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Abstract This population-based study investigated the risk of having had prior herpes zoster within five years preceding a diagnosis of head and neck cancer. We conducted a case-control study that included 9,191 patients with a diagnosis of head and neck cancer in Taiwan’s Longitudinal Health Insurance Database 2010 and 36,764 matched controls. We assessed the odds of patients with head and neck cancer having had a diagnosis of herpes zoster during the five years preceding head and neck cancer using multiple logistic regression analysis. The prevalence of prior herpes zoster among the total sample was 4.6%, 7.9% and 3.8% among patients with and without head and neck cancer, respectively (p

Abstract Little is known about a possible association of autoimmune inner ear disease among patients diagnosed with polymyositis (PM)/dermatomyositis (DM). This study aimed to explore differences in the prevalence of inner ear symptoms among patients with and without PM/DM using a nationwide population-based dataset. Data for this study were retrieved from the Taiwan National Health Insurance Research Database. The study sample included 1622 patients diagnosed with PM/DM and 8109 propensity-score matched comparison patients without PM/DM. We performed multivariate logistic regressions to calculate odds ratios (ORs) and 95% confidence interval (CI) for tinnitus, hearing loss, sudden deafness, and vertigo among patients with PM/DM versus comparison patients. Chi-square tests showed statistically significant differences between patients with PM/DM and comparison patients in the prevalence of tinnitus (16.1% vs. 12.7%, p

Abstract Background Although peripheral vestibular disorder is a non-fatal complication of Fabry disease, fatalities have been reported in some case reports and case series. To date, no studies have examined the relative risk of peripheral vestibular disorder in patients with Fabry disease compared to the general population without the condition. Due to the high prevalence of Fabry disease in East Asia and the potential shared pathogenic pathways between Fabry disease and vasculopathy, we conducted a study using a nationwide population-based dataset to compare the prevalence of peripheral vestibular disorder between patients with Fabry disease and matched comparison patients. Methods Data was sourced from Taiwan’s Longitudinal Health Insurance Database 2010. this study consists of 11,668 sampled patients, 2917 study patients with Fabry disease and 8751 propensity-score-matching comparison patients. We conducted multiple logistic regression analysis to study the association between peripheral vestibular disorder and Fabry disease. Results The study identified notable differences in the prevalence of various vestibular disorders between the study and comparison groups. Specifically, there was a 7.2% increased prevalence of peripheral vestibular disorder in the study group (28.3%) compared to the comparison group (20.9%), Meniere’s disease (5.4% vs. 3.7%), benign paroxysmal positional vertigo (5.1% vs. 3.3%), and other/ unspecified peripheral vestibular dizziness (15.6% vs. 11.8%) (all p

Abstract While Human Papillomavirus (HPV) particles have been detected in a small proportion of benign thyroid nodules or thyroid cancer cases, a role of HPV in these thyroid conditions has not been established. This study aims to investigate the association of HPV infection with thyroid cancer (TC) using a nationwide population-based study. We retrieved data for this case–control study from Taiwan's Longitudinal Health Insurance Database 2010. The study sample included 3062 patients with TC and 9186 propensity-scored matched controls. We employed multivariate logistic regression models to quantitatively evaluate the association of TC with HPV infections after taking age, sex, monthly income, geographic location and urbanization level of the patient's residence, diabetes, hypertension, and hyperlipidemia into considerations. Chi-squared test revealed that there was a significant difference in the prevalence of prior HPV infections between patients with TC and controls (15.3% vs. 7.6%, p

Background This study aimed to provide an updated prevalence of hearing loss, tinnitus, vertigo and sudden deafness on patients with Sjögren’s syndrome and matched comparison patients.Methods Data for this study were retrieved from the Taiwan Longitudinal Health Insurance Database and Taiwan’s registered catastrophic illness dataset. This study included 20 266 patients with Sjögren’s syndrome as the study group and 60 798 propensity score-matched comparison patients as the comparison group. We used multivariable logistic regressions to estimate the ORs and 95% CI for tinnitus, hearing loss, vertigo and sudden deafness among Sjögren’s syndrome patients versus comparison patients.Results χ2 tests showed there were statistically significant differences between the study group and comparison group in the prevalence of tinnitus (10.1% vs 6.3%, p

PurposeThis study aimed to examines the long-term trend of incidence of peripheral vestibular disorders between 2010 and 2018 in Taiwan.MethodsStudy-eligible patients were identified from Taiwan’s Longitudinal Health Insurance Database 2005 maintained by the Ministry of Health and Welfare in Taiwan. We retrieved 230,566 patients with a first-time diagnosis of peripheral vestibular disorders between 2010 and 2018. We calculated annual incidence rates of peripheral vestibular disorders per 100,000 population. We used the annual percent change (APC) to test the trend of peripheral vestibular disorders over time.ResultsThe mean annual incidence rate of peripheral vestibular disorders during the study period was 1489.6 per 100,000 population. Incidence showed a statistically significant steady decrease from 2010 to 2018 with a mean APC of −6.15% (95% CI = −6.97% ~ −5.32%). The decline was led by Meniere’s disease (APC = −9.83, 95% CI = −10.66% ~ −8.99%), followed by benign paroxysmal positional vertigo (APC = −3.69, 95% CI = −4.53% ~ −3.03%), vestibular neuritis (APC = −7.85, 95% CI = -8.96 ~ −6.73), and other peripheral vestibular dizziness (APC = −5.56, 95% CI = −6.69% ~ −4.43%).ConclusionThe incidence of peripheral vestibular disorders, overall, and the four major subgroups, benign paroxysmal positional vertigo, Meniere’s disease, vestibular neuritis, and other peripheral vestibular dizziness, all decreased substantially, year by year within the 2010–2018 period.

