Publications by authors named "Chung Y Hsu"

223 Publications

Association Between Preeclampsia Risk and Fine Air Pollutants and Acidic Gases: A Cohort Analysis in Taiwan.

Front Public Health 2021 31;9:617521. Epub 2021 Mar 31.

College of Medicine, Graduate Institute of Biomedical Sciences and School of Medicine, China Medical University, Taichung, Taiwan.

Fine air pollutant particles have been reported to be associated with risk of preeclampsia. The association between air pollutant exposure and preeclampsia risk in heavily air polluted Taiwan warrants investigation. We combined data from Taiwan National Health Insurance (NHI) Research Database (NHIRD) and Taiwan Air Quality Monitoring Database. Women aged 16-55 years were followed from January 1, 2000, until appearance of ICD-9 coding of preeclampsia withdrawal from the NHI program, or December 31, 2013. Daily concentration of NOx, NO, NO, and CO was calculated by Kriging method. The Cox proportional hazard regression model was used for risk assessment. For NOx, Relative to Quartile [Q] 1 concentrations, the Q2 (adjusted hazard ratio adjusted = 2.20, 95% CI = 1.50-3.22), Q3 (aHR = 7.28, 95% CI = 4.78-11.0), and Q4 (aHR = 23.7, 95% CI = 13.7-41.1) concentrations were associated with a significantly higher preeclampsia or eclampsia risk. Similarly, for NO, relative to Q1 concentrations, the Q2 (aHR = 1.82, 95% CI = 1.26-2.63), Q3 (aHR = 7.53, 95% CI = 5.12-11.0), and Q4 (aHR = 11.1, 95% CI = 6.72-18.3) concentrations were correlated with significantly higher preeclampsia or eclampsia risk. Furthermore, for NO, relative to Q1 concentration, the Q2 (aHR = 1.99, 95% CI = 1.37-2.90), Q3 (aHR = 6.15, 95% CI = 3.95-9.57), and Q4 (aHR = 32.7, 95% CI = 19.7-54.3) concentrations also associated with a significantly higher preeclampsia or eclampsia risk. Women exposed to higher NO, NO, NO, and CO concentrations demonstrated higher preeclampsia incidence.
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http://dx.doi.org/10.3389/fpubh.2021.617521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044398PMC
March 2021

Risk of Breast Cancer in Females With Hypothyroidism: A Nationwide, Population-Based, Cohort Study.

Endocr Pract 2021 Apr 15;27(4):298-305. Epub 2020 Dec 15.

Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.

Objectives: The results of studies investigating the relationship between breast cancer and hypothyroidism vary greatly from study to study. In this study, we analyzed a large and reliable, population-based database to gain a better understanding of the correlation.

Methods: This retrospective cohort study analyzed patients with hypothyroidism between January 1, 2000 and December 31, 2012 (hypothyroidism cohort) from the Longitudinal Health Insurance Database 2000 in Taiwan. For each woman with hypothyroidism, 1 woman without a history of breast cancer was randomly selected from the Longitudinal Health Insurance Database 2000 and frequency matched (1:4) with women without hypothyroidism by age and index year of hypothyroidism. The study outcome was the diagnosis of breast cancer during a 12-year follow-up period.

Results: In this study, 6665 women with hypothyroidism and 26 660 women without hypothyroidism were identified. The hypothyroidism cohort had a significantly higher risk of breast cancer than the nonhypothyroidism cohort (adjusted hazard ratio [aHR] 1.69 [95% CI, 1.15-2.49]; P = .01), especially in the group aged 40 to 64 years (aHR 2.07 [95% CI, 1.32-3.23]; P = .01). Women in the hypothyroidism cohort taking levothyroxine for a duration ˃588 days showed a significantly decreased risk of breast cancer (aHR 0.37 [95% CI, 0.19-0.71]; P = .003).

Conclusion: Women with hypothyroidism are at a higher risk of breast cancer than those without hypothyroidism. Levothyroxine may reduce the risk of breast cancer in a woman with hypothyroidism.
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http://dx.doi.org/10.1016/j.eprac.2020.09.007DOI Listing
April 2021

Chinese Herbal Products for Non-Motor Symptoms of Parkinson's Disease in Taiwan: A Population-Based Study.

Front Pharmacol 2020 27;11:615657. Epub 2021 Jan 27.

Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Combinations of Chinese herbal products (CHPs) are widely used for Parkinson's disease (PD) in Taiwan. Thereby, we investigated the use of CHPs in patients with PD. This study was a population-based cohort study that analyzed the data of patients with PD from the National Health Insurance Research Database. A total of 9,117 patients were selected from a random sample of one million individuals included in this database. We used multiple logistic regression models to estimate the adjusted odds ratios of the demographic factors and analyzed the formula and single CHPs commonly used for PD. Traditional Chinese medicine users were more commonly female, younger, of white-collar status, and residents of Central Taiwan. Chaihu-Jia-Longgu-Muli-Tang was the most commonly used formula, followed by Ma-Zi-Ren-Wan and then Shao-Yao-Gan-Cao-Tang. The most commonly used single herb was (Willd. ex Schult.) DC., followed by Blume and then ( L., Maxim ex Balf., Baill.). Chaihu-Jia-Longgu-Muli-Tang and (Willd. ex Schult.) DC have shown neuroprotective effects in previous studies, and they have been used for managing non-motor symptoms of PD. Chaihu-Jia-Longgu-Muli-Tang and (Willd. ex Schult.) DC are the most commonly used CHPs for PD in Taiwan. Our results revealed the preferences in medication prescriptions for PD. Further studies are warranted to determine the effectiveness of these CHPs for ameliorating the various symptoms of PD, their adverse effects, and the mechanisms underlying their associated neuroprotective effects.
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http://dx.doi.org/10.3389/fphar.2020.615657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873047PMC
January 2021

Women With Osteoarthritis Are at Increased Risk of Ischemic Stroke: A Population-Based Cohort Study.

J Epidemiol 2021 Feb 2. Epub 2021 Feb 2.

Management Office for Health Data, China Medical University Hospital.

Background: Osteoarthritis (OA) is more prevalent in women with age. Comorbidities are prevalent in OA patients. In this study, we conducted a follow-up study to evaluate whether women with OA are at an increased risk of ischemic stroke using insurance claims data of Taiwan.

Methods: We identified 13,520 women with OA aged 20-99 newly diagnosed in 2000-2006 and 27,033 women without OA for comparison, frequency matched by age and diagnosis date. Women with baseline history of hypertension and other disorders associated with stroke were excluded for this study. Incident ischemic stroke was assessed by the end of 2013. A nested case-control analysis was used to identify factors associated with the stroke in the OA cohort.

