Publications by authors named "Wei-Che Chiu"

42 Publications

Reply to "Does the decreased incidence of new-onset depression in patients with interferon-α therapy indicate the protective effect of interferon-α against depression?"

Brain Behav Immun 2021 Feb 25. Epub 2021 Feb 25.

Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan; Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2021.02.017DOI Listing
February 2021

Selective serotonin reuptake inhibitors use and hepatocellular carcinoma in patients with alcohol use disorder.

Drug Alcohol Depend 2021 Feb 31;219:108495. Epub 2020 Dec 31.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Background: Research has proposed that selective serotonin reuptake inhibitors (SSRIs) were associated with a reduction of the risk of hepatocellular carcinoma (HCC). The objective of this study is to investigate whether SSRIs use is associated with decreased risk of HCC in patients with alcohol use disorder (AUD).

Patients And Methods: We conducted a retrospective population-based cohort study using Taiwan's National Health Insurance Research Database (NHIRD) from 1997 to 2013 and enrolled patients with newly diagnosed AUD. After propensity scores matching at a ratio 1:4, total of 4945 SSRI users and 19,785 non-SSRI users were included in the matched cohort. Patients were followed up from the 365th day after the date of first exposure to SSRIs to occurrence of HCC, the date of death, or the end of 2013. Cox proportional hazard regressions were performed to evaluate hazard ratio (HRs) for HCC in SSRI-exposed patients compared with unexposed patients.

Results: In the main study cohort, SSRI use was associated with significant lower risk of HCC compared to the non-SSRI users after adjusting for age, sex, income, urbanization, alcoholic fatty liver, alcoholic hepatitis and diabetes (adjusted hazard ratio [aHR] = 0.31, 95 % CI = 0.24-0.39). The negative association of SSRI use and HCC was replicated in the matched cohort (aHR = 0.58, 95 % CI = 0.44-0.77). The effect of SSRI use on HCC was dose-related in both cohorts (p for trend < 0.0001).

Conclusions: This study showed that SSRIs use was associated with a reduction risk of HCC among AUD patients in a cumulative dose effect manner.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108495DOI Listing
February 2021

New Use for Old Drugs: The Protective Effect of Risperidone on Colorectal Cancer.

Cancers (Basel) 2020 Jun 12;12(6). Epub 2020 Jun 12.

Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.

The potential of old drugs in novel indications is being greatly valued. We propose a triple-model study involving population-based, cell, and animal studies to investigate the effects of risperidone, a type of second-generation antipsychotic (SGA) drug, on colorectal cancer. We used data from Taiwan's National Health Insurance Research Database between 1997 and 2013 to compare 101,989 patients with colorectal cancer and 101,989 controls. Conditional logistic regression analyses were used to explore the association between SGA exposure and the risk of colorectal cancer. The following bench studies were performed to evaluate the findings of the population-based study. We found that SGAs had been less commonly used in colorectal cancer patients than in controls. The colorectal cancer risk was reduced with an increase in the cumulative defined daily dose (cDDD) of SGAs. The adjusted odds ratio of antipsychotic use for cDDD days was 0.32 (95% CI: 0.25-0.42). Risperidone exhibited the most prominent tumor inhibition effect in a cell screen study. Bench data revealed that risperidone significantly induced apoptosis and elevated intracellular ROS in human SW480 cells and suppressed the proliferation of the xenografted SW480 tumor in nude mice. Conclusion: This triple-model study demonstrates the association between risperidone usage and a lower risk of colorectal cancer.
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http://dx.doi.org/10.3390/cancers12061560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352868PMC
June 2020

Comparison of cognitive function between early- and late-onset late-life depression in remission.

Psychiatry Res 2020 08 21;290:113051. Epub 2020 May 21.

King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.

Differences in cognitive function have been suggested in people with late-life depression between those with early- (EOD) and late-onset (LOD), possibly reflecting different etiologies. The cutoff point for EOD and LOD was the first depressive episode before age 60 or later. However, depressive symptoms at the time of disorder are important confounders. The study aimed to compare cognitive function in older people with EOD and LOD in the euthymic state. A sample of 135 participants aged 60+ with a history of major depressive disorder in remission, received neuropsychological evaluation including tests of memory, attention, processing speed, visuospatial function, language, and executive function. Individual test scores and a derived composite score were investigated as dependent variables against age of onset using multiple linear regressions adjusted for potential confounders, including residual depressive symptoms. We found EOD (N = 67) and LOD (N = 68) groups did not differ significantly in overall composite cognitive scores after adjustment. Of individual test scores, only those for immediate recall were significantly lower in participants with EOD compared to LOD. In conclusion, the study found no associations between cognitive function and age of onset in this sample of people with depressive disorder in remission. Active or residual depressive symptoms might have confounded this relationship in previous research.
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http://dx.doi.org/10.1016/j.psychres.2020.113051DOI Listing
August 2020

Depression-free after Interferon-α exposure indicates less incidence of depressive disorder: A longitudinal study in Taiwan.

Brain Behav Immun 2020 08 17;88:125-131. Epub 2020 May 17.