Abstract Patients with early onset vascular pathology have been reported to manifest neovascular age-related macular degeneration (AMD). While the blood vessels involved in pathogenesis of migraine remains controversial, it is generally accepted that a major contributor is blood vessel pathology. This study aimed to examine the association between migraine and AMD using a nationwide population-based dataset. Retrospective claims data were collected from the Taiwan National Health Insurance Research Database. We identified 20,333 patients diagnosed with neovascular AMD (cases), and we selected 81,332 propensity score-matched controls from the remaining beneficiaries in Taiwan’s National Health Insurance system. We used Chi-square tests to explore differences in the prevalence of migraine prior to the index date between cases and controls. We performed multiple logistic regressions to estimate the odds of prior migraine among neovascular AMD patients vs. controls after adjusting for age, sex, monthly income, geographic location, residential urbanization level, hyperlipidemia, diabetes, coronary heart disease, hypertension, and previous cataract surgery. A total of 5184 of sample patients (5.1%) had a migraine claim before the index date; 1215 (6.1%) among cases and 3969 (4.9%) among controls (p

Abstract Higher rates of poor cognitive performance are known to prevail among persons with tinnitus in all age groups. However, no study has explored the association between tinnitus and early-onset dementia. We hypothesize that tinnitus may precede or occur concurrently with subclinical or early onset dementia in adults younger than 65 years of age. This case–control study used data from the Taiwan National Health Insurance Research Database, identifying 1308 patients with early-onset dementia (dementia diagnosed before 65 years of age) and 1308 matched controls. We used multivariable logistic regressions to estimate odds ratios (ORs) for prior tinnitus among patients with dementia versus controls. Among total 2616 sample participants, the prevalence of prior tinnitus was 18%, 21.5% among cases and 14.5% among controls (p

Abstract With many previous studies indicating a higher prevalence of sexual problems in patients with tinnitus, the association between tinnitus and erectile dysfunction (ED) has become an interesting topic that warrants further research. In our study, we hypothesized that tinnitus may be associated with ED and aimed to further explore the relationship between these two medical conditions using a nationwide population-based database. After retrieving data of 19,329 patients with ED and 19,329 propensity score-matched patients without ED (controls) from Taiwan’s National Health Insurance Dataset, we defined the diagnosis date (the date of the first ED claim) for patients with ED as the index date for cases, and the date of the first utilization of ambulatory care by patients without ED during the index year of their matched case as the index date for controls. We found that 1247 out of 38,658 sampled patients (3.23%) had received a tinnitus diagnosis within the year before the index date, with 792 (4.10%) from cases and 455 (2.35%) from controls. We then utilized multiple logistic regression analysis and observed that cases were more likely to have had a prior tinnitus diagnosis compared to controls (OR 1.772; 95% CI 1.577–1.992; p

Background and PurposeIn this study, we aimed to evaluate the relationship between tinnitus and a subsequent diagnosis of major depressive disorder (MDD) by studying the incidence of both entities.DesignA retrospective cohort study.MethodsData for this observational follow-up study were retrieved from the Taiwan's National Health Insurance Dataset. A total of 375,272 patients with newly diagnosed tinnitus (study group) were retrieved. The date of first diagnosis of tinnitus was assigned as their index date. Comparison patients were selected by propensity score matching (one per case, n = 375,272 controls) from the same dataset, with their index date being the date of their first health service claim in the year of diagnosis of their matched index case. We tracked each patient's claims records for 1 year from the index date to identify those who received a diagnosis of MDD. Cox proportional hazards regression was performed to calculate the MDD hazard ratio for cases vs. controls.ResultsWe found that the overall incidence rate for MDD was 0.78 (95% CI = 0.76~0.80) per 100 person-years, being 1.17 (95% CI = 1.14~1.21) among the study cohorts and 0.38 (95% CI = 0.36~0.40) among the comparison cohorts. The log-rank test revealed that the patients in the study cohort had significantly lower one-year MDD-free survival when compared to the comparison cohort (p < 0.001). Cox proportional hazards analysis showed that the patients in the study cohort had a higher hazard of developing MDD than the patients in the comparison cohort (adjusted HR = 3.08, 95% CI = 2.90~3.27).ConclusionsIn this study, we demonstrate that tinnitus is associated with an increased hazard of subsequent MDD in Taiwan.

Abstract Background Tinnitus due to hyperactivity across neuronal ensembles along the auditory pathway is reported. We hypothesized that trigeminal neuralgia patients may subsequently suffer from tinnitus. Using nationwide, population-based data and a retrospective cohort study design, we investigated the risk of tinnitus within 1 year following trigeminal neuralgia. Methods We used the Taiwan National Health Insurance Research Dataset, a claims database, to identify all patients diagnosed with trigeminal neuralgia from January 2001 to December 2014, 12,587 patients. From the remaining patients, we identified 12,587 comparison patients without trigeminal neuralgia by propensity score matching, using sex, age, monthly income, geographic region, residential urbanization level, and tinnitus-relevant comorbidities (hyperlipidemia, diabetes, coronary heart disease, hypertension, cervical spondylosis, temporomandibular joint disorders and injury to head and neck and index year). All study patients (n = 25,174) were tracked for a one-year period to identify those with a subsequent diagnosis of tinnitus over 1-year follow-up. Results Among total 25,174 sample patients, the incidence of tinnitus was 18.21 per 100 person-years (95% CI = 17.66 ~ 18.77), the rate being 23.57 (95% CI = 22.68 ~ 24.49) among patients with trigeminal neuralgia and 13.17 (95% CI = 12.53 ~ 13.84) among comparison patients. Furthermore, the adjusted Cox proportional hazard ratio for tinnitus in the trigeminal neuralgia group was 1.68 (95% CI = 1.58 ~ 1.80) relative to the comparison cohort. Conclusions We found a significantly increased risk of tinnitus within 1 year of trigeminal neuralgia diagnosis compared to those without the diagnosis. Further studies in other countries and ethnicities are needed to explore the relationship between trigeminal neuralgia and subsequent tinnitus.

Abstract Background Several studies examined headaches as a symptom of brain neoplasms. Nevertheless, very few studies attempted to specifically evaluate the role of headaches as a risk factor. This study aimed to investigate the risk of migraine occurrence in the preceding years among patients diagnosed with brain tumors and unaffected controls. Methods Data were obtained from the Taiwan National Health Insurance Research Database. In total, 11,325 adults with a first-time brain tumor diagnosis were included as cases, together with 11,325 unaffected matched controls. Each individual was traced in the healthcare claims dataset for a prior diagnosis of migraines. Conditional logistic regressions were performed to calculate the odds ratio (OR) and the corresponding 95% confidence interval (CI) to present the association between brain tumors and having previously been diagnosed with migraines. Results We found that among patients with and those without brain tumors, 554 (4.89%) and 235 (2.08%) individuals, respectively, were identified as having a prior migraine diagnosis. Compared to unaffected controls, patients with brain tumors experienced an independent 2.45-fold increased risk of having a prior migraine diagnosis. The risks were even higher among men (odds ratio (OR) = 3.04, 95% confidence interval (CI) = 2.29~ 4.04) and after patients who had received a prior migraine diagnosis within 3 years were excluded (OR = 1.91, 95% CI = 1.59~ 2.29). Conclusions This is the first report demonstrating the occurrence of brain tumors to be associated with a prior migraine history, for both men and women, in a population-based study.

