Bacterial Pneumonia and Stroke Risk: A Nationwide Longitudinal Followup Study.

BACKGROUND: Pneumonia causes significant morbidity and mortality and has been associated with cardiovascular complications. Our study aimed to investigate the incidence of ischemic and hemorrhagic strokes following bacterial pneumonia. METHODS: Between 1997 and 2012, 10,931 subjects with bacterial pneumonia and 109,310 controls were enrolled from the Taiwan National Health Insurance Research Database, and were followed up to the end of 2013. The risk of stroke was estimated in Cox regression analyses with hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: When compared to the control group, subjects in the bacterial pneumonia group had a higher incidence of developing ischemic stroke (2.7% versus 0.4%, p <0.001) and hemorrhagic stroke (0.7% versus 0.1%, p <0.001). The risk of stroke increases with repeated hospitalizations due to bacterial pneumonia. Across bacterial etiologies, bacterial pneumonia was a significant risk factor among 775 subjects who developed ischemic stroke (HR, 5.72; 95% CI, 4.92-6.65) and 193 subjects who developed hemorrhagic stroke (HR, 5.33; 95% CI, 3.91-7.26). CONCLUSION: The risks of developing ischemic stroke and hemorrhagic stroke are significant following bacterial pneumonia infection. The risk factors, clinical outcomes, and the disease course should also be profiled to better inform the monitoring of stroke development and the clinical management of bacterial pneumonia patients.

Patient-centered and integrated outreach care for chronic hepatitis C patients with serious mental illness in Taiwan.

Patients with serious mental illness have a higher risk of hepatitis C virus (HCV) infection but suboptimal HCV care. The current study aimed to facilitate HCV treatment uptake by implementing an integrated outreach care model. Multidisciplinary outreach screening followed by HCV reflex testing and onsite treatment for schizophrenia patients was accomplished through the coordination of nongovernmental organizations, remote specialists, and local care providers. The objective was microelimination effectiveness, defined as the multiplication of the rates of anti-HCV antibodies screening, accurate HCV RNA diagnosis, treatment allocation, treatment completion, and sustained virological response (SVR12; no detectable HCV RNA throughout 12 weeks in the post-treatment follow-up period). A total of 1478 of the 2300 (64.3%) psychiatric patients received HCV mass screening. Seventy-three (4.9%) individuals were seropositive for anti-HCV antibodies. Of the 73 anti-HCV seropositive patients, all (100%) received HCV reflex testing, and 29 (37.7%) patients had HCV viremia. Eight patients (34.8%) had advanced liver disease, including 3 with liver cirrhosis and 2 with newly diagnosed hepatocellular carcinoma. Twenty-three of the 24 (95.8%) patients who stayed in the healthcare system received and completed 8 weeks of glecaprevir/pibrentasvir treatment and post-treatment follow-up without significant DDIs or adverse events. The SVR12 rate was 100%. The microelimination effectiveness in the current study was 61.6%. Individuals with serious mental illness are underserved and suffer from diagnostic delays. This patient-centered and integrated outreach program facilitated HCV care in this marginalized population.

The cysteine-altering p.R544C variant in the NOTCH3 gene is a probable candidate for blood pressure and relevant traits in the Taiwan Biobank.

BACKGROUND: The cysteine-altering variants in NOTCH3 have been suggested to be associated with stroke, dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), where aberrant blood pressure levels represent the characteristics of these diseases. We aimed to assess whether the cysteine-altering p.Arg544Cys (p.R544C; rs201118034) variant and common single nucleotide variants (SNVs) in NOTCH3 could contribute to systolic and diastolic blood pressure and related phenotypes in the Taiwan Biobank. METHODS: We employed a discovery sample of 68,925 individuals, an independent replication sample of 45,676 individuals, and a combined/total sample of 114,601 individuals; all from the Taiwan Biobank. Blood pressure, such as systolic and diastolic blood pressure, was measured for all participants. Association was evaluated using a general linear model, where results were considered statistically significant if the P value < 0.05 divided by the number of independent tests per model. RESULTS: From our analysis, we identified and replicated three novel candidates for blood pressure that have not previously been reported: the cysteine-altering p.R544C variant for systolic blood pressure, the common SNV rs11669950 for diastolic blood pressure, and the common SNV rs4808235 for diastolic blood pressure. We also generalized two previously identified SNVs (i.e., rs10418305 and rs7408868) in NOTCH3 for blood pressure in European and non-Taiwanese East Asian populations to the Taiwanese population. Moreover, the participants with NOTCH3 p.R544C had an increased stroke frequency (P < 1.0 × 10-5) and a higher dementia frequency (P = 2.0 × 10-4) compared with the whole Taiwan Biobank population in the combined/total sample. CONCLUSION: NOTCH3 is a strong candidate for a role in stroke, dementia, and CADASIL, which has previously been linked to blood pressure changes. While our preliminary study suggests that NOTCH3 p.R544C may influence blood pressure, stroke, and dementia in the Taiwan Biobank, replication in a well-powered external sample is required. This study also underlines considerable prospects of detecting novel genetic biomarkers in underrepresented worldwide populations.