Results: The incidence rate of ischemic stroke in the OA cohort was 1.5-fold greater than that in comparisons (1.93 versus 1.26 per 1,000 person-years), with an adjusted hazard ratio of 1.34 (95% confidence interval [CI], 1.09-1.66). The nested case-control analysis showed that stroke cases were twice as likely to develop hypertension during the follow-up period than controls without stroke. The ischemic stroke risk was significantly associated with hypertension (odds ratio [OR] 1.84; 95% CI, 1.37-2.46) and atrial fibrillation (OR 2.25; 95% CI, 1.24-4.09). Ischemic stroke was not associated with the use of non-steroidal anti-inflammatory drugs or aspirin.

Conclusion: Women with OA are at an elevated risk of ischemic stroke. A close monitoring of hypertension, atrial fibrillation, and other stroke related comorbidities is required for stroke prevention for OA patients.
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http://dx.doi.org/10.2188/jea.JE20200042DOI Listing
February 2021

Diabetes mellitus risk after hysterectomy: A population-based retrospective cohort study.

Medicine (Baltimore) 2021 Jan;100(4):e24468

Institute of Medical Sciences.

Abstract: We explored whether hysterectomy with or without bilateral oophorectomy was associated with the increasing incidence of diabetes mellitus (DM) in an East Asian population. This was a retrospective population-based cohort study that analyzed DM risk in Taiwanese women, using a health insurance research database of 1998 to 2013 containing nearly 1 million people. We identified 7088 women aged 30 to 49 years who had undergone hysterectomy with or without oophorectomy. The comparison group included 27,845 women without a hysterectomy who were randomly selected from the population and matched to women in the hysterectomy group by age (exact year) and year of the surgery. DM comorbidities were identified. The incidence and hazard ratios for DM were calculated with Cox proportional hazard regression models. The median ages of patients in the hysterectomy and comparison groups were both approximately 44 years. After a median 7.1 years of follow-up, the incidence of DM was 40% higher in the hysterectomized women as compared with the comparisons (9.12 vs 6.78/1000 person-years, P < .001), with an adjusted hazard ratio (aHR) of 1.37 (95% confidence interval [CI] = 1.23 -1.52). However, the DM risk was not increased in the women with hysterectomy plus oophorectomy (aHR=1.28, 95% CI = 0.93-1.76). Furthermore, among women aged 30 to 39 years, 40 to 49 years, the risk in hysterectomized women was higher than the comparisons (aHR = 1.75, 95% CI = 1.27-2.41; aHR = 1.33, 95% CI = 1.19-1.49, respectively). Our study provides essential and novel evidence for the association between hysterectomy and DM risk in women aged 30 to 49 years, which is relevant to these women and their physicians. Physicians should be aware of the increased DM risk associated with hysterectomy and take this into consideration when evaluating a patient for a hysterectomy. The current results might help gynecologists prevent DM and encourage diagnostic and preventive interventions in appropriate patients.
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http://dx.doi.org/10.1097/MD.0000000000024468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850756PMC
January 2021

Herpes zoster in patients with sciatica.

BMC Musculoskelet Disord 2020 Dec 5;21(1):813. Epub 2020 Dec 5.

Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung, 404, Taiwan.

Background: Several diseases are associated with herpes zoster (HZ). However, whether sciatica is a stressor leading to HZ development remains unclear. Here, we evaluated the occurrence of HZ in patients with sciatica.

Methods: The sciatica cohort consisted of patients first diagnosed as having sciatica between 2000 and 2012. All patients with sciatica were randomly age, sex and index year matched with control individuals without sciatica. The primary outcome was diagnosis of HZ. All individuals were followed until HZ diagnosis, withdrawal from the insurance, death, or December 31, 2013, whichever occurred first. HZ risk in the two cohorts was further analyzed with age, sex and comorbidity stratification.

Results: In total, 49,023 patients with sciatica and 49,023 matched controls were included. Female patients were more likely to have HZ development than were male patients [adjusted hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02-1.12]. After adjustments for all the covariates, HZ risk was significantly higher in the sciatica cohort than in the control cohort (adjusted HR = 1.19; 95% CI = 1.12-1.25).

Conclusion: Sciatica increased HZ risk. Thus, HZ risk should be addressed whenever physicians encounter patients with sciatica, HZ vaccination should be considered especially those aged over 50.
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http://dx.doi.org/10.1186/s12891-020-03847-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719251PMC
December 2020

Prognostic impact of renal dysfunction on embolic stroke of undetermined source-Role beyond CHA DS -VASc score: Results from Taiwan Stroke Registry.

Eur J Neurol 2021 Apr 22;28(4):1253-1264. Epub 2020 Dec 22.

Graduate Institute of Clinical Medical Science, China Medical University and Hospital, Taichung, Taiwan.

Background And Purpose: The CHA DS -VASc score has immense prognostic value in patients with embolic stroke of undetermined source (ESUS). We aimed to determine the usefulness of advanced renal dysfunction and its addition to the CHA DS -VASc score in improving predictive accuracy.

Methods: In total, 3775 ESUS patients were enrolled from a nationwide hospital-based prospective study. Advanced renal dysfunction was defined as estimated glomerular filtration rate <30 ml/min per 1.73 m or patients under dialysis. Clinical outcomes included recurrent stroke and 1-year all-cause mortality. Poor functional outcome was defined as a modified Rankin Scale >2 at first-, third-, and sixth-month post-stroke. The renal (R)-CHA DS -VASc score was derived by including advanced renal dysfunction in the CHA DS -VASc score. Risk stratification improvement after including advanced renal dysfunction was assessed using C statistic, integrated discrimination improvement (IDI), and category-free net reclassification index (NRI).

Results: After adjusting for confounding factors and CHA DS -VASc score, advanced renal dysfunction showed significant associations with all-cause mortality (HR: 2.88, 95% CI: 1.92-4.34) and poor functional outcome at third- (OR: 2.69, 95% CI: 1.47-4.94) and sixth-month post-stroke (OR: 2.67, 95% CI: 1.47-4.83). IDI and NRI showed that incorporating advanced renal dysfunction significantly improved risk discrimination over the original CHA DS -VASc score. R-CHA DS -VASc score ≥2 increased risk by 1.94-fold (95% CI: 1.15-3.27) for all-cause mortality, and ≥4 increased risk by 1.62-fold (95% CI: 1.05-2.50) of poor functional outcome at third-month post-stroke and by 1.81-fold (95% CI: 1.19-2.75) at sixth-month post-stroke.

Conclusions: Advanced renal dysfunction was significantly associated with clinical and functional outcomes in ESUS patients and may improve prognostic impact of the CHA DS -VASc score.
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http://dx.doi.org/10.1111/ene.14662DOI Listing
April 2021

Association between hyperthyroidism and risk of incident in Parkinson's disease.

Endocr Connect 2021 Jan;10(1):13-20

Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.