College of Medicine, China Medical University, Taichung, Taiwan; Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; An-Nan Hospital, China Medical University, Tainan, Taiwan.

Background: IFN-α-induced depression in patients undergoing hepatitis C virus (HCV) treatment provides powerful support for the inflammation hypothesis of depression. Most studies have focused on the occurrence of depressive symptoms, but there has been no study yet in depression-free HCV patients receiving IFN-α. We hypothesized that HCV patients who did not develop depression after IFN-α exposure might have a lower incidence of depressive disorders after the IFN-α treatment.

Methods: We conducted a twelve-year population-based cohort study of chronic HCV patients who received IFN-α therapy. The data were obtained from the Taiwan National Health Insurance Research Database. The study cohort was patients without any depressive disorder nor antidepressant use before and during IFN-α therapy. They were matched randomly by age, sex income and urbanization at a ratio of 1:4 with the control cohort of HCV patients without IFN-α therapy. The follow-up started after the last administration of IFN-α, and the primary outcome was the incidence of depressive disorders after IFN-α therapy.

Results: A total of 20,468 depression-free subjects were identified from records of HCV patients receiving IFN-α therapy. Patients without IFN-α-induced depression were associated with a significantly lower incidence (per 10,000 person-years) of new-onset depressive disorders (126.8, 95% Confidential Interval [CI] of 118.5-135.6) as compared to the control cohort (145.2, 95% CI of 140.0-150.6) (p < 0.001). After adjusting for age, sex, income, urbanization and comorbid diseases, the crude hazard ratio for the incident depressive disorder was 0.87 (95% CI, 0.80-0.87) and the adjusted hazard ratios was 0.79 (95% CI, 0.72-0.87) for IFN-α-induced depression-free subjects as compared to the controls.

Discussion: Our study indicates that IFN-α treated depression-free patients have a lower risk for depressive disorders. This hypothesized mechanism might derive from an IFN-α-induced resilience factor as yet to be defined.

Conclusions: Our study might suggest a new possibility for a new pharmacological strategy against depression.
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http://dx.doi.org/10.1016/j.bbi.2020.05.044DOI Listing
August 2020

Mental Disorders and Interferon Nontreatment in Hepatitis C Virus Infection-a Population Based Cohort Study.

Psychiatry Investig 2020 03 11;17(3):268-274. Epub 2020 Mar 11.

Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan.

Objective: This study investigates the association between mental disorders and interferon nontreatment in patients with chronic hepatitis C virus (HCV) infection in a large national sample.

Methods: Using the National Health Insurance Research Database of Taiwan, we conducted a nationwide population-based study. Each case was matched to five controls by age, sex, urbanization, and income. Conditional logistic regression was used to assess odds of HCV nontreatment in different mental disorders.

Results: From 1999 to 2013, we identified 92,970 subjects with HCV infection and 15,495 HCV cases (16.7%) had received IFN therapy. Other than chronic obstructive pulmonary disease, the medical diseases and mental disorders were significantly different between IFN and non-IFN treated HCV patients. After adjusting for medical diseases, depressive disorder and anxiety disorder was positively associated with receiving IFN therapy. Patients with schizophrenia, bipolar disorders and alcohol use disorders were significantly less likely to receive interferon. Antidepressant exposure (cumulative daily exposure or cumulative daily dose) was associated with lower odds of IFN treatment.

Conclusion: Our nationwide cohort study demonstrated that INF nontreatment rate was lower in certain mental disorders. Antidepressant exposure might lower the chance of receiving IFN treatment. Our results may help to identify and to overcome the obstacles for HCV treatment and further apply to DAAs regimen.
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http://dx.doi.org/10.30773/pi.2019.0254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113179PMC
March 2020

Antipsychotic use is inversely associated with gastric cancer risk: A nationwide population-based nested case-control study.

Cancer Med 2019 08 10;8(9):4484-4496. Epub 2019 Jun 10.

Department of Medicine, Chang Gung University, Taoyuan, Taiwan.

Objective: The association between antipsychotic use and gastric cancer risk remains unclear. Therefore, this study aimed to determine the association between antipsychotic exposure and the incidence of gastric cancer.

Methods: Using a nested case-control design, a total of 34 470 gastric cancer patients and 163 430 nongastric cancer controls were identified from Taiwan's National Health Insurance Research Database between 1 January 1997 and 31 December 2013. We analyzed the data using a conditional logistic regression model to adjust for possible confounding variables.

Results: Antipsychotic use was independently inversely associated with gastric cancer risk after controlling for potential confounding factors including income, urbanization, medications, physical and medical illness, aspirin use, nonsteroidal anti-inflammatory drug use and triple therapy. In addition, dose-dependent trends against gastric cancer risk were also shown with individual antipsychotic compounds including thioridazine, haloperidol, sulpiride, clozapine, olanzapine, quetiapine, amisulpride, and risperidone. A sensitivity analysis showed that second-generation antipsychotics had significant dose-dependent effects in reducing the risk of gastric cancer risk in patients with and without peptic ulcer disease.