Risk of retinal disease in patients with autism spectrum disorder.

BACKGROUND: Ocular abnormalities and visual dysfunction have been associated with autism spectrum disorder (ASD). Our study assessed the risks of developing retinal diseases in individuals with ASD. METHODS: In all, 18 874 patients with ASD and 188 740 controls were selected from the Taiwan National Health Insurance Research Database between 2001 and 2009. The control group was matched based on demographic characteristics and medical and ophthalmological comorbidities. The hazard ratios (HRs) with 95% confidence intervals were calculated with Cox-regression analyses adjusted for selected confounders. RESULTS: Individuals with ASD had a higher incidence of developing retinal diseases (1.48‰ vs 0.73‰, P < .001), and the diagnosis of retinal diseases occurred earlier than the controls (3.73 vs 6.28 years, P < .001). When compared to the control group, the HR of developing retinal diseases in the ASD group was 1.75 (95%: 1.04-2.94) and 7.84 (95%: 3.51-17.47) for retinal detachment. There was no association between the cumulative daily dose of atypical antipsychotics and the incidence of retinal diseases in the ASD group. CONCLUSION: Individuals with ASD have a higher risk of developing retinal detachment and are diagnosed with retinal diseases earlier than controls. Future research is needed to elucidate the mechanisms mediating the progression of retinal diseases in the ASD population.

Frailty affects employment outcomes in patients with schizophrenia in noncompetitive employment: A 4-year longitudinal study.

OBJECTIVES: Employment status is considered a crucial predictor of improved functioning for patients with psychotic disorders. Frailty affects not only physical well-being but also employment outcomes, but few studies have explored the association between frailty and employment outcomes in patients with schizophrenia. This study is a longitudinal follow-up study that aimed to determine whether frailty is associated with employment outcomes in schizophrenia. METHODS: All 561 stable patients with schizophrenia in a therapeutic community in Taiwan were recruited. Employment outcomes, defined as the cumulative annual work duration (months per year) and income (USD per year), were investigated repeatedly at the end of 1-, 2-, 3-, and 4-year follow-ups after enrollment. Generalized estimating equation models were constructed to determine the association between frailty and employment outcomes after controlling for variables, including age, sex, education, antipsychotic medication and daily dose, cognitive function, instrumental activities of daily living, medical comorbidity, and initial employment state at the beginning year. RESULTS: The average age was 53.78 years, and 64.7% were men. Among them, 57 patients (10.2%) met the frailty criteria at the baseline. After controlling for other factors, we found that patients with frailty were employed 1.01 month less (p = 0.004) and earned 17.2 USD less (p = 0.029) per year than those without frailty. CONCLUSIONS: Frailty may reduce duration of employment and income for patients with schizophrenia. The biopsychosocial care model for these patients should include development of strategies to prevent or reverse preexisting frailty to improve and preserve employment outcomes.

Symptomatic remission affects employment outcomes in schizophrenia patients.

BACKGROUND: Remission criteria were proposed by Andreasen et al. for classifying patients with schizophrenia according to the severity of psychopathology. Up to the present time, there have been no cohort studies exploring the association between remission status and employment outcomes in patients with schizophrenia. The study explored whether symptomatic remission is significantly associated with employment outcomes in a two-year longitudinal study. METHODS: All 525 stable patients with schizophrenia in the therapeutic community of a public mental hospital in Taiwan were recruited between 2013 and 2015. Employment outcomes, defined as the cumulative on-the-job duration (months/per year) and income (new Taiwan dollars, NT$/per year), were investigated at the end of 1- and 2-year follow-up periods after enrollment. For repeated measurements, linear mixed models were constructed to examine the association between symptomatic remission and employment outcomes after controlling for potential confounding variables including age, sex, education, type and daily dose of antipsychotics, cognitive function, psychosocial functioning and initial employment type. RESULTS: The average age of patients was 51.8 years, and 65.3% were males. Among them, 124 patients (23.6%, 124/525) met the remission criteria at baseline. The linear mixed-model analysis showed that patients who had symptomatic remission were employed 0.8 of a month longer (p = 0.029) and earned NT$3250 more (p = 0.001) within 1 year than those who did not show symptomatic remission. CONCLUSION: Our study suggests that assessing symptomatic remission is a useful part of monitoring treatment effectiveness for schizophrenia, and all strategies targeting the bio-psycho-social domains to attain symptomatic remission are paramount to maintaining favorable employment outcomes.