Hyperthyroidism contributes to many other disease conditions, including neurodegenerative diseases. Parkinson's disease (PD) is one of the most common neurodegenerative diseases. The purpose of this study was to investigate the risk of PD in patients with hyperthyroidism. A total of 8788 patients with hyperthyroidism and 8788 controls (without hyperthyroidism) matched by age, gender, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000 and 2012. Patients were then followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed PD were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% CI of PD incidence rate between patients with hyperthyroidism and unaffected controls. Patients with hyperthyroidism had a significantly increased risk of PD compared with unaffected controls (1.21 vs 0.45 per 1000 person-years, HR: 2.69, 95% CI: 1.08-6.66) after adjusting for age, gender, CCI score, comorbidities, and antithyroid therapy. Hyperthyroidism and PD may share common manifestations. After excluding the first year of observation, a similar result is obtained (HR: 2.57, 95% CI: 1.61-4.01). Also, this study found that older age (HR: 3.74-8.53), more comorbidities (HR: 1.58-1.63), and specific comorbidities (brain injury (HR: 1.57) and cerebrovascular disease (HR: 3.44)) were associated with an increased risk of developing PD. Patients with hyperthyroidism have an increased risk of developing PD. Additional prospective clinical studies are warranted to examine the relationship between hyperthyroidism and PD and determine if there is an intervention that could reduce PD risk.
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http://dx.doi.org/10.1530/EC-20-0554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923144PMC
January 2021

Regional Differences in the Response to Acute Blood Pressure Lowering After Cerebral Hemorrhage.

Neurology 2021 02 20;96(5):e740-e751. Epub 2020 Nov 20.

From the Department of Cerebrovascular Medicine (K. Toyoda, M.K., S.Y., K. Tanaka, K.M.), Center for Advancing Clinical and Translational Sciences (H.Y., M.F.-D., S.O.), and Department of Neurology (M.I.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Public Health Sciences (Y.Y.P., L.F.), Medical University of South Carolina, Charleston; Department of Neurology (Y.H.), St. Marianna University School of Medicine, Kawasaki; Department of Neurosurgery and Stroke Center (Y.S.), Kyorin University School of Medicine, Mitaka; Department of Neurosurgery (T.I.), Gifu University Graduate School of Medicine; Department of Neurosurgery (K.K.), Nakamura Memorial Hospital, Sapporo; Department of Neurology (H.H.), Tokyo Saiseikai Central Hospital, Japan; Department of Neurology (T.S.), Klinikum Frankfurt Höchst, Germany; Department of Neurology (B.-W.Y.), Seoul National University Hospital, South Korea; Beijing Tiantan Hospital (Y.W.), China; China Medical University (C.Y.H.), Taichung, Taiwan; and Zeenat Qureshi Stroke Research Center (A.I.Q.), University of Minnesota, Minneapolis.

Objective: To compare the impact of intensive blood pressure (BP) lowering right after intracerebral hemorrhage (ICH) on clinical and hematoma outcomes among patients from different geographic locations, we performed a prespecified subanalysis of a randomized, multinational, 2-group, open-label trial to determine the efficacy of rapidly lowering BP in hyperacute ICH (Antihypertensive Treatment of Acute Cerebral Hemorrhage [ATACH]-2), involving 537 patients from East Asia and 463 recruited outside of Asia.

Methods: Eligible patients were randomly assigned to a systolic BP target of 110 to 139 mm Hg (intensive treatment) or 140 to 179 mm Hg (standard treatment). Predefined outcomes were poor functional outcome (modified Rankin Scale score 4-6 at 90 days), death within 90 days, hematoma expansion at 24 hours, and cardiorenal adverse events within 7 days.

Results: Poor functional outcomes (32.0% vs 45.9%), death (1.9% vs 13.3%), and cardiorenal adverse events (3.9% vs 11.2%) occurred significantly less frequently in patients from Asia than those outside of Asia. The treatment-by-cohort interaction was not significant for any outcomes. Only patients from Asia showed a lower incidence of hematoma expansion with intensive treatment (adjusted relative risk [RR] 0.56, 95% confidence interval [CI] 0.38-0.83). Both Asian (RR 3.53, 95% CI 1.28-9.64) and non-Asian (RR 1.71, 95% CI 1.00-2.93) cohorts showed a higher incidence of cardiorenal adverse events with intensive treatment.

Conclusions: Poor functional outcomes and death 90 days after ICH were less common in patients from East Asia than those outside of Asia. Hematoma expansion, a potential predictor for poor clinical outcome, was attenuated by intensive BP lowering only in the Asian cohort.

Clinicaltrialsgov Identifier: NCT01176565.

Classification Of Evidence: This study provides Class II evidence that, for patients from East Asia with ICH, intensive blood pressure lowering significantly reduces the risk of hematoma expansion.
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http://dx.doi.org/10.1212/WNL.0000000000011229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884997PMC
February 2021

Risk of Rheumatoid Arthritis in Patients with Endometriosis: A Nationwide Population-Based Cohort Study.

J Womens Health (Larchmt) 2020 Nov 18. Epub 2020 Nov 18.

Department of Psychiatry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation & School of Medicine, Tzu Chi University, Hualien, Taiwan.

Abnormalities in the immune system of endometriosis has been demonstrated and may reflect the chronic inflammatory response or the autoimmune reaction to the presence of ectopic endometrial tissue. Rheumatoid arthritis (RA) is a chronic inflammatory joint disease of an autoimmune nature. The study aimed to investigate the risk of incident RA in patients with endometriosis. A total of 17,913 patients with endometriosis and 17,913 unaffected controls matched by age, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000 and 2012. Patients were followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed RA were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of RA incidence rate between patients with endometriosis and unaffected controls. Patients with endometriosis were associated with an increased risk of incident RA compared with unaffected controls after adjusting for age, CCI score, and hormonal and surgical treatments (3.56 vs. 1.30 per 10,000 person-years, HR: 3.71, 95% CI: 2.91-5.73). Among these adjusted variables, hormonal and surgical treatments were treated as time-dependent covariates. Stratification analyses also revealed similar risk associations linking endometriosis to subsequent RA in all stratified age and CCI score subgroups (adjusted HR all >1, although not all were significant) Patients with endometriosis was associated with an increased risk of incident RA. Additional prospective studies that take into account genetic vulnerability and environmental exposures are warranted to confirm this relationship.
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http://dx.doi.org/10.1089/jwh.2020.8431DOI Listing
November 2020

Association between Graves' disease and risk of incident systemic lupus erythematosus: A nationwide population-based cohort study.

Int J Rheum Dis 2021 Feb 19;24(2):240-245. Epub 2020 Nov 19.

Department of Psychiatry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

Objective: Previous case reports have linked Graves' disease to incident systemic lupus erythematosus (SLE). It has also been reported that antithyroid drugs used to treat Graves' disease can induce SLE development. The purpose of this study was to investigate the risk of SLE in patients with Graves' disease.

Methods: A total of 8779 patients with Graves' disease and 8779 controls (without Graves' disease) matched by age, gender, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000-2012. Patients were then followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed SLE were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of SLE incidence rate between patients with Graves' disease and unaffected controls.