Conclusions: Antipsychotic use was inversely associated with gastric cancer risk, and dose-dependent effects against gastric cancer were also seen with several individual antipsychotic compounds.
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http://dx.doi.org/10.1002/cam4.2329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675741PMC
August 2019

A preliminary evaluation of psychological stress amongst workers in Taiwan: a cross-sectional survey.

Int J Ment Health Syst 2019 16;13:34. Epub 2019 May 16.

6Division of Labor Relations, Institute of Labor Occupational Safety and Health, Ministry of Labor, 99, Lane 407, Hengke Rd., Sijhih District, New Taipei, Taiwan, ROC.

Background: Stress and psychological disorders have been assigned increasing significance in the field of occupational health. Based on Japan's psychiatric disability occupational disease recognition regulation, Taiwan's Council of Labor Affairs announced "Evaluation Guidelines for psychiatric diseases induced by work-related stress" in 2009. This evaluation tool was designed to assess the source and intensity of work-related and non-work-related mental stress, and references existing Japanese guidelines. However, empirical data from workers in various sectors in Taiwan are still required to validate the utility of the guidelines.

Methods: This study recruited 2319 workers from the manufacturing, service, and public administration sectors to participate in a survey between 2010  and  2011. The survey included questions regarding participants' demographic characteristics, job type or attributes, a life event stress intensity evaluation Table (35 work-related and 23 non-work-related items on a scale of 1-10). The Chinese version of the Copenhagen Burnout Inventory (C-CBI) and Chinese Health Questionnaire (CHQ-12) were also included to explore associations between work-related/non-work-related stress and health outcomes.

Results: Analyses of survey results showed events relating to employment security (e.g., "company bankruptcy" and "being fired or forced to retire" scores; mean stress intensity scores both 6.18) were the cause of the highest intensity work-related stress. Within different demographic/job type categories, women had higher stress intensity scores for most items than men (greatest difference in "sexual harassment in the workplace" score). Furthermore, executive class workers generally experienced more psychological stress than blue-collar workers (greatest difference in "serious injury or disease due to work" score). Results from regression analysis supported the observation that employees' burnout and work-related stress was more significant than non-work-related stress. Moreover, work-related/non-work-related stress intensity levels both had significant negative predictive effects on mental health.

Conclusions: Regarding policy, this study provides empirical evidence and practical suggestions for establishing a psychological stress intensity database of workers under specific social contexts in a newly industrialized East Asian country. Such a database can be employed to help identify workers with work-related psychological disorders. Additionally, this study also provides a point of reference for enterprises to prioritize agendas when developing employee stress management and support protocols.
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http://dx.doi.org/10.1186/s13033-019-0290-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521344PMC
May 2019

Homocysteine, rather than age of onset, is a better predictor for cognitive function in older adults with bipolar disorder.

Int J Geriatr Psychiatry 2019 10 11;34(10):1473-1480. Epub 2019 Jun 11.

King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.

Objectives: The association between older-age bipolar disorder and cognitive impairments may be mediated by vascular burden. The aim of the study was to examine the difference of cognitive function between older people with late-onset bipolar disorder (LOBD) and early-onset bipolar disorder (EOBD) by considering rigorous vascular risk burden evaluation, comprehensive cognitive tests, and relevant biochemistry data.

Methods: We recruited 95 outpatients aged over 55 with a DSM-IV-TR diagnosis of bipolar I disorder. Fifty had LOBD, defined by age of onset after 40. Cognitive function was evaluated through a battery of tests assessing verbal memory, attention/speed, visuospatial function, verbal fluency, and cognitive flexibility. Vascular risk assessments included individual disorders, 10-year Framingham cardiovascular risk scores, and serum levels of homocysteine, vitamin B12, folate, and triiodothyronine.

Results: No differences were observed between LOBD and EOBD on any cognitive test after adjusting for potential confounders. In addition to age and educational years, multiple linear regression analyses indicated significantly negative associations between serum homocysteine levels and cognitive performances in attention, psychomotor speed, verbal memory, and executive function.

Conclusions: Among older people with bipolar disorder, LOBD is not associated with more cognitive dysfunction in this study. However, higher serum homocysteine levels were significantly associated with worse cognitive performance in this particular group. Clinicians therefore have to pay attention to the cognitive function in older bipolar patients with higher levels of homocysteine.
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http://dx.doi.org/10.1002/gps.5156DOI Listing
October 2019

Effects of antidepressant treatments on health service utilization and medical costs among patients with depression: a nationwide population-based retrospective cohort study in Taiwan.

Int Clin Psychopharmacol 2019 07;34(4):170-178

School of Health Care Administration, College of Management, Taipei Medical University, Taipei.