NGF gene polymorphisms are not associated with heroin dependence in a Taiwanese male population.

BACKGROUND AND OBJECTIVES: Heroin dependence (HD) is a chronic relapsing brain illness with substantial heritability. Nerve growth factor (NGF) is a crucial modulator in the neurodevelopment, and may be a key mediator of reward processes in HD. The purpose of this genetic study was to investigate whether NGF gene polymorphisms associate with the occurrence of HD and the specific personality traits of patients with HD. METHODS: We selected a homogeneous Han Chinese male population to overcome possible confounding effects of population and gender. For the study, 272 HD patients and 141 controls completed the Tridimensional Personality Questionnaire to evaluate their personality traits. In addition, a further sample 303 HD patients and 204 controls was added (with totally 920 participants) for the gene association and genotype-phenotype interaction studies. RESULTS: Patients with HD had higher novelty seeking (NS) and harm avoidance (HA) scores than healthy subjects. Nonetheless, NGF gene polymorphisms did not associate with specific personality traits in HD patients and controls. There is no significant difference in NGF gene polymorphisms between patients with HD and controls. DISCUSSION AND CONCLUSIONS: The NGF gene may neither contribute to the risk of development of HD, nor mediate the relationship between specific personality traits and HD in Han Chinese male population. SCIENTIFIC SIGNIFICANCE: Patients with HD had higher novelty seeking (NS) and harm avoidance (HA) scores than healthy subjects. However, none of the polymorphisms in the NGF gene affected the NS and HA scores in both patients and healthy subjects. (Am J Addict 2018;27:516-523).

Familial expressed emotion among heroin addicts in methadone maintenance treatment: does it matter?

BACKGROUND: Expressed emotion (EE) is the quality of the atmosphere between a relative and a family member with mental illness. Substantial research has focused on the relationship between the level of EE and the outcomes of mental illness. However, no prior study has explored the role of EE relative to heroin addicts. AIM: The aims of this study were to investigate the influence of EE on patient outcome in methadone maintenance treatment (MMT) and the relationship between the EE of heroin addicts and other demographic and psychological variables. METHODS: A total of 117 heroin addicts who entered MMT were enrolled. Each subject underwent a comprehensive interview to record demographic data and drug use history. The Family Emotional Involvement Scale (FEICS), Beck Depression Inventory (BDI), and Beck Anxiety Depression Inventory (BAI) were used at baseline. All subjects were followed for 12 months. The results of monthly urine tests and the treatment retention were recorded for further analysis. RESULTS: Perceived criticism was correlated with depression (r=0.20, P<0.01). The overall retention rate in 12-month MMT was 54.70%. Lower perceived criticism (OR=1.84, 95% CI=1.20-3.60, P<0.01) and lower depression (OR=1.24, 95% CI=0.65-1.80, P=0.02) predicted longer retention in MMT. CONCLUSION: EE, especially perceived criticism, has its influences on outcomes among heroin addicts in MMT. This suggested the potential benefits of family therapy among high EE heroin addicts in MMT. Furthermore, the mechanism how EE affects the outcome of MMT needs to be further investigated.

Monoamine oxidase-A polymorphisms might modify the association between the dopamine D2 receptor gene and alcohol dependence.

OBJECTIVE: Low monoamine oxidase (MAO) activity and the neurotransmitter dopamine are 2 important factors in the development of alcohol dependence. MAO is an important enzyme associated with the metabolism of biogenic amines. Therefore, the present study investigates whether the association between the dopamine D2 receptor (DRD2) gene and alcoholism is affected by different polymorphisms of the MAO type A (MAOA) gene. METHODS: A total of 427 Han Chinese men in Taiwan (201 control subjects and 226 with alcoholism) were recruited for the study. Of the subjects with alcoholism, 108 had pure alcohol dependence (ALC) and 118 had both alcohol dependence and anxiety, depression or both (ANX/DEP ALC). All subjects were assessed with the Chinese Version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime. Alcohol dependence, anxiety and major depressive disorders were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. CONCLUSION: The genetic variant of the DRD2 gene was only associated with the ANX/DEP ALC phenotype, and the genetic variant of the MAOA gene was associated with pure ALC. Subjects carrying the MAOA 3-repeat allele and genotype A1/A1 of the DRD2 were 3.48 times (95% confidence interval = 1.47-8.25) more likely to be ANX/DEP ALC than the subjects carrying the MAOA 3-repeat allele and DRD2 A2/A2 genotype. The MAOA gene may modify the association between the DRD2 gene and ANX/DEP ALC phenotype.