Results: Patients with Graves' disease had a significantly increased risk of SLE than unaffected controls (8.81 vs 2.83 per 10 000 person-years, HR: 5.45, 95% CI: 1.74-17.0) after adjusting for antithyroid therapies (antithyroid drugs, radioactive iodine ablation, and surgery). Diagnostic bias may be present as patients with Graves' disease may seek more help from healthcare providers. After excluding the first 0.5 and 1 year of observation period, similar results were obtained (excluding 0.5 year - HR: 4.30, 95% CI: 2.78-8.57; excluding 1 year - HR: 4.63, 95% CI: 2.33-7.79).

Conclusion: This study shows that Graves' disease is associated with an increased risk of incident SLE. Further studies on the underlying pathogenesis linking Graves' disease and SLE are warranted.
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http://dx.doi.org/10.1111/1756-185X.14027DOI Listing
February 2021

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

Lancet 2020 11 8;396(10262):1574-1584. Epub 2020 Nov 8.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers.

Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903.

Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024).

Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734592PMC
November 2020

Association of Reperfusion After Thrombolysis With Clinical Outcome Across the 4.5- to 9-Hours and Wake-up Stroke Time Window: A Meta-Analysis of the EXTEND and EPITHET Randomized Clinical Trials.

JAMA Neurol 2021 Feb;78(2):236-240

Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.

Importance: Intravenous alteplase reduces disability after ischemic stroke in patients 4.5 to 9 hours after onset and with wake-up onset stroke selected using perfusion imaging mismatch. However, whether the benefit is consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke epochs is uncertain.

Objective: To examine the association of reperfusion with reduced disability, including by onset-to-randomization time strata in the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) randomized clinical trials.

Design, Setting, And Participants: Individual patient meta-analysis of randomized clinical trials performed from August 2001 to June 2018 with 3-month follow-up. Patients had acute ischemic stroke with 4.5-to 9-hours poststroke onset or with wake-up stroke were randomized to alteplase or placebo after perfusion mismatch imaging. Analysis began July 2019 and ended May 2020.

Exposures: Reperfusion was defined as more than 90% reduction in time to maximum of more than 6 seconds' lesion volume at 24- to 72-hour follow-up.

Main Outcomes And Measures: Ordinal logistic regression adjusted for baseline age and National Institutes of Health Stroke Scale score was used to analyze functional improvement in day 90 modified Rankin Scale score overall, including a reperfusion × time-to-randomization multiplicative interaction term, and in the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata. Symptomatic hemorrhage was defined as large parenchymal hematoma with a National Institutes of Health Stroke Scale score increase of 4 points or more.

Results: Reperfusion was assessable in 270 of 295 patients (92%), 68 of 133 (51%) in the alteplase group, and 38 of 137 (28%) in the placebo reperfused group (P < .001). The median (interquartile range) age was 76 (66-81) years in the reperfusion group vs 74 (64.5-81.0) years in the group with no reperfusion. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (7-15) in the reperfusion group vs 12 (8.0-17.5) in the no reperfusion group. Overall, reperfusion was associated with improved functional outcome (common odds ratio, 7.7; 95% CI, 4.6-12.8; P < .001). Reperfusion was associated with significantly improved functional outcome in each of the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata, with no evidence of association between time to randomization and beneficial effect of reperfusion (P = .63). Symptomatic hemorrhage, assessed in all 294 patients, occurred in 3 of 51 (5.9%) in the 4.5- to 6-hours group, 2 of 28 (7.1%) in the 6- to 9-hours group, and 4 of 73 (5.5%) in the wake-up stroke in patients treated with alteplase (Fisher P = .91).

Conclusions And Relevance: Strong benefits of reperfusion in all time strata without differential risk in symptomatic hemorrhage support the consistent treatment effect of alteplase in perfusion mismatch-selected patients throughout the 4.5- to 9-hours and wake-up stroke time window.
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http://dx.doi.org/10.1001/jamaneurol.2020.4123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607491PMC
February 2021

Tranexamic acid in patients with intracerebral haemorrhage (STOP-AUST): a multicentre, randomised, placebo-controlled, phase 2 trial.

Lancet Neurol 2020 12 28;19(12):980-987. Epub 2020 Oct 28.

Department of Neurology, Royal Adelaide Hospital, Adelaide, SA, Australia.

Background: Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage.

Methods: We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of >7, intracerebral haemorrhage volume <70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4·5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (>33% relative or >6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636).

Findings: Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14·6 mL (7·9-32·7) at baseline. The primary outcome was not different between the two groups: 26 (52%) patients in the placebo group and 22 (44%) in the tranexamic acid group had intracerebral haemorrhage growth (odds ratio [OR] 0·72 [95% CI 0·32-1·59], p=0·41). There was no evidence of a difference in the proportions of patients who died or had thromboembolic complications between the groups: eight (16%) in the placebo group vs 13 (26%) in the tranexamic acid group died and two (4%) vs one (2%) had thromboembolic complications. None of the deaths was considered related to study medication.

Interpretation: Our study does not provide evidence that tranexamic acid prevents intracerebral haemorrhage growth, although the treatment was safe with no increase in thromboembolic complications. Larger trials of tranexamic acid, with simpler recruitment methods and an earlier treatment window, are justified.

Funding: National Health and Medical Research Council, Royal Melbourne Hospital Foundation.
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http://dx.doi.org/10.1016/S1474-4422(20)30369-0DOI Listing
December 2020

Decreased stroke risk with combined traditional Chinese and western medicine in patients with ischemic heart disease: A real-world evidence.

Medicine (Baltimore) 2020 Oct;99(42):e22654

Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine.

Both ischemic heart disease (IHD) and stroke are major causes of death worldwide. We investigated the effects of combined Traditional Chinese medicine (TCM) and western medicine (WM) on stroke risk in IHD patients.Taiwanese patients with IHD were enrolled in the TCM study during their outpatient visit. Stroke events after TCM or non-TCM treatment were examined. Chi-square tests and Student t-tests were used to examine differences between patients using and not using TCM. The Cox proportional hazards regression model was used to estimate hazard ratios (HRs). Sex, age, and comorbidities were included in a multivariable Cox model to estimate the adjusted HR (aHR). The survival probability and the probability free of stroke were calculated by the Kaplan-Meier method.There were 733 IHD patients using TCM and 733 using non-TCM treatment, with the same proportion of sex and age within each cohort. Using single Chinese herb such as Dan Shen, San Qi, or Chuan Xiong would have lower stroke events and lower aHR than non-TCM in IHD patients. There was 0.3-fold lower stroke risk in IHD patients with combination TCM and non-TCM treatment (95% CI = 0.11-0.84, P = .02). Moreover, the survival rate was higher (P < .001) and the incidence of hemorrhagic stroke was significantly lower (P = .04) in IHD patients with TCM treatment.IHD patients using combined TCM and WM had a higher survival rate and lower risk of new onset stroke, especially hemorrhagic stroke than those who did not use TCM treatment.
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http://dx.doi.org/10.1097/MD.0000000000022654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571976PMC
October 2020

Outcomes of Intensive Systolic Blood Pressure Reduction in Patients With Intracerebral Hemorrhage and Excessively High Initial Systolic Blood Pressure: Post Hoc Analysis of a Randomized Clinical Trial.