[This corrects the article DOI: 10.1371/journal.pone.0199135.].

Even though the relationship between antiarrhythmic drug usage and subsequent prostate cancer (PCa) risk has recently been highlighted, relevant findings in the previous literature are still inconsistent. In addition, very few studies have attempted to investigate the association between sodium channel blockers or potassium channel blockers for arrhythmia and the subsequent PCa risk. Therefore, this cohort study aimed to find the relationship between antiarrhythmic drug usage and the subsequent PCa risk using a population-based dataset. The data used in this study were derived from the Longitudinal Health Insurance Database 2005, Taiwan, China. We respectively identified 9988 sodium channel blocker users, 3663 potassium channel blocker users, 65 966 beta-blocker users, 23 366 calcium channel blockers users, and 7031 digoxin users as the study cohorts. The matched comparison cohorts (one comparison subject for each antiarrhythmic drug user) were selected from the same dataset. Each patient was tracked for a 5-year period to define those who were subsequently diagnosed with PCa. After adjusting for sociodemographic characteristics, comorbidities, and age, Cox proportional hazard regressions found that the hazard ratio (HR) of subsequent PCa for sodium channel blocker users was 1.12 (95% confidence interval [CI]: 0.84-1.50), for potassium channel blocker users was 0.89 (95% CI: 0.59-1.34), for beta-blocker users was 1.08 (95% CI: 0.96-1.22), for calcium channel blocker users was 1.14 (95% CI: 0.95-1.36), and for digoxin users was 0.89 (95% CI: 0.67-1.18), compared to their matched nonusers. We concluded that there were no statistical associations between different types of antiarrhythmic drug usage and subsequent PCa risk.

Failure to deliver the standard stroke care is suspected to be a potential reason for disproportionately high mortality among patients with co-morbid bipolar disorder (BD). Few studies have explored adverse outcomes and medical care costs concurrently (as a proxy for care intensity) among patients with BD admitted for stroke. Data for this nationwide population-based study were extracted from the Taiwan National Health Insurance Research Database, on 580 patients with BD hospitalized for stroke (the study group) and a comparison group consisting of randomly selected 1740 stroke patients without BD matched by propensity scores. Conditional logistic regression was used to estimate odds ratios (OR) for adverse in-hospital outcomes between study group and comparison group. We found that stroke patients with BD had significantly lower in-hospital mortality (3.28% vs. 5.63%), acute respiratory failure (2.59% vs. 5.57%), and use of mechanical ventilation (6.55% vs. 10.23%) than the comparison group. After adjusting for geographical location, urbanization level, monthly income, hypertension, diabetes, hyperlipidemia, and coronary heart disease, the odds of in-hospital mortality, acute respiratory failure, and use of mechanical ventilation in the BD group were 0.56 (95% CI: 0.34-0.92), 0.46 (95% CI: 0.26-0.80), and 0.63 (95% CI: 0.44-0.91), respectively. No differences were found in hospitalization costs and the length of hospital stay. With comparable hospitalization costs and length of hospital stay, we concluded that stroke patients with BD had lower in-hospital mortality and serious adverse events compared to stroke patients without BD.

This study aimed to investigate differences in healthcare service utilization between patients with and those without benign prostatic hyperplasia (BPH) using Taiwan′s National Health Insurance population-based database. A total of 7413 patients with BPH and 7413 age-matched patients without BPH were included. The outcome variable was 1-year utilization of healthcare services including the number of outpatient visits, inpatient days, and the costs of outpatient and inpatient treatments. In addition, we separated healthcare services into urology services and nonurology services for analysis. We found that as to the utilization of outpatient urological services, patients with BPH had more outpatient services (7.84 vs 0.52, P< 0.001), higher outpatient costs (US$372 vs US$34, P< 0.001), a longer length of inpatient stay (0.55 vs 0.11, P< 0.001), higher in-patients costs (US$149 vs US$32, P< 0.001), and higher total costs (US$521 vs US$67, P< 0.001) than the comparison group. As for nonurological services, patients with BPH also had more outpatient services (49.11 vs 24.79, P< 0.001), higher outpatient costs (US$1794 vs US$1014, P< 0.001), a longer length of in-patient stay (3.72 vs 2.04, P< 0.001), higher inpatient costs (US$874 vs US$486, P< 0.001), and higher total costs (US$2668 vs US$1500, P< 0.001) compared to comparison patients. We also found that the average total cost was about 2-fold greater for patients with BPH than comparison patients. We concluded that patients with BPH had higher healthcare utilization than comparison patients without BPH.

An amendment to this paper has been published and can be accessed via the original article.

This study aimed to evaluate the relationship between sudden sensorineural hearing loss (SSNHL) and MVP using a population-based dataset. Data for this case-control study were retrieved from the Taiwan Longitudinal Health Insurance Database. In total, 3399 cases of newly diagnosed SSNHL were identified. We used propensity score matching to select 3399 comparison patients (one for every case) from the same dataset. The selected matching variables included age, sex, monthly income, geographical location, urbanization level of the patient's residence, hypertension, diabetes, and hyperlipidemia. Chi-squared tests were used to compare differences in sociodemographic characteristics, while conditional logistic regression analyses were used to examine the association of SSNHL with previously diagnosed MVP. Of the 6798 sampled subjects, 131 (1.93%) patients had received a diagnosis of MVP prior to the index date. A significant difference in the prevalence of prior MVP between cases and controls (2.41% vs. 1.44%, p = 0.004) was observed. The conditional logistic regression analysis conditioned on gender, age, monthly income, urbanization level, geographic region, hyperlipidemia, diabetes, and hypertension suggested that the odds ratio of prior MVP for cases was 1.69 (95% confidence interval (CI): 1.18~2.42) compared to controls. Our study found that patients with MVP had a 1.69-fold higher risk of getting SSNHL compared to patients without MVP.

