Whole exome sequencing and MicroRNA profiling of lung adenocarcinoma identified risk prediction features for tumors at stage I and its substages.

OBJECTIVES: About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking. MATERIALS AND METHODS: We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort. RESULTS: We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients. CONCLUSION: Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients.

Hypermethylation of ACADVL is involved in the high-intensity interval training-associated reduction of cardiac fibrosis in heart failure patients.

BACKGROUND: Emerging evidence suggests that DNA methylation can be affected by physical activities and is associated with cardiac fibrosis. This translational research examined the implications of DNA methylation associated with the high-intensity interval training (HIIT) effects on cardiac fibrosis in patients with heart failure (HF). METHODS: Twelve HF patients were included and received cardiovascular magnetic resonance imaging with late gadolinium enhancement for cardiac fibrosis severity and a cardiopulmonary exercise test for peak oxygen consumption ([Formula: see text]O2peak). Afterwards, they underwent 36 sessions of HIIT at alternating 80% and 40% of [Formula: see text]O2peak for 30 min per session in 3-4 months. Human serum from 11 participants, as a means to link cell biology to clinical presentations, was used to investigate the exercise effects on cardiac fibrosis. Primary human cardiac fibroblasts (HCFs) were incubated in patient serum, and analyses of cell behaviour, proteomics (n = 6) and DNA methylation profiling (n = 3) were performed. All measurements were conducted after completing HIIT. RESULTS: A significant increase (p = 0.009) in [Formula: see text]O2peak (pre- vs. post-HIIT = 19.0 ± 1.1 O2 ml/kg/min vs. 21.8 ± 1.1 O2 ml/kg/min) was observed after HIIT. The exercise strategy resulted in a significant decrease in left ventricle (LV) volume by 15% to 40% (p < 0.05) and a significant increase in LV ejection fraction by approximately 30% (p = 0.010). LV myocardial fibrosis significantly decreased from 30.9 ± 1.2% to 27.2 ± 0.8% (p = 0.013) and from 33.4 ± 1.6% to 30.1 ± 1.6% (p = 0.021) in the middle and apical LV myocardium after HIIT, respectively. The mean single-cell migration speed was significantly (p = 0.044) greater for HCFs treated with patient serum before (2.15 ± 0.17 µm/min) than after (1.11 ± 0.12 µm/min) HIIT. Forty-three of 1222 identified proteins were significantly involved in HIIT-induced altered HCF activities. There was significant (p = 0.044) hypermethylation of the acyl-CoA dehydrogenase very long chain (ACADVL) gene with a 4.474-fold increase after HIIT, which could activate downstream caspase-mediated actin disassembly and the cell death pathway. CONCLUSIONS: Human investigation has shown that HIIT is associated with reduced cardiac fibrosis in HF patients. Hypermethylation of ACADVL after HIIT may contribute to impeding HCF activities. This exercise-associated epigenetic reprogramming may contribute to reduce cardiac fibrosis and promote cardiorespiratory fitness in HF patients. TRIAL REGISTRATION: NCT04038723. Registered 31 July 2019, https://clinicaltrials.gov/ct2/show/NCT04038723 .

Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice.

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

Comorbidity of Narcolepsy and Psychotic Disorders: A Nationwide Population-Based Study in Taiwan.

BACKGROUND: Narcolepsy is a chronic sleep disorder that is likely to have neuropsychiatric comorbidities. Psychotic disorders are characterized by delusion, hallucination, and reality impairments. This study investigates the relationship between narcolepsy and psychotic disorders. DESIGN AND METHODS: This study involves patients who were diagnosed with narcolepsy between January 2002 and December 2011 (n = 258) and age- and gender-matched controls (n = 2580) from Taiwan's National Health Insurance database. Both the patients and the controls were monitored from January 1, 2002 to December 31, 2011 to identify any occurrence of a psychotic disorder. Drugs that have been approved for treating narcolepsy: immediate-release methylphenidate (IR-MPH), osmotic controlled-release formulations of methylphenidate (OROS-MPH), and modafinil, were analyzed. A multivariate logistic regression model was used to evaluate the potential comorbidity of narcolepsy with psychotic disorders. RESULTS: During the study period, 8.1% of the narcoleptic patients exhibited comorbidity with a psychotic disorder, whereas only 1.5% of the control subjects (1.5%) had psychotic disorders (aOR, 4.07; 95% CI, 2.21-7.47). Of the narcolepsy patients, 41.5, 5.4, and 13.2% were treated with MPH-IR, MPH-OROS, and modafinil, accordingly. Pharmacotherapy for narcolepsy did not significantly affect the risk of exhibiting a psychotic disorder. CONCLUSIONS: This nationwide study revealed that narcolepsy and psychotic disorders commonly co-occur. Pharmacotherapy for narcolepsy was not associated with the risk of psychotic disorders. Our findings serve as a reminder that clinicians must consider the comorbidity of narcolepsy and psychosis.