JAMA Neurol 2020 Nov;77(11):1355-1365

Center for Advancing Clinical and Translational Sciences, National Cerebral and Cardiovascular Center, Suita, Japan.

Importance: The safety and efficacy of intensive systolic blood pressure reduction in patients with intracerebral hemorrhage who present with systolic blood pressure greater than 220 mm Hg appears to be unknown.

Objective: To evaluate the differential outcomes of intensive (goal, 110-139 mm Hg) vs standard (goal, 140-179 mm Hg) systolic blood pressure reduction in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more vs less than 220 mm Hg.

Design, Setting, And Participants: This post hoc analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage-II trial was performed in November 2019 on data from the multicenter randomized clinical trial, which was conducted between May 2011 to September 2015. Patients with intracerebral hemorrhage and initial systolic blood pressure of 180 mm Hg or more, randomized within 4.5 hours after symptom onset, were included.

Interventions: Intravenous nicardipine infusion titrated to goals.

Main Outcomes And Measures: Neurological deterioration and hematoma expansion within 24 hours and death or severe disability at 90 days, plus kidney adverse events and serious adverse events until day 7 or hospital discharge.

Results: A total of 8532 patients were screened, and 999 individuals (mean [SD] age, 62.0 [13.1] years; 620 men [62.0%]) underwent randomization and had an initial SBP value. Among 228 participants with initial systolic blood pressures of 220 mm Hg or more, the rate of neurological deterioration within 24 hours was higher in those who underwent intensive (vs standard) systolic blood pressure reduction (15.5% vs 6.8%; relative risk, 2.28 [95% CI, 1.03-5.07]; P = .04). The rate of death and severe disability (39.0% vs 38.4%; relative risk, 1.02 [95% CI, 0.73-1.78]; P = .92) was not significantly different between the 2 groups. There was a significantly higher rate of kidney adverse events in participants randomized to intensive systolic blood pressure reduction (13.6% vs 4.2%; relative risk, 3.22 [95% CI, 1.21-8.56]; P = .01), but no difference was observed in the rate of kidney serious adverse events.

Conclusions And Relevance: The higher rate of neurological deterioration within 24 hours associated with intensive treatment in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more, without any benefit in reducing hematoma expansion at 24 hours or death or severe disability at 90 days, warrants caution against generalization of recommendations for intensive systolic blood pressure reduction.
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http://dx.doi.org/10.1001/jamaneurol.2020.3075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489424PMC
November 2020

Systolic Blood Pressure Reduction and Acute Kidney Injury in Intracerebral Hemorrhage.

Stroke 2020 10 25;51(10):3030-3038. Epub 2020 Aug 25.

Center for Advancing Clinical and Translational Sciences, National Cerebral and Cardiovascular Center, Suita, Japan. (H.Y.).

Background And Purpose: We determined the rates and predictors of acute kidney injury (AKI) and renal adverse events (AEs), and effects of AKI and renal AEs on death or disability in patients with intracerebral hemorrhage.

Methods: We analyzed data from a multicenter trial which randomized 1000 intracerebral hemorrhage patients with initial systolic blood pressure ≥180 mm Hg to intensive (goal 110-139 mm Hg) over standard (goal 140-179 mm Hg) systolic blood pressure reduction within 4.5 hours of symptom onset. AKI was identified by serial assessment of daily serum creatinine for 3 days post randomization.

Results: AKI and renal AEs were observed in 149 patients (14.9%) and 65 patients (6.5%) among 1000 patients, respectively. In multivariate analysis, the higher baseline serum creatinine (≥110 μmol/L) was associated with AKI (odds ratio 2.4 [95% CI, 1.2-4.5]) and renal AEs (odds ratio 3.1 [95% CI, 1.2-8.1]). Higher area under the curve for intravenous nicardipine dose was associated with AKI (odds ratio 1.003 [95% CI, 1.001-1.005]) and renal AEs (odds ratio 1.003 [95% CI, 1.001-1.006]). There was a higher risk to death (relative risk 2.6 [95% CI, 1.6-4.2]) and death or disability (relative risk 1.5 [95% CI, 1.3-1.8]) at 90 days in patients with AKI but not in those with renal AEs.

Conclusions: Intracerebral hemorrhage patients with higher baseline serum creatinine and those receiving higher doses of nicardipine were at higher risk for AKI and renal AEs. Occurrence of AKI was associated higher rates of death or disability at 3 months. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT01176565.
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http://dx.doi.org/10.1161/STROKEAHA.120.030272DOI Listing
October 2020

Call to Action: SARS-CoV-2 and CerebrovAscular DisordErs (CASCADE).

J Stroke Cerebrovasc Dis 2020 Sep 8;29(9):104938. Epub 2020 May 8.

Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.

Background And Purpose: The novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), now named coronavirus disease 2019 (COVID-19), may change the risk of stroke through an enhanced systemic inflammatory response, hypercoagulable state, and endothelial damage in the cerebrovascular system. Moreover, due to the current pandemic, some countries have prioritized health resources towards COVID-19 management, making it more challenging to appropriately care for other potentially disabling and fatal diseases such as stroke. The aim of this study is to identify and describe changes in stroke epidemiological trends before, during, and after the COVID-19 pandemic.

Methods: This is an international, multicenter, hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. We will describe patterns in stroke management, stroke hospitalization rate, and stroke severity, subtype (ischemic/hemorrhagic), and outcomes (including in-hospital mortality) in 2020 during COVID-19 pandemic, comparing them with the corresponding data from 2018 and 2019, and subsequently 2021. We will also use an interrupted time series (ITS) analysis to assess the change in stroke hospitalization rates before, during, and after COVID-19, in each participating center.

Conclusion: The proposed study will potentially enable us to better understand the changes in stroke care protocols, differential hospitalization rate, and severity of stroke, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that management of cerebrovascular comorbidity is appropriately prioritized during the global crisis. It will also guide public health guidelines for at-risk populations to reduce risks of complications from such comorbidities.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205703PMC
September 2020

Increased risk of knee osteoarthritis in patients using oral N-acetylcysteine: a nationwide cohort study.

BMC Musculoskelet Disord 2020 Aug 10;21(1):531. Epub 2020 Aug 10.

Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

Background: Knee osteoarthritis (OA) is known to be a progressive degenerative disorder; however, recent evidence suggests that inflammatory mediators contribute to cartilage degradation. Studies have reported that N-acetylcysteine (NAC) had a promising effect on the reduction of the synthesis of proinflammatory and structural mediators by synovial cells. Given the lack of relevant clinical trials, we conducted this study to determine the relationship between NAC use and risk of knee OA.