Little is known regarding the long-term adverse effects of a sialoadenectomy. The purpose of this study was to estimate the risk of coronary heart disease (CHD) among patients receiving a sialoadenectomy procedure by utilizing a cohort study based on a population-based database in Taiwan. This study retrieved data of the study sample from the Longitudinal Health Insurance Database 2005. This retrospective cohort study included 608 patients who underwent a sialoadenectomy and 1824 propensity score-matched comparison patients. We individually tracked each sampled patient for a 3-year period from their index date to discriminate those who subsequently received a diagnosis of CHD during the follow-up period. We found that respective incidence rates of CHD during the 3-year follow-up period were 3.87 (95% confidence interval (CI): 3.01-4.91) and 1.79 (95% CI: 1.45-2.18) per 100 person-years for patients who did and those who did not undergo a sialoadenectomy. The stratified Cox proportional analysis revealed that the hazard ratio of CHD during the 3-year follow-up period was 2.43 (95% CI: 1.77-3.33) than comparison patients. This study demonstrates an association between sialoadenectomy and CHD.

Whether statins and an angiotensin-converting enzyme inhibitors (ACEIs) / angiotensin receptor blockors (ARBs) are associated with reduced risks of infection events is still inconclusive. This study aimed to explore the risk of hospitalization for pneumonia among patients who had received treatment with ACEIs/ARBs and/or statins using a population-based dataset. This study included 19,281 patients as cases who were hospitalized for pneumonia and 19,281 controls. We used a logistic regression to compute the odds ratio (OR) and 95% confidence interval (CI) for having previously used statins or an ACEI/ ARB between patients who were hospitalized for pneumonia treatment and controls. We found there were significant associations between hospitalization for pneumonia and statin-only users (p

Patients with gastroesophageal reflux disease (GERD) present with comorbid complications with implications for healthcare utilization. To date, little is known about the effects of GERD treatment with a proton-pump inhibitor (PPI) on patients' subsequent healthcare utilization for acute respiratory infections (ARIs). This population-based study compared ARI episodes captured through outpatient visits, one year before and one year after GERD patients received PPI treatment. We used retrospective data from the Longitudinal Health Insurance Database 2005 in Taiwan, comparing 21,486 patients diagnosed with GERD from 2010 to 2012 with 21,486 age-sex matched comparison patients without GERD. Annual ARI episodes represented by ambulatory care visits for ARI (visits during a 7-day period bundled into one episode), were compared between the patient groups during the 1-year period before and after the index date (date of GERD diagnosis for study patients, first ambulatory visit in the same year for their matched comparison counterpart). Multiple regression analysis using a difference-in-difference approach was performed to estimate the adjusted association between GERD treatment and the subsequent annual ARI rate. We found that the mean annual ARI episode rate among GERD patients reduced by 11.4%, from 4.39 before PPI treatment, to 3.89 following treatment (mean change = -0.5 visit, 95% confidence interval (CI) = (-0.64, -0.36)). In Poisson regression analysis, GERD treatment showed an independent association with the annual ARI rate, showing a negative estimate (with p

[This corrects the article DOI: 10.1371/journal.pone.0082952.].

[This corrects the article DOI: 10.1371/journal.pone.0072097.].

Associations of hepatitis C virus infection with Alzheimer's disease have not been studied among higher risk, bipolar disorder patients. This population-based case-control study investigated the risks of hepatitis C virus infection among Alzheimer's disease patients with bipolar disorder in the years preceding their Alzheimer's disease diagnosis. We used 2000-2013 data from the Longitudinal Health Insurance Database in Taiwan. Among patients with bipolar disorder, 73 were diagnosed with Alzheimer's disease (cases), who were compared with 365 individuals with bipolar disorder but without Alzheimer's disease (randomly selected controls matched on sex, age, and index year with cases). Prior claims (before the diagnosis year/index year for controls) were screened for a diagnosis of hepatitis C virus infection. Conditional logistic regression models were used for analysis. We found that 23 (31.51%) and 60 (16.44%) patients with bipolar disease were identified with a hepatitis C diagnosis among those with and without Alzheimer's disease, respectively. Compared to controls, patients with Alzheimer's disease showed 2.31-fold (95% confidence interval = 1.28-4.16) increased risk of hepatitis C infections adjusted for demographics and socio-economic status. Findings suggest an association of Alzheimer's disease with a preceding diagnosis of hepatitis C infection among patients with bipolar disorder. Findings may suggest a need for increased awareness of and appropriate surveillance for Alzheimer's disease in patients with bipolar disorder diagnosed with hepatitis C infection.

This retrospective cohort study aimed to examine the relationship between herpes zoster ophthalmicus (HZO) and the subsequent risk of dementia using a population-based database. We retrieved the study sample from the Taiwan Longitudinal Health Insurance Database 2005. The study group included 846 patients with HZO, and the comparison group included 2538 patients without HZO. Each patient was individually followed for a 5-year period to identify those patients who subsequently received a diagnosis of dementia. We performed a Cox proportional hazards regression to calculate the hazard ratios (HRs) along with 95% confidence intervals (CIs) for dementia during the follow-up period between patients with HZO and comparison patients. The respective incidence rates of dementia per 1000 person-years were 10.15 (95% CI: 7.22~13.87) and 3.61 (95% CI: 2.61~4.89) for patients with HZO and comparison patients. The Cox proportional analysis showed that the crude HR of dementia during the 5-year follow-up period was 2.83 (95% CI: 1.83-4.37) for patients with HZO than comparison patients. After adjusting for patients' characteristics and comorbidities, HZO patients were still at a 2.97-fold greater risk than comparison patients for developing dementia. Furthermore, we found that of sampled male patients, the crude HR of dementia for patients with HZO was as high as 3.35 (95% CI = 1.79-6.28) compared to comparison patients. This study demonstrated an association between HZO and dementia. Clinicians must be alert to suspect dementia in patients with cognitive impairment who had prior HZO.

Androgen deprivation therapy (ADT) results in testosterone suppression, a hypothesized mechanism linking ADT to depressive symptoms. This study investigated the relationship between ADT and the risk of subsequently being diagnosed with depressive disorder (DD) during a 3-year follow-up period. The patient sample for this population-based, retrospective cohort study was retrieved from the Taiwan Longitudinal Health Insurance Database 2005. We included all 1714 patients aged over 40 years with a first-time diagnosis of prostate cancer (PC) during 2001 to 2010 who did not have an orchiectomy. Among them, we defined 868 patients who received ADT during the 3-year follow-up period as the study group, and 846 patients who did not receive ADT as the comparison group. The incidence rates of DD per 1000 person-years were 13.9 (95% confidence interval (CI): 9.5~19.6) and 6.7 (95% CI: 3.7~11.0), respectively. Cox proportional hazard regressions showed that the adjusted hazard ratio for DD for ADT recipients was 1.93 (95% CI: 1.03~3.62) relative to the comparison group. This study presents epidemiological evidence of an association between ADT and a subsequent DD diagnosis.