Possible interaction between MAOA and DRD2 genes associated with antisocial alcoholism among Han Chinese men in Taiwan.

Both monoamine oxidase A (MAOA) and dopamine D(2) receptor (DRD2) genes have been considered as candidate genes for antisocial personality disorder with alcoholism (Antisocial ALC) [Parsian, A., 1999. Sequence analysis of exon 8 of MAO-A gene in alcoholics with antisocial personality and normal controls. Genomics. 45, 290-295.; Samochowiec, J., Lesch, K.P., Rottmann, M., Smolka, M., Syagailo, Y.V., Okladnova, O., Rommelspacher, H., Winterer, G., Schmidt, L.G., Sander, T., 1999. Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism. Psychiatry. Res. 86, 67-72.; Schmidt, L.vG., Sander, T., Kuhn, S., Smolka, M., Rommelspacher, H., Samochowiec, J., Lesch, K.P., 2000. Different allele distribution of a regulatory MAO-A gene promotor polymorphism in antisocial and anxious-depressive alcoholics. J. Neural .Transm. 107, 681-689.]. However, the association between alcoholism and MAOA or DRD2 gene has not been universally accepted [Lee, J.F., Lu, R.B., Ko, H.C., Chang, F.M., Yin, S.J., Pakstis, A.J., Kidd, K.K., 1999. No association between DRD(2) locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population. Alcohol. Clin. Exp. Res. 23, 592-599.; Lu, R.B., Lin, W.W., Lee, J.F., Ko, H.C., Shih, J.C., 2003. Neither antisocial personality disorder nor antisocial alcoholism association with MAOA gene among Han Chinese males in Taiwan. Alcohol. Clin. Exp. Res. 27, 889-893.]. Since dopamine is metabolized to 3,4-dihydroxyphenyl-acetaldehyde (DOPAL) via monoamine oxidase (MAO) [Westerink, B.H., de Vries, J.B., 1985. On the origin of dopamine and its metabolite in predominantly noradrenergic innervated brain areas. Brain. Res. 330, 164-166.], the interaction between MAOA and DRD2 genes might be related to Antisocial ALC. The present study aimed to determine whether Antisocial ALC might be associated with the possible interactions of DRD2 gene with MAOA gene. Of the 231 Han Chinese subjects who were recruited for the study, 73 participants were diagnosed with Antisocial ALC and 158 subjects were diagnosed with antisocial personality disorder without alcoholism (Antisocial Non-ALC). The DRD2 TaqI A and MAOA-uVNTR (variable number of tandem repeat located upstream) polymorphisms were not found to be associated with Antisocial ALC. However, an association between DRD2 TaqI A polymorphisms and Antisocial ALC was shown only after stratification for the MAOA-uVNTR 4-repeat polymorphism. Additionally, after multiple logistic regressions, we found that, under stratification of MAOA-uVNTR 4-repeat polymorphism and in comparison with the DRD2 A1/A1 genotype as a reference group, the DRD2 A1/A2 genotype has a possible protective effect against alcoholism in individuals with antisocial personality disorder (ASPD). We concluded that the possible interactions between MAOA-uVNTR polymorphism and DRD2 TaqI A polymorphism might be related to Antisocial ALC among Han Chinese men in Taiwan.

No alcoholism-protection effects of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan.

BACKGROUND: suggested that the genetic variation at ADH1B and ALDH2 influences the risk of alcoholism. The ADH1B*2 and ALDH2*2 alleles had been thought to be protective against alcoholism. Recent studies have suggested that either physiological tolerance of blood acetaldehyde, or innate insensitivity to it, or both may play a crucial role in keeping alcoholism from developing by protecting against adverse reactions. ALDH inactive form resulting from ALDH2*2, which slows the elimination of acetaldehyde and the more active isozymes produced by ADH1B*2, could generate higher acetaldehyde levels and thus deter heavy drinking (). The genotype frequency of ADH1B*2/*2 and ALDH2*(1/*2 or 2/*2), which are regarded protective against drinking behavior, is about 70% and 50%, respectively, among the Han Chinese population in Taiwan (Chen et al., 1999a). Most previous studies, however, have failed to separate the effects of antisocial personality disorder from those of alcoholism because of their high comorbidity. To understand the relationship among alcoholism, antisocial personality disorder, and the protective effects of ADH and ALDH, it is necessary to recruit individuals with antisocial personality disorder but without alcoholism. This study was designed to stratify subjects by various ADH1B and ALDH2 genotypes for a more effective association study. The strata were: antisocial alcoholics, antisocial non-alcoholics, community alcoholics, and normal controls. METHODS: We recruited 579 Han Chinese individuals in Taiwan, intending to examine the alcoholism-protection effects of different ADH1B and ALDH2 genotypes with or without antisocial personality disorder. RESULTS: We found no difference of ADH1B*2 allele frequency between the subjects of antisocial alcoholism and subjects of antisocial non-alcoholism, but we found significant difference of ALDH2*2 allele between these two groups. CONCLUSIONS: We concluded that there is no alcoholism-protection effect of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan.