Methods: We designed a retrospective cohort study from 2000 to 2013. Patients who received oral NAC over 28 days within 1 year after the first prescription were defined as the case group, whereas those without NAC use were considered as candidates of the control group. We adopted 1:4 propensity-score matching by age, sex, index year, and comorbidities to obtain the control group. The primary outcome was a new diagnosis of knee OA during the follow-up period.

Results: Our study sample comprised 12,928 people who used NAC and 51,715 NAC nonusers. NAC users had a significantly higher incidence of osteoarthritis (adjusted hazard ratio: 1.42, P < .001) than did NAC nonusers. Also, in analyses stratified by age group and sex, all subgroups exhibited a significantly higher incidence of knee osteoarthritis (P < .0001) among NAC users than among NAC nonusers. The use of oral NAC was associated with nearly four-fold increased the risk of knee OA in the young age group.

Conclusions: Long-term use of oral NAC is associated with a higher risk of knee OA.
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http://dx.doi.org/10.1186/s12891-020-03562-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418329PMC
August 2020

Intravenous tissue plasminogen activator for acute ischemic stroke in patients with renal dysfunction.

QJM 2020 Aug 8. Epub 2020 Aug 8.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.

Objective: This study used the Taiwan stroke registry data to evaluate the efficacy and safety of intravenous tissue plasminogen activator (tPA) in treating acute ischemic stroke in patients with renal dysfunction.

Design: We identified 3525 ischemic stroke patients and classified them into 2 groups according to the estimated glomerular filtration rate (eGFR) at the emergency department: ≥ 60, and <60 mL/min/1.73m2 or on dialysis and by the propensity score from August 2006 to May 2015. The odds ratio (OR) of poor functional outcome (modified Rankin Scale (mRS) ≥ 2) was calculated for patients with tPA treatment (N = 705), compared to those without tPA treatment (N = 2820), by eGFR levels, at 1, 3 and 6 months after ischemic stroke. We also evaluated the risks of intracerebral hemorrhage, upper gastrointestinal bleeding, mortality, between the two groups by eGFR levels.

Results: Among patients with eGFR levels of less than 60 mL/min/1.73m2, tPA therapy reduced the OR of poor functional outcome to 0.60 (95% CI = 0.42-0.87) at 6 months after ischemic stroke. The tPA therapy was not associated with increased overall risk of upper gastrointestinal bleeding, but with increased risk of intracerebral hemorrhage. The low eGFR was not a significant risk factor of intracerebral hemorrhage among ischemic stroke patients receiving tPA treatment.

Conclusions: tPA for acute ischemic stroke could improve functional outcomes without increasing the risks of upper gastrointestinal bleeding for patients with or without renal dysfunction. The low eGFR was not a significant risk factor for intracerebral hemorrhage among patients receiving tPA treatment.
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http://dx.doi.org/10.1093/qjmed/hcaa237DOI Listing
August 2020

Risk of systemic lupus erythematosus in patients with endometriosis: A nationwide population-based cohort study.

Arch Gynecol Obstet 2020 11 6;302(5):1197-1203. Epub 2020 Aug 6.

Department of Psychiatry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707, Sec. 3, Chung Yang Rd, Hualien, 970, Taiwan.

Purpose: The etiology of endometriosis is mostly under-explored, but abnormalities in the immune system leading to an autoimmune reaction have been suggested. The systemic lupus erythematosus (SLE) is one of the most common autoimmune diseases. The purpose of this study was to investigate the risk of SLE in patients with endometriosis.

Methods: A total of 17,779 patients with endometriosis and 17,779 controls (without endometriosis) matched by age, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000 and 2012. Patients were then followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed SLE were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of SLE incidence rate between patients with endometriosis and unaffected controls.

Results: After adjusting for age, CCI score, and different treatment options, patients with endometriosis were at increased risk of SLE compared to unaffected controls (0.85 versus 0.57 per 1000 person-years, HR 1.86, 95% CI 1.36-2.53). Also, higher baseline CCI scores (CCI score 1-2 and  ≥ 3 vs. 0-HR 2.33-4.98) were at increased risk of SLE. During follow-up, hormonal treatment for endometriosis could reduce the risk of SLE (short-term and long-term vs. non-use HR 0.48-0.62), while surgical treatment appeared to have a limited impact on the risk of SLE.

Conclusion: Patients with endometriosis were at increased risk of SLE, and adequate hormonal treatment could reduce the risk of SLE, providing a reference for developing prevention interventions.
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http://dx.doi.org/10.1007/s00404-020-05726-9DOI Listing
November 2020

Risk of systemic lupus erythematosus in patients with endometriosis: A nationwide population-based cohort study.

Arch Gynecol Obstet 2020 11 6;302(5):1197-1203. Epub 2020 Aug 6.

Department of Psychiatry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707, Sec. 3, Chung Yang Rd, Hualien, 970, Taiwan.

Purpose: The etiology of endometriosis is mostly under-explored, but abnormalities in the immune system leading to an autoimmune reaction have been suggested. The systemic lupus erythematosus (SLE) is one of the most common autoimmune diseases. The purpose of this study was to investigate the risk of SLE in patients with endometriosis.

Methods: A total of 17,779 patients with endometriosis and 17,779 controls (without endometriosis) matched by age, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000 and 2012. Patients were then followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed SLE were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of SLE incidence rate between patients with endometriosis and unaffected controls.

Results: After adjusting for age, CCI score, and different treatment options, patients with endometriosis were at increased risk of SLE compared to unaffected controls (0.85 versus 0.57 per 1000 person-years, HR 1.86, 95% CI 1.36-2.53). Also, higher baseline CCI scores (CCI score 1-2 and  ≥ 3 vs. 0-HR 2.33-4.98) were at increased risk of SLE. During follow-up, hormonal treatment for endometriosis could reduce the risk of SLE (short-term and long-term vs. non-use HR 0.48-0.62), while surgical treatment appeared to have a limited impact on the risk of SLE.

Conclusion: Patients with endometriosis were at increased risk of SLE, and adequate hormonal treatment could reduce the risk of SLE, providing a reference for developing prevention interventions.
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http://dx.doi.org/10.1007/s00404-020-05726-9DOI Listing
November 2020

Risk of Viral Infection in Patients Using Either Angiotensin-converting Enzyme Inhibitors or Angiotensin Receptor Blockers: A Nationwide Population-based Propensity Score Matching Study.

Clin Infect Dis 2020 12;71(10):2695-2701

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan.

Background: We hypothesized that renin-angiotensin system (RAS) blockers have systemic protective effects beyond the respiratory tract and could reduce the risk of viral infections.

Methods: We used the National Health Insurance Research Database and identified 2 study cohorts: the angiotensin receptor blocker (ARB) cohort and angiotensin-converting enzyme inhibitor (ACEI) cohort. Propensity score matching was applied at a 1:1 ratio by all associated variables to select 2 independent control cohorts for the ARB and ACEI cohorts. A Cox proportional hazards model was applied to assess the end outcome of viral infection.