BACKGROUND:Physicians are considered to be the most informed consumers in the use of medical services since they have more information about diseases or medical technology. However, although plenty of researchers have suggested that different medical seeking behavior exists among physicians, very few empirical studies have been conducted to investigate differences in medical utilization between physicians and the general population. OBJECTIVE:We explored differences in the utilization of healthcare services between physicians and the general population using a population-based dataset. DESIGN:A cross-sectional study. PARTICIPANTS:Data for this study were sourced from the Taiwan Longitudinal Health Insurance Database 2000. We included 1426 physicians and 1426 sex- and age-matched comparison subjects. METHODS:We used Wilcoxon-Mann-Whitney tests to explore differences in variables of healthcare resource utilization between physicians and comparison subjects. We further used Kruskal-Wallis tests to examine differences in variables of healthcare resource utilization between physician practice location and comparison subjects. RESULTS:We found that physicians had significantly fewer outpatient visits (13.2 vs. 15.7, p

Some of the prior literature investigated the potential association between rheumatoid arthritis (RA) and Alzheimer's disease (AD) because these two diseases may share similar inflammatory mechanisms. Nevertheless, to date, findings of the previous literature are still controversial, and some methodological limitations were observed in those studies. The aim of this case-control study was to investigate the relationship between prior RA and AD using a large population-based dataset. This study used the Taiwan Longitudinal Health Insurance Database 2005. We included 2271 patients with AD who had received prescriptions for acetylcholinesterase inhibitors (AChEIs) as cases and 6813 patients without AD as controls in this study. In addition, we performed a conditional logistic regression to examine the odds ratio (OR) and 95% confidence interval (CI) for prior RA between cases and controls. The study found that 330 (3.63%) of the total sampled patients had an RA diagnosis before the index date. Additionally, prior RA was found in 60 (2.64%) cases and in 270 (3.96%) controls. The conditional logistic regression analysis showed that the crude OR of prior RA for cases was 0.66 (95% confidence interval (CI): 0.49~0.87) compared to controls. After adjusting for patients' geographic location, urbanization level, and comorbidities, the adjusted OR of prior RA for patients with AD was 0.73 (95% CI: 0.55~0.98) compared to those without AD. We concluded that there was an inverse association between prior RA and AD even after adjusting for potential confounders.

The etiology of chronic urticaria (CU) is diverse, with chronic infections and inflammation being reported as considerable contributing factors. Although the prevalence of metabolic syndrome was found to be significantly elevated in patients with CU, no one has specifically estimated the effects on CU following hyperlipidemia. This study aimed to examine the association between hyperlipidemia and CU using a population-based dataset in Taiwan. This study included 9798 adults with CU as cases and 9798 sex- and age-matched controls. These patients were examined for whether they had received a prior diagnosis of hyperlipidemia. We used conditional logistic regression analyses to calculate the odds ratio (OR) and its corresponding 95% confidence interval (CI) for having been previously diagnosed with hyperlipidemia between cases and controls. In total, 7066 (36.1%) patients had received a prior diagnosis of hyperlipidemia, including 4287 (43.8%) among CU cases and 2779 (28.4%) among controls. The conditional logistic regression revealed that the OR of prior hyperlipidemia for cases was 1.97 (95% CI: 1.85~2.09) compared to the controls. Furthermore, compared to patients without CU, patients with CU independently experienced a 1.65-fold (95% CI = 1.55~1.76; p

Previous studies investigated the impacts of a partial nephrectomy (PN) or radical nephrectomy (RN) on cardiovascular events and death. However, the association between the type of nephrectomy (PN vs. RN) and cardiovascular disease is still equivocal. This retrospective cohort study aimed to compare the risk of coronary heart disease (CHD) between patients who underwent a PN and those who underwent an RN. We used data from the Taiwan Longitudinal Health Insurance Database 2005. In total, 60 patients who underwent a PN and 545 patients who underwent an RN were included. Each patient was tracked for 1-, 2-, 3-, and 5-year periods to identify those who were subsequently diagnosed with CHD. Cox proportional hazard regression analyses were used to calculate hazard ratios (HRs) for CHD during 1-, 2-, 3-, and 5-year follow-up periods between these two cohorts. For the 1-year follow-up period, the adjusted HR was 0.39 (95% CI: 0.05~2.90, p = 0.355) for patients who underwent a PN compared to those who underwent an RN. Additionally, the adjusted HRs of CHD in patients who underwent a PN for 2-, 3- and 5-year follow-up periods were 1.40 (95% CI: 0.62~3.16, p = 0.417), 1.09 (95% CI: 0.52~2.31, p = 0.814), and 1.02 (95% CI: 0.48~2.18, p = 0.961), respectively, compared to those who underwent an RN. We concluded that there was no significant difference in the risk of CHD between patients who underwent a PN and those who underwent an RN.

Although the vermiform appendix is commonly considered a vestigial organ, adverse health consequences after an appendectomy have garnered increasing attention. In this study, we investigated the risks of gallstone occurrence during a 5-year follow-up period after an appendectomy, using a population-based dataset. We used data from the Taiwan Longitudinal Health Insurance Database 2005. The exposed cohort included 4916 patients who underwent an appendectomy. The unexposed cohort was retrieved by randomly selecting 4916 patients matched with the exposed cohort in terms of sex, age, and year. We individually tracked each patient for a 5-year period to identify those who received a diagnosis of gallstones during the follow-up period. Cox proportional hazard regressions were performed for the analysis. During the 5-year follow-up period, the incidence rate per 1000 person-years was 4.71 for patients who had undergone an appendectomy, compared to a rate of 2.59 for patients in the unexposed cohort (p