This study aimed to assess the associations between the use of different types of antidepressants and health service utilization and costs among depressed patients. Data used in this study were retrieved from the Taiwan National Health Insurance Research Database. We identified 447 411 new antidepressant users during the study period (2011-2015) and they were individually followed for a 1-year period. Two-part generalized estimating equation models were conducted. Results demonstrated that there was a substantial decrease in outpatient service utilized by patients undertaking serotonin antagonists and reuptake inhibitors (β = -0.2074), serotonin-norepinephrine reuptake inhibitors (β = -0.0452), tricyclic antidepressants (β = -0.1308), or other antidepressants (β = -0.0637), compared with their counterparts in the selective serotonin reuptake inhibitors group (all P < 0.05). Compared with patients who were treated with selective serotonin reuptake inhibitors, those who were prescribed serotonin antagonists and reuptake inhibitors (β = -0.4934, P < 0.05) or tricyclic antidepressants (β = -0.4194, P < 0.05) had incurred lower costs pertaining to outpatient service, while considerably higher costs were borne by those patients embarked on the treatment of serotonin-norepinephrine reuptake inhibitors (β = 0.3228, P < 0.05) or other antidepressants (β = 0.1118, P < 0.05). We concluded that the initiation of various classes of antidepressants led to significant variations in health service utilization and costs among depressed patients.
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http://dx.doi.org/10.1097/YIC.0000000000000262DOI Listing
July 2019

Effects of antidepressant treatments on health service utilization and medical costs among patients with depression: a nationwide population-based retrospective cohort study in Taiwan.

Int Clin Psychopharmacol 2019 07;34(4):170-178

School of Health Care Administration, College of Management, Taipei Medical University, Taipei.

This study aimed to assess the associations between the use of different types of antidepressants and health service utilization and costs among depressed patients. Data used in this study were retrieved from the Taiwan National Health Insurance Research Database. We identified 447 411 new antidepressant users during the study period (2011-2015) and they were individually followed for a 1-year period. Two-part generalized estimating equation models were conducted. Results demonstrated that there was a substantial decrease in outpatient service utilized by patients undertaking serotonin antagonists and reuptake inhibitors (β = -0.2074), serotonin-norepinephrine reuptake inhibitors (β = -0.0452), tricyclic antidepressants (β = -0.1308), or other antidepressants (β = -0.0637), compared with their counterparts in the selective serotonin reuptake inhibitors group (all P < 0.05). Compared with patients who were treated with selective serotonin reuptake inhibitors, those who were prescribed serotonin antagonists and reuptake inhibitors (β = -0.4934, P < 0.05) or tricyclic antidepressants (β = -0.4194, P < 0.05) had incurred lower costs pertaining to outpatient service, while considerably higher costs were borne by those patients embarked on the treatment of serotonin-norepinephrine reuptake inhibitors (β = 0.3228, P < 0.05) or other antidepressants (β = 0.1118, P < 0.05). We concluded that the initiation of various classes of antidepressants led to significant variations in health service utilization and costs among depressed patients.
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http://dx.doi.org/10.1097/YIC.0000000000000262DOI Listing
July 2019

Device Thrombogenicity Emulation: An In Silico Predictor of In Vitro and In Vivo Ventricular Assist Device Thrombogenicity.

Sci Rep 2019 02 27;9(1):2946. Epub 2019 Feb 27.

Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.

Ventricular assist devices (VAD), a mainstay of therapy for advanced and end-stage heart failure, remain plagued by device thrombogenicity. Combining advanced in silico and in vitro methods, Device Thrombogenicity Emulation (DTE) is a device design approach for enhancing VAD thromboresistance. Here we tested DTE efficacy in experimental VAD designs. DTE incorporates iterative design modifications with advanced CFD to compute the propensity of large populations of platelets to activate by flow-induced stresses (statistically representing the VAD 'Thrombogenic Footprint'). The DTE approach was applied to a VAD (MIN) design with a favorable thromboresistance profile and compared against a design (MAX) that generated an intentionally poor thromboresistance profile. DTE predictions were confirmed by testing physical prototypes in vitro by measuring VAD thrombogenicity using the modified prothrombinase assay. Chronic in vivo studies in VAD implanted calves, revealed MIN calf surviving well with low platelet activation, whereas the MAX animal sustained thromboembolic strokes. DTE predictions were confirmed, correlating with in vitro and in vivo thrombogenicity, supporting utility in guiding device development, potentially reducing the need for animal studies.
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http://dx.doi.org/10.1038/s41598-019-39897-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393420PMC
February 2019

Blood damage in Left Ventricular Assist Devices: Pump thrombosis or system thrombosis?

Int J Artif Organs 2019 Mar 24;42(3):113-124. Epub 2018 Oct 24.

1 Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, Italy.

Introduction:: Despite significant technical advancements in the design and manufacture of Left Ventricular Assist Devices, post-implant thrombotic and thromboembolic complications continue to affect long-term outcomes. Previous efforts, aimed at optimizing pump design as a means of reducing supraphysiologic shear stresses generated within the pump and associated prothrombotic shear-mediated platelet injury, have only partially altered the device hemocompatibility.

Methods:: We examined hemodynamic mechanisms that synergize with hypershear within the pump to contribute to the thrombogenic potential of the overall Left Ventricular Assist Device system.

Results:: Numerical simulations of blood flow in differing regions of the Left Ventricular Assist Device system, that is the diseased native left ventricle, the pump inflow cannula, the impeller, the outflow graft and the anastomosed downstream aorta, reveal that prothrombotic hemodynamic conditions might occur at these specific sites. Furthermore, we show that beyond hypershear, additional hemodynamic abnormalities exist within the pump, which may elicit platelet activation, such as recirculation zones and stagnant platelet trajectories. We also provide evidences that particular Left Ventricular Assist Device implantation configurations and specific post-implant patient management strategies, such as those allowing aortic valve opening, are more hemodynamically favorable and reduce the thrombotic risk.

