayed matching to sample (DMS) task for visual memory. We examined the effects of ADHD, DAT1 CT haplotype, and the ADHD × CT haplotype interaction on the functional connectivity of five striatal seeds. We also correlated visual memory performance with the functional connectivity of striatal subregions, which showed significant diagnosis × genotype interactions. RESULTS: Compared with TD youths, ADHD youths showed significant hypoconnectivity of the left dorsal caudate (DC) with bilateral sensorimotor clusters. Significant diagnosis × genotype interactions were found in the connectivity between the left DC and the right sensorimotor cluster, and between the right DC and the left dorsolateral prefrontal/bilateral anterior cingulate clusters. Furthermore, the connectivity of the left DC showing significant diagnosis × genotype interactions was associated with DMS performance in youths with ADHD who carried the DAT1 CT haplotype. CONCLUSIONS: A novel gene-brain-behavior association between the left DC functional connectivity and visual memory performance in ADHD youths with the DAT1 rs27048 (C)/rs429699 (T) haplotype suggests a differential effect of DAT1 genotype altering specific brain function causing neuropsychological dysfunction in ADHD.