The use and cost of computed tomography (CT) and magnetic resonance imaging (MRI) are both very high. The purpose of this study was to evaluate the relation between physicians’ characteristics and the CT and MRI repeated within 90 days, using a nationwide population-based data set from Taiwan’s National Health Insurance system. Methods: All physicians who ordered CT and MRI examinations in 2004–2005 were identified. We analyzed the total number of CT and MRI scans, the number of repeat scans, and the repeat scan rate, according to physician characteristics (specialty, age, sex, and type of practice hospital). A multivariate logistic regression analysis was performed to explore the adjusted relationship between physician characteristics and their rate of ordering repeat CT and MRI. Results: A total of 16,307 physicians were responsible for a total of 2,152,292 CT and MRI scans during 2004–2005 in Taiwan. The repeat scans accounted for 21.5% of the total scans. Male physicians and physicians aged 41–50 years ordered more repeat scans. Internal medicine physicians ordered 44.3% of all scans and 50.6% of all repeat scans. Surgeons ordered 40.4% of the total scans and 38.5% of repeat scans. Internal medicine physicians were the most frequent users of CT/MRI scans. Family doctors, obstetricians/gynecologists, and pediatricians ranked last among the specialists. Physicians who practiced in medical centers ordered the most CT/MRI scans. Conclusion: Our study shows that repeat use of CT and MRI scans is related to physicians’ characteristics. We recommend that different monitoring standards should be set for CT and MRI repeat use by physicians of different specialties and in hospitals of different accreditation levels.

Benign prostatic hyperplasia is one of the chronic inflammatory conditions in ageing male populations. Rheumatoid arthritis (RA) is a major autoimmune disease and is also regarded as a chronic inflammatory disorder. Although RA and benign prostatic enlargement (BPE) may share the same underlying etiologies, almost no study has ever attempted to explore the relationship between RA and BPE. The aim of this study was to explore the relationship between RA and BPE using a population-based dataset. This case-control study used data retrieved from the Taiwan Longitudinal Health Insurance Database 2005. This study comprised 18,716 patients with BPE and 18,716 age-matched patients without BPE. Conditional logistic regression analyses were performed to calculate the odds ratio (OR) for having been previously diagnosed with RA between patients with BPE and comparison patients. In total, 485 of the 37,432 sampled patients (1.3%) had received a prior RA diagnosis. There was a significant difference in the prevalence of prior RA between cases and controls (1.6% vs. 1.0%, p

Most available studies focusing on the association between neovascular age-related macular degeneration (AMD) and dementia have conflicting results. This study aimed to investigate the association between previously diagnosed AMD and dementia using a population-based dataset in Taiwan.Data for this case-control study were retrospectively collected from the Taiwan National Health Insurance Research Database. We identified 13,402 subjects who had a diagnosis of dementia as cases, and 40,206 subjects without dementia as controls. A conditional logistic regression was used to examine the association of dementia with previously diagnosed neovascular AMD.We found that of the study sample of 53,608 subjects, 1.01% had previously diagnosed neovascular AMD, 1.35% and 0.90% for cases and the controls, respectively (p

Prior studies indicate a possible association between depression and cholecystectomy, but no study has compared the risk of post-operative depressive disorders (DD) after cholecystectomy. This retrospective follow-up study aimed to examine the relationship between cholecystectomy and the risk of DD in patients with gallstones in a population-based database.Using ambulatory care data from the Longitudinal Health Insurance Database 2000, 6755 patients who received a first-time principal diagnosis of gallstones at the emergency room (ER) were identified. Among them, 1197 underwent cholecystectomy. Each patient was then individually followed-up for two years to identify those who were later diagnosed with DD. Cox proportional hazards regressions were performed to estimate the risk of developing DD between patients with gallstone who did and those who did not undergo cholecystectomy.Of 6755 patients with gallstones, 173 (2.56%) were diagnosed with DD during the two-year follow-up. Among patients who did and those who did not undergo cholecystectomy, 3.51% and 2.36% later developed depressive disorder, respectively. After adjusting for the patient's sex, age and geographic location, the hazard ratio (HR) of DD within two years of gallstone diagnosis was 1.43 (95% CI, 1.02-2.04) for patients who underwent cholecystectomy compared to those who did not. Females, but not males, had a higher the adjusted HR of DD (1.61; 95% CI, 1.08-2.41) for patients who underwent cholecystectomy compared to those who did not.There is an association between cholecystectomy and subsequent risk of DD among females, but not in males.

Although obstructive sleep apnea (OSA) is not a life-threatening disease, very few studies have compared differences in healthcare service utilization between patients with and those without OSA in an Asian population according to different age groups. This study attempted to investigate differences in healthcare service utilization between patients with and those without OSA in different age groups in Taiwan.Sampled subjects and data on their health service utilization were retrieved from the Taiwan Longitudinal Health Insurance Database 2005. We included 568 patients with OSA and 2840 subjects without OSA. Each subject was followed for a 1-year period to evaluate their healthcare resource utilization. Wilcoxon-Mann-Whitney tests were performed to compare differences in healthcare utilization between patients with and those without OSA during the 1-year follow-up period.As to all healthcare service utilization, patients with OSA had significantly more outpatient visits (30.3 vs. 18.6), outpatient costs (US$1231.2 vs. US$764.8), inpatient days (1.8 vs. 1.2), inpatient costs (US$563.6 vs. US$276.7), and total costs (US$1794.8 vs. US$1041.5) than comparison subjects during the 1-year follow-up period. Moreover, patients with OSA aged 40~49 and 50~59 years respectively incurred 2.11- and 2.02-fold higher total costs compared to patients without OSA. However, patients with OSA aged over 70 years did not have higher total costs compared to those without OSA.This study found that patients with OSA had greater healthcare service utilization than those without OSA. Additionally, patients with OSA in the 40~49- and 50~59-year age groups had about 2-fold higher total costs of healthcare services than those without OSA.