Conclusion:: We extend the perspective of pump thrombosis secondary to the supraphysiologic shear stress environment of the pump to one of Left Ventricular Assist Device system thrombosis, raising the importance of comprehensive characterization of the different prothrombotic risk factors of the total system as the target to achieve enhanced hemocompatibility and improved clinical outcomes.
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http://dx.doi.org/10.1177/0391398818806162DOI Listing
March 2019

Novel Polymeric Valve for Transcatheter Aortic Valve Replacement Applications: In Vitro Hemodynamic Study.

Ann Biomed Eng 2019 Jan 7;47(1):113-125. Epub 2018 Sep 7.

Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794-8151, USA.

Transcatheter aortic valve replacement (TAVR) is a minimally-invasive approach for treating severe aortic stenosis. All clinically-used TAVR valves to date utilize chemically-fixed xenograft as the leaflet material. Inherent limitation of the tissue (e.g., calcific degeneration) motivates the search for alternative leaflet material. Here we introduce a novel polymeric TAVR valve that was designed to address the limitations of tissue-valves. In this study, we experimentally evaluated the hemodynamic performance of the valve and compared its performance to clinically-used valves: a gold standard surgical tissue valve, and a TAVR valve. Our comparative testing protocols included: (i) baseline hydrodynamics (ISO:5840-3), (ii) complementary patient-specific hydrodynamics in a dedicated system, and (iii) thrombogenicity. The patient-specific testing system facilitated comparing TAVR valves performance under more realistic conditions. Baseline hydrodynamics results at CO 4-7 L/min showed superior effective orifice area (EOA) for the polymer valve, most-notably as compared to the reference TAVR valve. Regurgitation fraction was higher in the polymeric valve, but within the ISO minimum requirements. Thrombogenicity trends followed the EOA results with the polymeric valve being the least thrombogenic, and clinical TAVR being the most. Hemodynamic-wise, the results strongly indicate that our polymeric TAVR valve can outperform tissue valves.
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http://dx.doi.org/10.1007/s10439-018-02119-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475193PMC
January 2019

Antidepressant medication use and nasopharyngeal cancer risk: a nationwide population-based study.

Neuropsychiatr Dis Treat 2018 30;14:1101-1106. Epub 2018 Apr 30.

Department of Psychiatry, Chang Gung University, Taoyuan, Taiwan.

Background: The association between antidepressant exposure and nasopharyngeal cancer (NPC) has not been previously explored. The purpose of this study was to investigate the association between antidepressant prescription, including novel antidepressants, and the risk of NPC in a population-based study.

Materials And Methods: Data for the analysis were derived from National Health Insurance Research Database. We identified 16,957 cases with a diagnosis of NPC and 83,231 matched controls by using a nested case-control design. A conditional logistic regression model was used, with adjustments for potentially confounding variables (eg, comorbid physical diseases, comorbid psychiatric diseases, and other medications).

Results: We report no association between NPC incidence and antidepressant prescription. For all classes of antidepressants, antidepressant exposure, regardless of cumulative dose, had no significant effect on NPC incidence (adjusted odds ratio of cumulative selective serotonin reuptake inhibitor exposure ≥336 defined daily dose was 1.18 [95% CI: 0.90-1.53]; tricyclic antidepressant exposure ≥336 defined daily dose was 1.18 [95% CI: 0.80-1.74]).

Conclusion: There was no association between antidepressant prescription and incident NPC.
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http://dx.doi.org/10.2147/NDT.S161049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933360PMC
April 2018

Prostate cancer and antidepressants: A nationwide population-based nested case-control study.

J Affect Disord 2018 02 13;227:834-839. Epub 2017 Nov 13.

Department of Medicine, Mackay Medical College, Taipei, Taiwan; Section of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan. Electronic address:

Background: We aimed to evaluate the association between antidepressant and prostate cancer by comparing exposures to antidepressants between those with and without prostate cancer.

Methods: A nationwide insurance claims database was used to identify our case subjects. Age- and gender-matched controls were selected at a 1:5 ratio. Conditional logistic regression model was used.

Results: 11,515 patients with prostate cancer were identified and matched with 55,373 controls. No increased associations between prostate cancer and most classes of antidepressants were found. However, a positive association with adjusted odds ratios ranged from 1.20 to 1.35 was noted in different doses of imipramine. Nevertheless, this association became statistically insignificant at higher cumulative doses.

Conclusions: Our results indicate that there is no association between mechanistically dissimilar antidepressants and increased hazard for prostate cancer.
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http://dx.doi.org/10.1016/j.jad.2017.11.039DOI Listing
February 2018

Antidepressant Prescription and Risk of Lung Cancer: A Nationwide Case-Control Study.

Pharmacopsychiatry 2019 Mar 16;52(3):134-141. Epub 2018 Apr 16.

Chang Gung University, Taoyuan, Taiwan.