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma.

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93-28.32, p < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.

High-Intensity Interval Training is Associated with Improved Long-Term Survival in Heart Failure Patients.

This matched-control cohort study explored the effects of high-intensity interval training (HIIT) on left ventricle (LV) dimensions and survival in heart failure (HF) patients between 2009 and 2016. HF patients who underwent the multidisciplinary disease management program (MDP) were enrolled. Non-exercising participants, aged (mean (95% confidence interval)) 62.8 (60.1⁻65.5) years, were categorized as the MDP group (n = 101). Participants aged 61.5 (58.7⁻64.2) years who had completed 36 sessions of HIIT were treated as the HIIT group (n = 101). Peak oxygen consumption (VO2peak) and LV geometry were assessed during the 8-year follow-up period. The 5-year all-cause mortality risk factors and overall survival rates were determined in the longitudinal observation. An increased VO2peak of 14⁻20% was observed in the HIIT group after exercise training. Each 1-mL/kg/min increase in VO2peak conferred a 58% improvement in 5-year mortality. Increased LV end-systolic diameter (LVESD) was significantly (p = 0.0198) associated with increased mortality. The 8-month survival rate was significantly improved (p = 0.044) in HIIT participants compared to non-exercise participants. HF patients with VO2peak ≥14.0 mL/kg/min and LVESD <44 mm had a significantly better 5-year survival rate (98.2%) than those (57.3%) with lower VO2peak and greater LVESD. Both HIIT-induced increased VO2peak and decreased LVESD are associated with improved survival in HF patients.

Tumor mutation burden and recurrent tumors in hereditary lung cancer.

Lung cancer is the leading cause of cancer death worldwide and cancer relapse accounts for the majority of cancer mortality. The mechanism is still unknown, especially in hereditary lung cancer without known actionable mutations. To identify genetic alternations involved in hereditary lung cancer and relapse is urgently needed. We collected genetic materials from a unique hereditary lung cancer patient's blood, first cancer tissue (T1), adjacent normal tissue (N1), relapse cancer tissue (T2), and adjacent normal tissue (N2) for whole genome sequencing. We identified specific mutations in T1 and T2, and attributed them to tumorigenesis and recurrence. These tumor specific variants were enriched in antigen presentation pathway. In addition, a lung adenocarcinoma cohort from the TCGA dataset was used to confirm our findings. Patients with high mutation burdens in tumor specific genes had decreased relapse-free survival (P = 0.017, n = 186). Our study may provide important insight for designing immunotherapeutic treatment for hereditary lung cancer.

Association of Bone Metastasis With Early-Stage Breast Cancer in Women With and Without Precancer Osteoporosis According to Osteoporosis Therapy Status.