Many studies have reported a possible association of an appendectomy with rheumatoid arthritis (RA). However, findings of the relationship between an appendectomy and RA remain inconsistent. Furthermore, all such studies were conducted in Western societies, and relevant studies on the relationship between an appendectomy and RA in Asian countries are still lacking. In this study, we investigated the relationship between an appendectomy and the subsequent risk of RA using a population-based dataset. We retrieved data for this retrospective cohort study from the Taiwan "Longitudinal Health Insurance Database 2005". We included 4,294 subjects who underwent an appendectomy in the study cohort and 12,882 matched subjects in the comparison cohort. We individually tracked each subject for a 5-year period from their index date to identify those who developed RA. A stratified Cox proportional hazard regression was performed to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI) for the subsequent development of RA during the 5-year follow-up period between subjects who underwent an appendectomy and comparison subjects. Of the sampled subjects, 93 (0.54%) received a diagnosis of RA during the 5-year follow-up period: 33 from the study cohort (0.77% of subjects who underwent an appendectomy) and 60 from the comparison cohort (0.47% of comparison subjects) (p

BackgroundPsoriasis is a prevalent autoimmune disorder. Various studies have reported on the relationship between psoriasis and chronic diseases but very few have explored the association between psoriasis and subsequent acute infection. This retrospective cohort study aimed to compare the risk of pneumonia between subjects with and those without psoriasis.MethodsThe medical records of 14,022 patients with psoriasis and 14,022 without psoriasis were obtained from the Taiwan Longitudinal Health Insurance Database 2000. Each patient was followed-up for a three-year period. Cox proportional hazard regressions were performed to compare difference of subsequent pneumonia incidence between subjects with and those without psoriasis.ResultsThere were 206 (1.47%) subjects with psoriasis and 138 (0.98%) without psoriasis hospitalized for pneumonia. By Cox proportional hazard regressions analysis, the HR (hazard ratio) of pneumonia requiring hospitalization for patients with psoriasis was 1.50 (95% confidence interval [CI]: 1.21-1.86) compared to patients without psoriasis. The adjusted HR was 1.40 (95% CI: 1.12-1.73). The adjusted HR of pneumonia hospitalization for subjects with mild and severe psoriasis was 1.36 (95% CI: 1.09-1.70) and 1.68 (95% CI: 1.12-2.52), respectively, compared to those without psoriasis.ConclusionsPatients with psoriasis have significantly higher incidence of pneumonia compared to those without psoriasis.

BackgroundThis study aims to investigate the differences in the utilization of healthcare services between patients with bladder pain syndrome/interstitial cystitis (BPS/IC) and patients without using a population-based database in Taiwan.MethodsThis study comprised of 350 patients with BPS/IC and 1,750 age-matched controls. Healthcare resource utilization was evaluated in the one-year follow-up period as follows: number of outpatient visits and inpatient days, and the mean costs of outpatient and inpatient treatment. A multivariate regression analysis was used to evaluate the relationship between BPS/IC and total costs of health care services.ResultsFor urological services, patients with BPS/IC had a significantly higher number of outpatient visits (2.5 vs. 0.2, pConclusionsThis study found that patients with BPS/IC have a significantly higher number of healthcare related visits, and have significantly higher healthcare related costs than age-matched controls. The high level of healthcare services utilization accrued with BPS/IC was not necessarily exclusive for BPS/IC, but may have also been associated with medical co-morbidities.

BackgroundWhile chronobiological studies have reported seasonal variation in panic attacks (PA) episodes, information on the timing of PA by week-days may enable better understanding of the triggers of PA episodes and thereby provide pointers for suitable interventional approaches to minimize PA attacks. This study investigated weekly variation in potential PA admissions including associations with holidays using a population-based longitudinal, administrative claims-based dataset in an Asian population.MethodsThis study used ambulatory care data from the "Longitudinal Health Insurance Database 2000. We identified 993 patients with panic disorder (PD), and they had 4228 emergency room (ER) admissions for potential PA in a 3-year period between 1 January 2009 and 31 December 2011. One-way analysis of variance (ANOVA) was used to examine associations between the potential PA admissions and holidays/weekend days/work-days of the week.ResultsThe daily mean number of potential PA admissions was 3.96 (standard deviation 2.05). One-way ANOVA showed significant differences in potential PA admissions by holiday and day of the week (pConclusionsWe found that potential PA admissions among persons with PD varied systematically by day of the week, with a significant peak on weekends and holidays.

BackgroundThis study aimed to investigate the relationship between the use of gonadotropin-releasing hormone (GnRH) agonists and subsequent risk of pneumonia in patients with prostate cancer (PC) using a population-based dataset.MethodsWe obtained the data from Taiwan's Longitudinal Health Insurance Database 2000. We included 2064 PC in this study. Of the sampled PC patients, 1207 received treatment with GnRH agonists. We individually traced each PC patient for a 1-year period to identify those who were hospitalized with pneumonia. We performed a Cox proportional hazard regression to explore the association between the use of GnRH agonists and the risk of pneumonia during the 1-year follow-up period.ResultsIncidence rates of pneumonia during the 1-year follow-up period were 4.35 (95% confidence interval (CI): 1.89∼9.64) per 100 person-years and 2.14 (95% CI: 1.31∼3.32) per 100 person-years for PC patients who did and those who did not receive treatment with GnRH agonists, respectively. The log-rank test suggested that there was a significant difference in the 1-year pneumonia-free survival rate between PC patients who did and those who did not receive treatment with GnRH agonists (pConclusionsPC patients who received treatment with GnRH agonists had an increased risk of pneumonia.

BackgroundThe majority of previous studies investigating the health care utilization of people with dementia were conducted in Western societies. There is little information on the economic burden on the healthcare system attributable to dementia in Asian countries. This study thus investigated differences in utilization of healthcare services between subjects with and those without a diagnosis of dementia using Taiwan's National Health Insurance population-based database.MethodsThis study comprised 5,666 subjects with a dementia diagnosis and 5,666 age- and gender-matched comparison subjects without a dementia diagnosis. We individually followed each subject for a 1-year period starting from their index date to evaluate their healthcare resource utilization. Healthcare resource utilization included the number of outpatient visits and inpatient days, and the mean costs of outpatient and inpatient treatments. In addition, we divided healthcare resource utilization into psychiatric and non-psychiatric services.ResultsAs for utilization of psychiatric services, subjects with a dementia diagnosis had significantly more outpatient visits (2.2 vs. 0.3, pConclusionsWe concluded that subjects who had received a clinical dementia diagnosis had significantly higher utilization of all healthcare services than comparison subjects.