Introduction: In recent decades, concern about safety of antidepressants has been raised but the risk between antidepressants and lung cancer has not yet been established.

Methods: A case-control study was conducted by using a nationwide database in Taiwan. The case groups were new onset lung cancer diagnosis during 1999-2008 and age- and gender-matched controls were selected among those without any cancer. The cumulative exposure dose before the lung cancer diagnosis was added and risks were calculated according to the levels of defined daily dose and classes of antidepressants.

Results: A total of 39,001 individuals with lung cancer and 189,906 individuals without lung cancer between 1999 and 2008 were included in the analysis. Antidepressants, of any class, were not associated with elevated risks for lung cancer with the exception of bupropion at high exposure levels (odds ratio=4.81, 95% confidence interval=1.39-16.71).

Discussion: Antidepressant prescription was not associated with elevation of lung cancer incidence using a nationally representative sample. The elevated risk for lung cancer with bupropion at high doses may be a bias by indication and warrant longitudinal investigation.
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http://dx.doi.org/10.1055/a-0596-0819DOI Listing
March 2019

SSRIs associated with decreased risk of hepatocellular carcinoma: A population-based case-control study.

Psychooncology 2018 01 8;27(1):187-192. Epub 2017 Aug 8.

Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.

Background: Hepatocellular carcinoma (HCC) is the second leading cancer-related cause of mortality worldwide. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are commonly used worldwide. Available evidence investigating the association between SSRIs use and HCC risk is limited.

Objective: The present study aimed to investigate if the effect of all kinds of SSRIs on HCC was the same or not using population-based study.

Methods: The nationwide population-based study herein using Taiwan's National Health Insurance Research Database included a total of 59 859 cases with HCC and 285 124 matched controls. Conditional logistic regression analyses were adjusted for confounding variables.

Results: All common kinds of SSRIs including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine were associated with lower HCC risk, and the findings were dose-dependent (eg, fluoxetine: 1-28 DDD [defined daily dose]: adjusted odds ratio [aOR]: 0.81, 95% confidence interval [CI], 0.73-0.89; 29-365 DDD: aOR: 0.71, 95% CI, 0.64-0.79; and ≥366 DDD: aOR: 0.55, 95% CI, 0.45-0.67) (P for trend < .001).

Conclusions: All kinds of SSRIs were associated with decreased risk of HCC.
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http://dx.doi.org/10.1002/pon.4493DOI Listing
January 2018

The association between subjective memory complaint and objective cognitive function in older people with previous major depression.

PLoS One 2017 7;12(3):e0173027. Epub 2017 Mar 7.

King's College London (Institute of Psychiatry), Department of Psychological Medicine, London, United Kindom.

The goal of this study is to investigate associations between subjective memory complaint and objective cognitive performance in older people with previous major depression-a high-risk sample for cognitive impairment and later dementia. A cross-sectional study was carried out in people aged 60 or over with previous major depression but not fulfilling current major depression criteria according to DSM-IV-TR. People with dementia or Mini-Mental State Examination score less than 17 were excluded. Subjective memory complaint was defined on the basis of a score ≧4 on the subscale of Geriatric Mental State schedule, a maximum score of 8. Older people aged equal or over 60 without any psychiatric diagnosis were enrolled as healthy controls. Cognitive function was evaluated using a series of cognitive tests assessing verbal memory, attention/speed, visuospatial function, verbal fluency, and cognitive flexibility in all participants. One hundred and thirteen older people with previous major depression and forty-six healthy controls were enrolled. Subjective memory complaint was present in more than half of the participants with depression history (55.8%). Among those with major depression history, subjective memory complaint was associated with lower total immediate recall and delayed verbal recall scores after adjustment. The associations between subjective memory complaint and worse memory performance were stronger in participants with lower depressive symptoms (Hamilton Depression Rating Scale score<7). The results suggest subjective memory complaint may be a valid appraisal of memory performance in older people with previous major depression and consideration should be given to more proactive assessment and follow-up in these clinical samples.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173027PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340362PMC
September 2017

Effects of selective serotonin reuptake inhibitors on glaucoma: A nationwide population-based study.

PLoS One 2017 3;12(3):e0173005. Epub 2017 Mar 3.

Department of Neurology, Kaoshiung Medical University Hospital, Kaoshiung, Taiwan.

Background: Selective serotonin reuptake inhibitors (SSRIs) are one of the most commonly prescribed classes of antidepressants. Glaucoma is the second leading cause of blindness globally and iatrogenic glaucoma has been implicated across disparate medication classes. Available studies that have sought to determine the association between SSRI exposure and glaucoma have provided mixed results. The aim of the study herein was to investigate whether an association exists between SSRI exposure and glaucoma incidence.

Methods: Glaucoma cases were identified from Taiwan's National Health Insurance Research Database with a new primary diagnosis of glaucoma between 1997 and 2009. The date wherein the cases were diagnosed with glaucoma was operationalized as the index date. The control group was comprised of individuals within the database who were not diagnosed with glaucoma. 15,865 glaucoma cases were compared to 77,014 sex-, age-, residence- and insurance premium-matched controls on measures of prescribed duration and dosage of SSRIs up to 365 days before index date to proxy SSRIs exposure.