Importance: Deaths from cancer are attributed more to secondary than primary tumors, but the pathogenesis of organ-specific cancer metastasis has not been determined. Objective: To investigate whether precancer osteoporosis and osteoporosis therapy are associated with alteration of bone metastasis patterns. Design, Setting, and Participants: This nationwide retrospective cohort study was performed from January 1, 2002, to December 31, 2013, using 2 cohorts from the Taiwan National Health Insurance Research Database: a random sample of 1 million beneficiaries from the Longitudinal Health Insurance Database who were enrolled in 2005 (LHID2005) and a specific data set of all the patients with osteoporosis. Patients diagnosed with breast cancer and precancer osteoporosis from January 1, 2002, to December 31, 2011, were included in the study, and their records were examined through December 31, 2013. From LHID2005, we selected 9104 women with early-stage breast cancer, of whom 705 had precancer osteoporosis. We identified 29 183 patients from the cohort of patients with breast cancer and osteoporosis, 14 020 of whom had precancer osteoporosis. Data analysis was performed from December 31, 2016, to August 31, 2018. Exposures: Precancer osteoporosis and osteoporosis therapy. Main Outcomes and Measures: The risk of bone metastasis in patients with and without precancer osteoporosis and patients receiving and not receiving osteoporosis therapy as well as time to bone metastasis development. Results: Among 9104 patients with breast cancer from the Longitudinal Health Insurance Database (mean [SD] age, 46.7 [14.0] years), precancer osteoporosis was not associated with a difference in risk of bone metastasis (adjusted hazard ratio [aHR], 0.87; 95% CI, 0.58-1.30; P = .49). Among 14 020 patients with precancer osteoporosis from the other cohort (mean [SD] age, 58.9 [11.6] years), osteoporosis therapy had no association with the risk of bone metastasis (bisphosphonates: aHR, 1.47; 95% CI, 1.00-2.17; P = .05; nonbisphosphonate drugs: aHR, 1.00; 95% CI, 0.72-1.39; P > .99). Compared with those without precancer osteoporosis (median time to bone metastasis development, 2.87 years; interquartile range [IQR], 1.34-4.86 years), among those with precancer osteoporosis, the median time to develop bone metastasis was shorter in those who did not receive treatment (1.74 years; IQR, 0.58-3.60 years; P < .001), whereas this time was the same for those who received treatment (bisphosphonates: 2.34 years; IQR, 1.23-3.13 years; nonbisphosphonate drugs: 2.08 years; IQR, 0.92-4.95 years). Conclusions and Relevance: Precancer osteoporosis was not associated with risk of bone metastasis, but untreated osteoporosis was associated with accelerated progression of bone metastasis when it occurred. Organ microenvironments interact with disseminated cancer mostly after the specific organ has been predetermined to be the designated location. Because recurrences and metastases are major obstacles to cancer treatments, determining which organs may be at risk for metastases may be crucial to treating the disease.

Involvement of swallowing therapy is associated with improved long-term survival in patients with post-stroke dysphagia.

BACKGROUND: The effects of swallowing therapy (ST) on long-term clinical outcomes in patients with post-stroke dysphagia (PSD) remain unclear. AIM: This study explores the effect of ST, initiated within 6 months of the stroke onset, on long-term pneumonia-free and overall survival rates in PSD patients. DESIGN: Retrospective cohort study. SETTING: Longitudinal Health Insurance Database. POPULATION: The study included 2994 eligible PSD patients between 2005 and 2013. METHODS: Among the scrutinized PSD patients, ST was initiated during the nasogastric intubation (NGI) period and was implemented by physician discretion. Therefore, subjects who underwent ST were classified into the ST-intervention (STI) group and those without ST were classified into the non-ST (NST) group. Propensity score matching (PSM) was used to match age, sex, pneumonia events during the NGI period, the Charlson comorbidity index, and the National Institutes of Health Stroke Scale between the two groups. We started to follow all selected PSD patients 6 months after the onset of stroke for four years. Multivariable adjusted Cox regression and Kaplan-Meier estimations were conducted to assess the effects of ST and the ST duration on pneumonia-free and overall survival. RESULTS: Overall, 1497 PSD patients aged approximately 68 years in each group were selected in this study. The pneumonia-free survival rate in STI subjects was 57.4% and was significantly greater (P=0.003) than that (54.2%) in NST subjects during the follow-up (F/U). A significantly improved (P<0.0001) overall survival rate was observed in STI subjects (75.0%) compared to NST subjects (63.7%) during the F/U. In STI subjects, ST duration ≥ 1 month was significantly (P=0.009) associated with reduced pneumonia incidence compared to those with ST duration<1 month. CONCLUSIONS: Participation of ST within 6 months of the stroke onset is associated with decreased pneumonia incidence and improved long-term survival in selected PSD patients. In the selected STI subjects, longer ST duration may be valuable in pneumonia prevention. CLINICAL REHABILITATION IMPACT: This study reveals that ST initiated within 6 months of the stroke onset may be associated with improved long-term survival in selected PSD patients.