Sequence variants and haplotype analysis of serotonin transporter gene and association with bipolar affective disorder in Taiwan.

OBJECTIVES: Serotonin transporter (SLC6A4) is responsible for serotonin re-uptake into presynaptic terminals, thus fine-tuning brain serotonergic neurotransmission. Current studies have found associations of SLC6A4 polymorphisms with several psychiatric traits including bipolar affective disorder (BPD) in various populations; however, studies with contradictory results were also reported. This study examined the role of SLC6A4 in etiology of BPD in a Taiwanese population. METHODS: Ten markers including two variable number tandem repeat and eight single nucleotide polymorphisms (SNPs) on the SLC6A4 gene were used to study the genetic association with 90 unrelated BPD, type I patients and 103 controls. RESULTS: Two SNPs were not informative in a Taiwanese population and the other eight polymorphic markers were analyzed by Fisher's exact test and haplotype analysis. No association was detected for any single SLC6A4 marker and BPD. Additional statistic analyses including other factors also showed lack of association between the SLC6A4 gene polymorphisms and BPD. Significant linkage disequilibrium was obtained among eight SLC6A4 markers and eight common haplotypes were constructed that can be found in 95% of the total subjects. The four commonest haplotypes in both patients and controls were identical. However, the fifth commonest haplotype differed in patients and controls and was significantly associated with a protection from BPD. CONCLUSIONS: This study suggested that a particular SLC6A4 haplotype harboring functional sequence variant could play a significant role in BPD etiology in Taiwan. However, due to its modest sample size, the conclusion is not final and should be confirmed in the future studies.

Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence.

BACKGROUND: The role of the dopamine D2 receptor (DRD2) gene in the development of alcohol abuse or dependence is controversial. The controversy is due in part to the disparate definitions pertaining to the control groups used and to the definitions of subtypes in alcohol dependence. In the Han Chinese population, the alcohol dehydrogenase 1B*2/*2 (ADH1B*2/*2) genotype and the aldehyde dehydrogenase 2*2 (ALDH2*2) allele have been considered as protective factors against alcohol abuse or dependence. Moreover, the ADH1B and ALDH2 genes might be involved in dopamine metabolism. We hypothesized that the ADH1B and ALDH2 genes might interact with the DRD2 gene and that the association between the DRD2 gene and alcohol dependence might be affected by different ADH1B and ALDH2 genotypes. This study examined whether the DRD2 gene is associated with specific subtypes of alcohol dependence and evaluated the relationship between the DRD2 gene and alcohol-metabolizing genes in a specific subtype of alcohol dependence. METHODS: Of the 465 Han Chinese subjects who were recruited for the study, 71 were classified with pure alcohol dependence, 113 with both alcohol dependence and anxiety-depression (ANX/DEP ALC), and 129 with anxiety-depression but without alcohol dependence (ANX/DEP). The remaining 152 subjects were supernormal controls. All subjects were interviewed with the Chinese version of the modified Schedule of Affective Disorders and Schizophrenia-Lifetime; all alcohol dependence, anxiety, and major depressive diagnoses were made according to DSM-IV criteria. RESULTS: The DRD2 gene was not found to be associated with pure alcohol dependence or ANX/DEP, but was found to be associated with ANX/DEP ALC. Furthermore, the association between the DRD2 gene and ANX/DEP ALC was shown to be under the control of the ALDH2*1/*1 and ADH1B*1/*2 genotypes. CONCLUSIONS: ANX/DEP ALC is a specific subtype of alcohol dependence. Because ANX/DEP ALC was associated with the DRD2 gene only under the stratification of ADH1B*1/*2 or ALDH2*1/*1, the DRD2 gene might interact with the ADH1B gene and the ALDH2 gene, respectively, in the development of ANX/DEP ALC in the Taiwan Han Chinese population.