Results: Individuals receiving SSRIs were at greater risk of glaucoma incidence (OR = 1.39; 95% CI = 1.29-1.50); the foregoing increased likelihood was reduced after adjusting for confounding variables (aOR = 1.09; 95% CI = 1.00,1.18). SSRI treatment of longer duration (i.e. >365 days) and higher doses (≥1 defined daily dose) were associated with greater risk of glaucoma incidence (aOR = 1.36; 95% CI = 1.08-1.71). Subgroup analysis showed that the effect of SSRIs on glaucoma was limited to individuals younger than 65 years of age (aOR = 1.37; 95% CI = 1.25-1.50), without diabetes (aOR = 1.39; 95% CI = 1.27-1.52), without hypertension (aOR = 1.46; 95% CI = 1.31-1.63) or hypercholesterolemia (aOR = 1.35; 95% CI = 1.23-1.48).

Conclusion: Treatment with SSRIs was associated with greater risk of having a diagnosis of glaucoma, particularly in individuals with longer duration and/or higher average dose of SSRI. Our findings suggest that individuals receiving SSRIs treatment for extended periods of time and/or at relatively higher therapeutic doses should be monitored for symptoms associated with glaucoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173005PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336262PMC
August 2017

Ventricular Assist Device Implantation Configurations Impact Overall Mechanical Circulatory Support System Thrombogenic Potential.

ASAIO J 2017 May/Jun;63(3):285-292

From the *Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York; †Department of Surgery, Stony Brook University, Stony Brook, New York; and ‡Departments of Medicine and Biomedical Engineering, Sarver Heart Center, University of Arizona, Tucson, Arizona.

Ventricular assist devices (VADs) became in recent years the standard of care therapy for advanced heart failure with hemodynamic compromise. With the steadily growing population of device recipients, various postimplant complications have been reported, mostly associated with the hypershear generated by VADs that enhance their thrombogenicity by activating platelets. Although VAD design optimization can significantly improve its thromboresistance, the implanted VAD need to be evaluated as part of a system. Several clinical studies indicated that variability in implantation configurations may contribute to the overall system thrombogenicity. Numerical simulations were conducted in the HeartAssist 5 (HA5) and HeartMate II (HMII) VADs in the following implantation configurations: 1) inflow cannula angles: 115° and 140° (HA5); 2) three VAD circumferential orientations: 0°, 30°, and 60° (HA5 and HMII); and 3) 60° and 90° outflow graft anastomotic angles with respect to the ascending aorta (HA5). The stress accumulation of the platelets was calculated along flow trajectories and collapsed into a probability density function, representing the "thrombogenic footprint" of each configuration-a proxy to its thrombogenic potential (TP). The 140° HA5 cannula generated lower TP independent of the circumferential orientation of the VAD. Sixty-degree orientation generated the lowest TP for the HA5 versus 0° for the HMII. An anastomotic angle of 60° resulted in lower TP for HA5. These results demonstrate that optimizing the implantation configuration reduces the overall system TP. Thromboresistance can be enhanced by combining VAD design optimization with the surgical implantation configurations for achieving better clinical outcomes of implanted VADs.
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http://dx.doi.org/10.1097/MAT.0000000000000488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411323PMC
January 2018

Hepatocellular carcinoma and antidepressants: a nationwide population-based study.

Oncotarget 2017 May;8(18):30464-30470

Department of Psychiatry, Chang Gung University, Taoyuan, Taiwan.

Hepatocellular carcinoma (HCC) is highly prevalent in Asia. Antidepressants have been associated with increase in hepatocellular carcinoma. This is the first Asian population-based study to evaluate the association between antidepressant use and risk of HCC. Based on Taiwan's National Health Insurance Research Database, we conducted a nationwide population-based study. A total of 49,998 cases with HCC were identified and paired with 244,236 randomly selected controls. The data was analyzed via the conditional logistic regression model adjusting for several confounding factors. Use of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) was associated with lower risk for HCC. No apparent association was found between use of other classes of antidepressants and HCC, including monoamine oxidase inhibitors (MAOIs), serotonin norepinephrine reuptake inhibitors (SNRIs), trazodone, mirtazapine and bupropion. The findings of a protective effect of TCAs and SSRIs for HCC should be interpreted with caution and warrants further research.
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http://dx.doi.org/10.18632/oncotarget.12826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444756PMC
May 2017

Antidepressants and colorectal cancer: A population-based nested case-control study.

J Affect Disord 2017 Jan 1;207:353-358. Epub 2016 Oct 1.

School of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan. Electronic address:

Background: Experimental evidence indicates that serotonin is associated with both proliferative and pro-carcinogenic effects on colorectal tumors. The present study aims to investigate the associations between antidepressant use and colorectal cancer in an epidemiological sample.

Methods: We conducted a population-based case-control study utilizing Taiwan's National Health Insurance Research Database (NHIRD). We identified 49,342 cases with colorectal cancer and 240,985 controls between 1997 and 2008. We conducted conditional logistic regression analyses to assess the association between antidepressant use and colorectal cancer risk. Sensitivity analyses were conducted to assess whether genotoxic antidepressants (i.e. antidepressants which may exert procarcinogenic effects) would increase risk for colorectal cancer.