The human C-type lectin 18 is a potential biomarker in patients with chronic hepatitis B virus infection.

BACKGROUND: Hepatitis B virus (HBV) infection is a common disease worldwide and is known to cause liver disease. C-type lectin 18 (CLEC18) is a novel secretory lectin highly expressed in human hepatocytes. Because the liver is the major target of HBV infection, we investigated whether the expression of CLEC18 can be used as a biomarker for HBV infection. METHODS: The expression level of CLEC18 in human liver chimeric mice with/without HBV infection was measured by quantitative real time polymerase chain reaction (qPCR) assay. Baseline plasma CLEC18 levels in 271 treatment-naive patients with chronic hepatitis B (CHB) undergoing nucleos(t)ide analogue (NUC) therapy and 35 healthy donors were measured by enzyme-linked immunosorbent assay, and the relationships to other clinical data were analyzed. RESULTS: The expression of CLEC18 was down-regulated in the human liver chimeric mice after HBV infection. Plasma CLEC18 levels were lower in the patients with CHB compared to the healthy donors and positively correlated with HBV DNA and HBsAg levels (P <  0.05). Multivariate Cox proportional hazard regression analysis identified a baseline plasma CLEC18 level of 320-2000 pg/mL to be an independent predictor of HBeAg loss (hazard ratio (HR): 2.077, P = 0.0318), seroconversion (HR: 2.041, P = 0.0445) and virological response (HR: 1.850, P = 0.0184) in 101 HBeAg-positive patients with CHB undergoing NUC therapy. CONCLUSIONS: Plasma CLEC18 levels were correlated with the stage of HBV infection and could predict HBeAg loss and seroconversion in the patients with CHB undergoing NUC therapy.

Serum Glutamine Levels as a Potential Diagnostic Biomarker in Sepsis following Surgery for Peritonitis.

Few diagnostic biomarkers for sepsis after emergency peritonitis surgery are available to clinicians, and, thus, it is important to develop new biomarkers for patients undergoing this procedure. We investigated whether serum glutamine and selenium levels could be diagnostic biomarkers of sepsis in individuals recovering from emergency peritonitis surgery. From February 2012 to March 2013, patients who had peritonitis diagnosed at the emergency department and underwent emergency surgery were screened for eligibility. Serum glutamine and selenium levels were obtained at pre-operative, post-operative and recovery time points. The average level of pre-operation serum glutamine was significantly different from that on the recovery day (0.317 ± 0.168 vs. 0.532 ± 0.155 mM, P < 0.001); moreover, serum glutamine levels were unaffected by surgery. Selenium levels were significantly lower on the day of surgery than they were at recovery (106.6 ± 36.39 vs. 130.68 ± 56.98 ng/mL, P = 0.013); no significant difference was found between pre-operation and recovery selenium levels. Unlike selenium, glutamine could be a sepsis biomarker for individuals with peritonitis. We recommend including glutamine as a biomarker for sepsis severity assessment in addition to the commonly used clinical indicators.

Comorbidity of narcolepsy and depressive disorders: a nationwide population-based study in Taiwan.

OBJECTIVE: Narcolepsy is a chronic sleep disorder that is likely to have neuropsychiatric comorbidities. Depression is a serious mood disorder that affects individuals' daily activities and functions. The current study aimed to investigate the relationship between narcolepsy and depressive disorders. METHODS: The study consisted of patients diagnosed with narcolepsy between January 2002, and December 2011 (n = 258), and age-matched and gender-matched controls (n = 2580) from Taiwan's National Health Insurance database. Both the patients and the controls were monitored through December 31, 2011, to identify the occurrence of a depressive disorder. A multivariate logistic regression model was used to assess the narcolepsy's potential influence on the comorbidity of a depressive disorder. RESULTS: During the study period, 32.7%, 24.8%, and 10.9% of the narcoleptic patients were comorbid with any depressive disorder, dysthymic disorder, and major depressive disorder, respectively. When compared to the control subjects, the patients with narcolepsy were at greater risks of having any depressive disorder (aOR 6.77; 95% CI 4.90-9.37), dysthymic disorder (aOR 6.62; 95% CI 4.61-9.57), and major depressive disorder (aOR 6.83; 95% CI 4.06-11.48). Of the narcoleptic patients that were comorbid with depression, >50% had been diagnosed with depression prior to being diagnosed with narcolepsy. CONCLUSIONS: This nationwide data study revealed that narcolepsy and depression commonly co-occurred. Since some symptoms of narcolepsy overlapped with those of depressive disorders, the findings serve as a reminder that clinicians must pay attention to the comorbidity of narcolepsy and depression.