Results: The number of ARB and ACEI users was 20 207 and 18 029, respectively. The median age of ARB users and nonusers was 53.7 and 53.8 years, respectively. The median follow-up duration of ARB users and nonusers was 7.96 and 7.08 years; the median follow-up duration of ACEI users and nonusers was 8.70 and 8.98 years, respectively. The incidence rates of viral infections in ARB users and nonusers were 4.95 and 8.59 per 1000 person-years, respectively, and ARB users had a lower risk of viral infection than nonusers (adjusted hazard ratio [aHR], 0.53 [95% confidence interval {CI}, .48-.58]). The incidence rates of viral infections in ACEI users and nonusers were 6.10 per 1000 person-years and 7.72 per 1000 person-years, respectively, and ACEI users had a lower risk of viral infection than nonusers (aHR, 0.81 [95% CI, .74-.88]).

Conclusions: Hypertensive patients using either ARBs or ACEIs exhibit a lower risk of viral infection than nonusers.
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http://dx.doi.org/10.1093/cid/ciaa734DOI Listing
December 2020

Management of acute ischemic stroke in patients with COVID-19 infection: Insights from an international panel.

Am J Emerg Med 2020 07 11;38(7):1548.e5-1548.e7. Epub 2020 May 11.

Tiantan Comprehensive Stroke Center, Beijing Tiantan Hospital, Capital Medical University Beijing, China.

Objective: To present guidance for clinicians caring for adult patients with acuteischemic stroke with confirmed or suspected COVID-19 infection.

Methods: The summary was prepared after review of systematic literature reviews,reference to previously published stroke guidelines, personal files, and expert opinionby members from 18 countries.

Results: The document includes practice implications for evaluation of stroke patientswith caution for stroke team members to avoid COVID-19 exposure, during clinicalevaluation and conduction of imaging and laboratory procedures with specialconsiderations of intravenous thrombolysis and mechanical thrombectomy in strokepatients with suspected or confirmed COVID-19 infection.

Results: Conclusions-The summary is expected to guide clinicians caring for adult patientswith acute ischemic stroke who are suspected of, or confirmed, with COVID-19infection.
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http://dx.doi.org/10.1016/j.ajem.2020.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211609PMC
July 2020

Continuous positive pressure therapy usage and incident stroke in patients with obstructive sleep apnea: A nationwide population-based cohort study.

Clin Respir J 2020 Sep 12;14(9):822-828. Epub 2020 Jun 12.

Department of Psychiatry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien, Taiwan.

Introduction: Continuous positive airway pressure (CPAP) is the main treatment for obstructive sleep apnea (OSA). To date, the link between CPAP usage and incident stroke has been inconsistent.

Objective: This nationwide population study is designed to examine the effect of CPAP on stroke incidence in OSA patients.

Methods: Using Taiwan's National Health Insurance Research Database (NHIRD), this study collected data from 4275 OSA patients diagnosed between 2000 and 2011 and divided them into two groups according to whether they received CPAP treatment. After matching baseline demographics and comorbidities, both cohorts contained 959 OSA patients and were followed to a newly diagnosed stroke or until the end of 2013. Cox regression analysis was performed to examine the incidence of stroke between patients with OSA receiving CPAP or no CPAP treatment.

Results: CPAP treatment for OSA patients predicted a lower incidence rate (3.41 vs 5.43 per 1000 person-years) and tended to protect against the development of stroke (hazard ratio (HR): 0.68, 95% confidence interval (95% CI): 0.38-1.23) compared to those without CPAP treatment, but the estimate was not statistically significant. Similar results were also observed by dividing stroke into ischemic (2.65 vs 4.30 per 1000 person-years; HR: 0.67, 95% CI: 0.35-1.31) or hemorrhagic origin (0.76 vs 1.12 per 1000 person-years; HR: 0.67, 95% CI: 0.19-2.40).

Conclusions: It is possible that treatment with CPAP might be beneficial for protection against stroke, but this conclusion should be interpreted with caution. Future studies with satisfactory CPAP quality and duration are needed to validate this observation.
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http://dx.doi.org/10.1111/crj.13214DOI Listing
September 2020

Renal Function-Dependent Associations of Statins with Outcomes of Ischemic Stroke.

J Atheroscler Thromb 2021 Feb 15;28(2):146-156. Epub 2020 May 15.

Graduate Institute of Clinical Medical Science, China Medical University and Hospital.

Aim: Chronic kidney disease (CKD) is associated with unfavorable outcomes in patients with ischemic stroke. One major metabolic derangement of CKD is dyslipidemia, which can be managed by statins. This study aimed to investigate whether the association of statins with post-stroke outcomes would be affected by renal function.

Methods: We evaluated the association of statin therapy at discharge with 3-month outcomes according to the estimated glomerular filtration rate (eGFR) of 50,092 patients with acute ischemic stroke from the Taiwan Stroke Registry from August 2006 to May 2016. The outcomes were mortality, functional outcome as modified Rankin Scale (mRS), and recurrent ischemic stroke at 3 months after index stroke.

Results: Statin therapy at discharge was associated with lower risks of mortality (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.34 to 0.50) and unfavorable functional outcomes (mRS 3-5; aHR, 0.80; 95% CI, 0.76 to 0.84) in ischemic stroke patients. After stratification by eGFR, the lower risk of mortality associated with statins was limited to patients with an eGFR above 15 mL/min/1.73 m. Using statins at discharge was correlated with a lower risk of unfavorable functional outcomes in patients with an eGFR of 60-89 mL/min/1.73 m. Statin therapy in patients with an eGFR of 60-89 mL/min/1.73 m may be associated with a higher risk of recurrent ischemic stroke compared with nonusers (aHR, 1.29; 95% CI, 1.07 to 1.57).

Conclusions: In patients with acute ischemic stroke, the associations of statins with mortality and functional outcomes was dependent on eGFR.
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http://dx.doi.org/10.5551/jat.55210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957032PMC
February 2021

Untargeted metabolomics predicts the functional outcome of ischemic stroke.

J Formos Med Assoc 2021 Jan 13;120(1 Pt 1):234-241. Epub 2020 May 13.

Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan. Electronic address:

Background/purpose: Metabolites in blood have been found associated with the occurrence of vascular diseases, but its role in the functional recovery of stroke is unclear. The aim of this study is to investigate whether the untargeted metabolomics at the acute stage of ischemic stroke is able to predict functional recovery.

Methods: One hundred and fifty patients with acute ischemic stroke were recruited and followed up for 3 months. Fasting blood samples within 7 days of stroke were obtained, liquid chromatography and mass spectrometry were applied to identify outcome-associated metabolites. The patients' clinical characteristics and identified metabolites were included for constructing the outcome prediction model using machine learning approaches.