This study investigated the association between statin use and herpes zoster (HZ) occurrence in a population-based case-control study.Study subjects were retrieved from the Taiwan Longitudinal Health Insurance Database 2000. This study included 47,359 cases with HZ and 142,077 controls. We performed conditional logistic regression analyses to calculate the odds ratio (OR) to present the association between HZ and having previously been prescribed statin.We found that 13.0% of the sampled subjects had used statins, at 15.5% and 12.1% for cases and controls, respectively (p

Some studies suggested that psychological stress may be associated with the severity and duration of infectious diseases. In this population-based study, we investigated associations between depressive disorder (DD) and pneumonia outcomes in Taiwan with a large-scale database from the National Health Insurance.Our study defined 112,198 patients who were hospitalized with a principal diagnosis of pneumonia. We defined their admission date for treatment of pneumonia as the index date. Subsequently, we selected 2,394 patients with DD within 3 years prior to their index date and 11,970 matched patients without DD. We carried out separate conditional logistic regressions to explore the association of clinical pneumonia treatment outcome (ICU admission, use of mechanical ventilation, acute respiratory failure and in-hospital death) with previously diagnosed DD.Patients with DD had a significantly higher probability of an intensive care unit admission (18.1% vs. 12.9%; p

BackgroundPeople with schizophrenia have been demonstrated to have higher overall morbidity and all-cause mortality rates from general medical conditions. However, little attention has been given to the urinary system of people with schizophrenia. As no direct evidence has been reported demonstrating a link between schizophrenia and urinary calculi, this study utilized a population-based case-control study design to investigate the possibility of an association between schizophrenia and the occurrence of urinary calculi.MethodThis study used data from the Taiwan Longitudinal Health Insurance Database. Cases consisted of 53,965 urinary calculi patients newly diagnosed between 2002 and 2008. In total, 269,825 controls were randomly selected and matched with the cases in terms of age and sex. Each person was traced to discern whether he had previously received a diagnosis of schizophrenia. Conditional logistic regression models were performed for the analysis.ResultsA total of 3,119 (1.0%) subjects had been diagnosed with schizophrenia prior to the index date. This included 0.7% of the patients with urinary calculi, and 1.0% of the controls. A prior diagnosis of schizophrenia was independently associated with a 30% decrease (95% CI = 0.62-0.76) in the occurrence of urinary calculi. The reduction was even more remarkable in males (38%, 95% CI = 0.55-0.71) and in elder individuals independent of gender (48% in those aged >69, 95% CI = 0.36-0.77).ConclusionOur findings suggest that there is an inverse association between schizophrenia and urinary calculi. Future studies are needed to elucidate the mechanisms by which schizophrenia negatively associates with urinary calculi.

BackgroundUnderstanding the reasons underlying the emerging trend and the changing demographics of Asian prostate cancer (PC) has become an important field of study. This study set out to explore the possibility that urinary calculi (UC) and PC may share an association by conducting a case-control study on a population-based database in Taiwan.MethodsThe cases of this study included 2,900 subjects ≥ 40 years-old who had received their first-time diagnosis of PC and 14,500 randomly selected controls without PC. Conditional logistic regressions were employed to explore the association between PC and having been previously diagnosed with UC.ResultsWe found that prior UC was found among 608 (21.0%) cases and 2,037 (14.1%) controls (pConclusionsThis investigation detected an association between PC and prior UC. These results highlight a potential target population for PC screening.

BackgroundAlthough the etiology of bladder pain syndrome/interstitial cystitis (BPS/IC) is still unclear, a common theme with BPS/IC patients is comorbid disorders which are related to the autonomic nervous system that connects the nervous system to end-organs. Nevertheless, no study to date has reported the association between hyperthyroidism and BPS/IC. In this study, we examined the association of IC/BPS with having previously been diagnosed with hyperthyroidism in Taiwan.DesignData in this study were retrieved from the Longitudinal Health Insurance Database. Our study consisted of 736 female cases with BPS/IC and 2208 randomly selected female controls. We performed a conditional logistic regression to calculate the odds ratio (OR) for having previously been diagnosed with hyperthyroidism between cases and controls.ResultsOf the 2944 sampled subjects, there was a significant difference in the prevalence of prior hyperthyroidism between cases and controls (3.3% vs. 1.5%, pConclusionsOur study results indicated an association between hyperthyroidism and BPS/IC. We suggest that clinicians treating female subjects with hyperthyroidism be alert to urinary complaints in this population.

BACKGROUND: Mounting evidence supports the use of laparoscopic techniques for the treatment of simple appendicitis. However, most of the advantages of these techniques are of limited clinical relevance. This study compares the treatment outcomes of laparoscopic appendectomies and open appendectomies performed in Taiwan. METHODS: This study uses data from the 2007 to 2009 Taiwan National Health Insurance Research Database. The study sample included 65,339 patients, hospitalized with a discharge diagnosis of acute appendicitis (33.8% underwent laparoscopic appendectomy). A generalized estimated equation (GEE) was performed to explore the relationship between the use of laparoscopy and 30-day re-admission. Hierarchical linear regressions were performed to examine the relationship between the use of laparoscopy, the length of stay (LOS), and the cost per discharge. RESULTS: A significantly lower proportion of patients undergoing laparoscopic appendectomies were re-admitted within 30 days of their index appendectomy, in comparison to patients undergoing open appendectomies (0.66% versus 1.925, p

BACKGROUND: The impact of anti-hypertensive treatment on fetus was unclear, and hence, remains controversial. We set out in this study to estimate the prevalence of adverse pregnancy outcomes, including low birth weight, preterm delivery and small for gestational age amongst women with chronic hypertension, and to determine whether the use of anti-hypertensive drugs increases the risk of such adverse pregnancy outcomes. METHODOLOGY/PRINCIPAL FINDINGS: A total of 2,727 hypertension mothers and 8,181 matched controls were identified from the population-based cohort. These hypertension women were divided into seven sub-groups according to different types of prescribed anti-hypertensive drugs. Multivariable logistic regressions were conducted to estimate the risk of low birth weight, preterm birth and small for gestational age. Increased risk of low birth weight (OR = 2.29, 95% CI = 1.95-2.68), preterm birth (OR = 2.18, 95% CI = 1.89-2.52) and small for gestational age (OR = 1.62, 95% CI = 1.45-1.81) were all discernible within the hypertension group after adjusting for potential confounding factors. The increased ORs were found to differ with different types of anti-hypertensive drugs. Women who received vasodilators were associated with the highest risk of low birth weight (OR = 2.96, 95% CI = 2.06-4.26), preterm birth (OR = 2.92 95% CI = 2.06-4.15) and small for gestational age (OR = 2.12, 95% CI = 1.60-2.82). CONCLUSIONS/SIGNIFICANCE: This finding is important for practitioners, because it indicates the need for caution while considering the administration of anti-hypertensive drugs to pregnant women. These observations require confirmation in further studies that can better adjust for the severity of the underlying HTN.