Trend, characteristics, and pharmacotherapy of adults diagnosed with attention-deficit/hyperactivity disorder: a nationwide survey in Taiwan.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) in adults may result in functional impairment warranting clinical interventions. However, few studies have investigated the diagnosis and treatment rates of adult ADHD in non-Caucasian ethnic groups. This study used nationwide population-based data to investigate the rate of diagnosis, associated characteristics, and pharmacological treatment for adult ADHD in Taiwan. METHODS: Adults (age ≥18 years) newly diagnosed with ADHD (n=5,397) between January 2000 and December 2011 were enrolled from the National Health Insurance database in Taiwan. All patients were monitored until December 31, 2011. Patients who received treatment with immediate-release methylphenidate (IR-MPH), osmotic release oral system-methylphenidate (OROS-MPH), and atomoxetine (ATX) were analyzed. RESULTS: The cumulative prevalence of adult ADHD was 0.028%, and the incidence increased 10.9-fold from 2000 to 2011. The male to female ratio was 1.16, and 74.9% of the patients had the inattentive type. Overall, 55% of the patients received drug therapy for ADHD, and the average treatment duration was 478.3 days. Of the total patients, 50.4%, 13.3%, and 1.7% were prescribed with IR-MPH, OROS-MPH, and ATX, for a mean duration of 453.9, 327.7, and 161.4 days, respectively. CONCLUSION: This population-based study showed an increasing trend in the diagnosis rate of adult ADHD; however, this rate is still low compared with Western countries. Approximately 45% of the adult patients with ADHD never received medication for their ADHD. Continuous efforts are needed to increase public awareness of adult ADHD.

Meta-analytic framework for liquid association.

MOTIVATION: Although coexpression analysis via pair-wise expression correlation is popularly used to elucidate gene-gene interactions at the whole-genome scale, many complicated multi-gene regulations require more advanced detection methods. Liquid association (LA) is a powerful tool to detect the dynamic correlation of two gene variables depending on the expression level of a third variable (LA scouting gene). LA detection from single transcriptomic study, however, is often unstable and not generalizable due to cohort bias, biological variation and limited sample size. With the rapid development of microarray and NGS technology, LA analysis combining multiple gene expression studies can provide more accurate and stable results. RESULTS: In this article, we proposed two meta-analytic approaches for LA analysis (MetaLA and MetaMLA) to combine multiple transcriptomic studies. To compensate demanding computing, we also proposed a two-step fast screening algorithm for more efficient genome-wide screening: bootstrap filtering and sign filtering. We applied the methods to five Saccharomyces cerevisiae datasets related to environmental changes. The fast screening algorithm reduced 98% of running time. When compared with single study analysis, MetaLA and MetaMLA provided stronger detection signal and more consistent and stable results. The top triplets are highly enriched in fundamental biological processes related to environmental changes. Our method can help biologists understand underlying regulatory mechanisms under different environmental exposure or disease states. AVAILABILITY AND IMPLEMENTATION: A MetaLA R package, data and code for this article are available at http://tsenglab.biostat.pitt.edu/software.htm. CONTACT: ctseng@pitt.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Initiation and Persistence of Pharmacotherapy for Youths with Attention Deficit Hyperactivity Disorder in Taiwan.