Results: By using multivariate analysis, 220 differentially expressed metabolites (DEMs) were discovered between patients with favorable outcomes (modified Rankin Scale, mRS ≤ 2 at 3 months, n = 77) and unfavorable outcomes (mRS ≥ 3 at 3 months, n = 73). After feature selection, 63 DEMs were chosen for constructing the outcome prediction model. The predictive accuracy was below 0.65 when including patients' clinical characteristics, and could reach 0.80 when including patients' clinical characteristics and 63 selected DEMs. The functional enrichment analysis identified platelet activating factor (PAF) as the strongest outcome-associated metabolite, which involved in proinflammatory mediators release, arachidonic acid metabolism, eosinophil degranulation, and production of reactive oxygen species.

Conclusion: Metabolomics is a potential method to explore the blood biomarkers of acute ischemic stroke. The patients with unfavorable outcomes had a lower PAF level compared to those with favorable outcomes.
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http://dx.doi.org/10.1016/j.jfma.2020.04.026DOI Listing
January 2021

Risk of obstructive sleep apnea in patients with schizophrenia: a nationwide population-based cohort study.

Soc Psychiatry Psychiatr Epidemiol 2020 Dec 13;55(12):1671-1677. Epub 2020 May 13.

Department of Psychiatry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707, Sec. 3, Chung Yang Rd, Hualien, 970, Taiwan.

Purpose: Patients with schizophrenia (SCZ) have a higher prevalence of known risk factors for obstructive sleep apnea (OSA). This study aims to determine if SCZ patients are at increased risk of incident OSA.

Methods: A total of 5092 newly diagnosed SCZ patients and 5092 non-SCZ controls matched by gender, age, and index year were included between 2000 and 2012 and followed to 2013. Participants newly diagnosed with OSA were defined as incidents. Cox regression analysis was used to calculate the hazard ratio (HR) with 95% confidence intervals (CI) of the OSA incidence rate between the two groups studied.

Results: SCZ patients were at increased risk of OSA compared to non-SCZ controls after adjusting for gender, age, comorbidities, and duration of antipsychotic use (2.12 versus 1.01 per 1000 person-years, HR: 1.97, 95% CI: 1.36-2.85). Also, this study confirmed the existence of some known risk factors for OSA, including male gender (HR 1.65, 95% CI 1.14-2.37), obesity (HR 2.62, 95% CI 1.19-5.80), hypertension (HR 1.61, 95% CI 1.06-2.47), hyperlipidemia (HR 1.55, 95% CI 1.04-2.38), diabetes (HR 1.53, 95% CI 1.01-2.38), and antipsychotic use (duration < 1 year (HR 1.57, 95% CI 1.13-2.37), 1-3 years (HR 1.62, 95% CI 1.06-2.82), and 3-5 years (HR 1.45, 95% CI 1.06-2.44)).

Conclusion: This study shows SCZ patients are at increased risk of OSA, and there is still an association with higher risk of OSA after controlling for known risk factors, indicating that it is necessary to develop targeted interventions in SCZ patients to reduce the negative impact of OSA on health.
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http://dx.doi.org/10.1007/s00127-020-01870-4DOI Listing
December 2020

Poststroke Parkinsonism associates with an increased mortality risk in patients.

Ann Transl Med 2020 Apr;8(7):471

Graduate Institute of Biomedical Sciences, China Medical University, Taichung.

Background: To determine whether poststroke Parkinsonism (PSP) increases mortality risk in poststroke patients by using Taiwan National Health Insurance Research Database (NHIRD).

Methods: We analyzed NHIRD data of ≥40-year-old patients diagnosed as having stroke [International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes 430-438] between 2000 and 2013. Poststroke patients were divided into those with subsequent PSP (ICD-9-CM codes 332, 332.0, and 332.1) and without PSP (non-Parkinsonism, PSN) cohorts, all compared with a sex-, age-, comorbidity-, and index date-matched comparison cohort. We calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of all-cause mortality risk in these cohorts after adjustments for age, sex, and comorbidities.

Results: PSP was noted in 11.87% (1,644/13,846) of poststroke patients. In the PSN, PSP, and comparison cohorts, mortality incidence rates were 69.1, 124.9, and 38.8 per 1,000 person-years, respectively. Compared with the comparison cohort, the mortality risks in patients aged 40 to 64, 65 to 74, and ≥75 years were respectively 2.21-, 1.91-, and 1.86-fold higher mortality risks in the PSN cohort and 4.57-, 2.84-, and 2.27-fold higher mortality risks in the PSP cohort. Male sex further increased mortality risk in poststroke patients with PSP.

Conclusions: Long-term all-cause mortality risk is increased by 1.39 times in poststroke patients with PSP than in those without. Our findings depict vital information in incidence and risk of PSP. Those would aid clinicians and the government to improve future poststroke care.
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http://dx.doi.org/10.21037/atm.2020.03.90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210154PMC
April 2020

Risks of Sulpiride-Induced Parkinsonism in Peptic Ulcer and Gastroesophageal Reflux Disease Patients in Taiwan: A Nationwide Population-Based Study.

Front Pharmacol 2020 24;11:433. Epub 2020 Apr 24.

Department of Exercise and Health Promotion, College of Education, Chinese Culture University, Taipei, Taiwan.

Background: Sulpiride is a highly selective dopamine D2 receptor antagonist and is commonly used in psychiatric disorders, Tourette syndrome, peptic ulcer disease (PUD), and gastroesophageal reflux disease (GERD). However, sulpiride has been recognized as a potential cause of drug-induced parkinsonism (DIP) for a long time. In this study, we aimed to focus on analysis of sulpiride-induced parkinsonism (SIP) in PUD and GERD patients based on a nationwide population.

Methods: Data were obtained from the Taiwan's National Health Insurance Research Database. The study enrolled 5,275 PUD or GERD patients, of whom were divided into two groups, based on their exposure (1,055 cases) or non-exposure (4,220 cases) to sulpiride.

Results: During the study period (2000-2012), the incidence rate of parkinsonism was 261.5 and 762.2 per 100,000 person-years in the control and sulpiride-treated groups, respectively. For patients with at least 14 days of prescription for sulpiride, the adjusted hazard ratio (aHR) was 2.89, 95% confidence interval (CI): 2.04-4.11. Patients with age more than 65 years (aHR = 4.99, 95% CI = 2.58-9.65), hypertension (aHR = 2.39, 95% CI = 1.49-3.82), depression (aHR = 2.00, 95% CI = 1.38-2.91), and anxiety (aHR = 1.45, 95% CI = 1.01-2.09) had significant higher risk of developing parkinsonism. An average annual cumulative sulpiride dose > 1,103 mg was accompanied by the greatest risk of SIP; sulpiride use for ≥ 9 days is a cut-off point for predicting future SIP.

Conclusion: At the population level, sulpiride may be frequently prescribed and apparently effective for PUD and GERD. SIP is associated with older age, hypertension, depression or anxiety comorbidities. Physicians should be aware of the neurogenic adverse effects, even when the drug is only used in low-dose or a short duration.
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http://dx.doi.org/10.3389/fphar.2020.00433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193075PMC
April 2020