BACKGROUND: Pharmacotherapy is an effective therapeutic option for attention deficit hyperactivity disorder (ADHD). Understanding the patterns of medication treatment is crucial for clinical practice. This study employed nationwide population-based data to elucidate the initiation and persistence of pharmacotherapy (immediate-release methylphenidate [IR-MPH], osmotic controlled-release formulations of methylphenidate [OROS-MPH] and atomoxetine [ATX]) for youths with ADHD in Taiwan. METHODS: Patients first receiving an ADHD diagnosis at age 18 or younger between January 2000 and December 2009 (n = 112,140; mean age at ADHD diagnosis: 7.7 years) were selected from Taiwan's National Health Insurance database. All patients were monitored through December 31, 2011, with an average follow-up time of 5.8 years. The initiation of ADHD drug therapy was defined as the first patient prescription, and discontinuation was defined as the cessation of ADHD medication for 180 days or longer. RESULTS: Within the first year after ADHD diagnosis, 47.3%, 14.4%, and 0.8% of the patients were prescribed IR-MPH, OROS-MPH, and ATX, respectively. Regarding the patients prescribed IR-MPH, OROS-MPH, and ATX, 17.8%, 12.6%, and 18.8%, respectively, received the prescription only once and never returned for a drug refill, and 51.0%, 38.9%, and 58.8%, respectively, discontinued drug therapy within 1 year after the first prescription. Male sex and neuropsychiatric comorbidities were associated with higher probabilities of being prescribed one of the medications. An older age at first prescription and a higher daily dose of prescription were significant predictors of early discontinuation of ADHD medication. CONCLUSIONS: The current findings suggest that IR-MPH is the most frequently prescribed drug for ADHD treatment in Taiwan. Patients treated with OROS-MPH possessed the highest persistence rate, whereas those treated with ATX had the lowest persistence rate. The results provide insight into the delivery of pediatric mental health services and have crucial implications for ADHD medication treatment in real clinical settings.

ePIANNO: ePIgenomics ANNOtation tool.

Recently, with the development of next generation sequencing (NGS), the combination of chromatin immunoprecipitation (ChIP) and NGS, namely ChIP-seq, has become a powerful technique to capture potential genomic binding sites of regulatory factors, histone modifications and chromatin accessible regions. For most researchers, additional information including genomic variations on the TF binding site, allele frequency of variation between different populations, variation associated disease, and other neighbour TF binding sites are essential to generate a proper hypothesis or a meaningful conclusion. Many ChIP-seq datasets had been deposited on the public domain to help researchers make new discoveries. However, researches are often intimidated by the complexity of data structure and largeness of data volume. Such information would be more useful if they could be combined or downloaded with ChIP-seq data. To meet such demands, we built a webtool: ePIgenomic ANNOtation tool (ePIANNO, http://epianno.stat.sinica.edu.tw/index.html). ePIANNO is a web server that combines SNP information of populations (1000 Genomes Project) and gene-disease association information of GWAS (NHGRI) with ChIP-seq (hmChIP, ENCODE, and ROADMAP epigenomics) data. ePIANNO has a user-friendly website interface allowing researchers to explore, navigate, and extract data quickly. We use two examples to demonstrate how users could use functions of ePIANNO webserver to explore useful information about TF related genomic variants. Users could use our query functions to search target regions, transcription factors, or annotations. ePIANNO may help users to generate hypothesis or explore potential biological functions for their studies.

Seasonal Patterns of Medications for Treating Attention-Deficit/Hyperactivity Disorder: Comparison of Methylphenidate and Atomoxetine.

PURPOSE: Medication is a first-line effective treatment for attention-deficit/hyperactivity disorder (ADHD). Currently, immediate-release methylphenidate (IR-MPH), the osmotic, controlled-release formulation of methylphenidate (OROS-MPH), and atomoxetine (ATX) are the only 3 medications approved in Taiwan for the treatment of ADHD. Short-term discontinuation of ADHD treatment is often seen among patients undergoing drug therapy. The goal of this study was to evaluate potential seasonal patterns in ADHD prescriptions and compare the seasonal changes of IR-MPH, OROS-MPH, and ATX use. METHODS: Taiwan's National Health Insurance database was used to gather information on patients diagnosed with ADHD (N = 145,269) from January 2000 to December 2011. The monthly data regarding person-days and receipt of treatment with IR-MPH, OROS-MPH, and ATX were analyzed. Time series analyses and autoregressive integrated moving average models were used to examine the seasonal patterns in person-days receiving ADHD pharmacotherapy. A general linear model with a post hoc test was used to determine the differences in monthly consumption of ADHD medications. FINDINGS: This study comprised 145,269 patients (mean age: 7.7 years; 78.6% were boys) diagnosed with ADHD. The prescriptions of IR-MPH (seasonal autoregressive: estimate [SE], 0.92 [0.04], t = 22.87, P < 0.001) and OROS-MPH (estimate [SE], 0.84 [0.09], t = 9.41, P < 0.001) both showed significant seasonal patterns, but ATX prescriptions did not (estimate [SE], 0.50 [0.55]; t = 0.90; P = 0.373). IR-MPH and OROS-MPH prescriptions shared similar seasonal trends. The mean person-days of consumption in July were lower than in other months, with the exception of February and August. Meanwhile, for ATX, the person-days of consumption in February were the lowest. The mean person-days in February were significantly lower than in March and May but did not differ from those in other months. IMPLICATIONS: The seasonal patterns of IR-MPH and OROS-MPH use coincide with school holidays. These findings suggest that discontinuing a drug during the holiday period may be popular for people undergoing ADHD pharmacotherapy, especially with regard to methylphenidate prescriptions. However, additional research is necessary to determine whether temporary discontinuation of drug therapy is related to patient outcomes.

Impact of negative media publicity on attention-deficit/hyperactivity disorder medication in Taiwan.

PURPOSE: This study explores trends in attention-deficit/hyperactivity disorder (ADHD) medications in Taiwan from 2000 to 2011 and whether negative media coverage of Ritalin in January 2010 impacted ADHD prescriptions throughout the country. METHOD: Patients throughout Taiwan who had been newly diagnosed with ADHD (n = 145,269) between January 2000 and December 2011 were selected from Taiwan's National Health Insurance database as subjects for this study. We analyzed monthly and yearly data on person-days of treatment with immediate-release methylphenidate (IR-MPH), osmotic controlled-release formulation of methylphenidate (OROS-MPH), and atomoxetine (ATX) using linear models of curve estimation and the time series expert modeler. RESULTS: Of our sample, 57.8%, 28.9%, and 4.3% had been prescribed one or more doses of IR-MPH, OROS-MPH, or ATX, respectively. The annual person-days of IR-MPH use increased regularly from 2000 to 2009, dropped abruptly in 2010, and then increased again the next year. Furthermore, the person-days of OROS-MPH prescriptions did not reach their expected goal in 2010; however, the person-days of ATX prescriptions have increased constantly since entering the market in 2007. Compared with patients newly diagnosed with ADHD in 2009, those newly diagnosed in 2010 were less likely to be treated with medication. CONCLUSION: These findings suggest that negative publicity affected the writing of stimulant prescriptions for ADHD patients throughout Taiwan. Media reporting has a vital role in influencing children with ADHD, their parents, and their willingness to accept pharmacotherapy as treatment.

Attention-deficit hyperactivity disorder, its treatment with medication and the probability of developing a depressive disorder: A nationwide population-based study in Taiwan.

OBJECTIVE: The purpose of this study is to determine the risk of developing depressive disorders by evaluating children with attention-deficit/hyperactivity disorder (ADHD) in comparison to controls that do not have ADHD, as well as to analyze whether the medications used to treat ADHD, methylphenidate (MPH) and atomoxetine (ATX), influence the risk of depression. METHODS: A group of patients newly diagnosed with ADHD (n=71,080) and age- and gender-matching controls (n=71,080) were chosen from Taiwan's National Health Insurance database during the period of January 2000 to December 2011. Both the patients and controls were monitored through December 31, 2011. We also explore the potential influence of the length of MPH and ATX treatment on developing depressive disorders. RESULTS: The ADHD patients showed a significantly increased probability of developing a depressive disorder when compared to the control group (ADHD: 5.3% vs. CONTROLS: 0.7%; aHR, 7.16, 99% CI: 6.28-8.16). Regarding treatment with MPH, a longer MPH use demonstrates significant protective effects against developing a depressive disorder (aOR, 0.91, 99%CI: 0.88-0.94). However, the duration of ATX treatment could not be significantly correlated with the probability of developing a depressive disorder. LIMITATIONS: The database employed in this study lacks of comprehensive clinical information for the patients with ADHD. Potential moderating factors between ADHD and depression were not considered in-depth in this study. CONCLUSIONS: The results of this study reveal that youths diagnosed with ADHD have a greater risk of developing depressive disorders. Long-term treatment with MPH correlated to the reduced probability of developing a depressive disorder among youths with ADHD.