Results: Selective serotonin reuptake inhibitors (adjusted OR=1.00, 95% CI=0.94-1.06), tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and serotonin antagonist and reuptake inhibitors were not associated with increased incidence of colorectal cancer. Monoamine oxidase inhibitors were, however, associated with an increased incidence of colorectal cancer (adjusted OR=1.22, 95% CI=1.06-1.41). Higher cumulative dose of mirtazapine was associated with a decreased incidence of colorectal cancer (adjusted OR=0.39, 95% CI=0.17-0.90). A small sample size of individuals who received mirtazapine, however, precludes definitive conclusions regarding protective effects with mirtazapine.

Limitations: We could not discern the effects of obesity and other risk factors for colorectal cancer from the NHIRD.

Conclusions: Contemporary first-line antidepressants (i.e. SSRI, SNRI), as well as older agents (i.e. TCA), are not associated with increased incidence of colorectal cancer.
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http://dx.doi.org/10.1016/j.jad.2016.09.057DOI Listing
January 2017

Endometrial cancer and antidepressants: A nationwide population-based study.

Medicine (Baltimore) 2016 Jul;95(29):e4178

Department of Child Psychiatry, Linkou Chang Gung Memorial Hospital Department of Psychiatry, Chang Gung University, Taoyuan Department of Psychiatry, Cathay General Hospital, Taipei Department of Speech, Language Pathology and Audiology, Chung Shan Medical University, Taichung, Taiwan Mood Disorders Psychopharmacology Unit, University Health Network Department of Psychiatry, University of Toronto, Toronto, ON, Canada Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.

To our knowledge, the association between antidepressant exposure and endometrial cancer has not been previously explored. Herein, we aim to investigate the association between antidepressant prescription, including novel antidepressants, and the risk for endometrial cancer in a population-based study.Data for the analysis were derived from National Health Insurance Research Database. We identified 8392 cases with a diagnosis of endometrial cancer and 82,432 matched controls. A conditional logistic regression model was used, with adjusting for potentially confounding variables (e.g., comorbid psychiatric diseases, comorbid physical diseases, and other medications). Risk for endometrial cancer in the population-based study sample was categorized by, and assessed as a function of, antidepressant prescription and cumulative dosage.We report no association between endometrial cancer incidence and antidepressant prescription, including those prescribed either selective serotonin reuptake inhibitors (adjusted odds ratio [OR] = 0.98; 95% confidence interval [CI], 0.84-1.15) or serotonin norepinephrine reuptake inhibitors (adjusted OR = 1.14; 95% CI, 0.76-1.71). We also did not identify an association between higher cumulative doses of antidepressant prescription and endometrial cancer.There was no association between antidepressant prescription and endometrial cancer.
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http://dx.doi.org/10.1097/MD.0000000000004178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5265757PMC
July 2016

Methionine synthase 2756AA polymorphism is associated with the risk of cognitive impairment in patients with late-life depression.

Asia Pac Psychiatry 2017 Mar 25;9(1). Epub 2016 Apr 25.

Department of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan.

Backgrounds: Apolipoprotein E epsilon-4 (APOE ε4) allele, methylenetetrahydrofolate reductase (MTHFR C677T), and methionine synthase (MTR A2756G) were tested their associations with cognitive impairment in people with late-life depression (LLD).

Methods: People with LLD were assessed by mini-mental state examination and were examined the distribution of APOE ε4 allele, MTHFR, and MTR polymorphisms.

Results: Odds ratio of MTR 2756 AA to MTR 2756 AG and GG genotypes for the risk of cognitive impairment was 5.80 (95% confidence interval = 1.18-28.50; P = 0.03).

Conclusion: People with LLD carrying MTR2756 AA genotype have higher risk of cognitive impairment than those carrying G allele.
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http://dx.doi.org/10.1111/appy.12242DOI Listing
March 2017

Change in employment status in bipolar disorder: a longitudinal study using national claims data.

J Clin Psychiatry 2016 04;77(4):e429-35

School of Health Care Administration, Taipei Medical University, Taiwan.

Objective: To assess change in employment status in patients with bipolar disorder in comparison with non-mentally ill controls from 1 year before bipolar incidence to 10 years after. Sociodemographic factors of change in employment status were also examined for patients with bipolar disorder.

Method: A cohort of 502 patients with ICD-9-CM bipolar disorder was identified using claims data from the National Health Insurance Research Database of Taiwan between 1998 and 2001 and compared to non-mentally ill controls through December 31, 2008. The primary outcome measure was the time from bipolar incidence to the time of change in employment status, ie, from earning income to not earning income.

Results: The probability of changing to a non-income earner was significantly higher (P < .0001) in patients with bipolar disorder than in controls over time, even before the incidence of bipolar disorder (27% vs 14% for patients with bipolar disorder vs controls, respectively). Risks of occupational deterioration in patients with bipolar disorder were greater in the year before incidence and in the following year, with gradually decreasing risks over the subsequent 2 years, and comparable to controls from the third year onward. The adjusted hazard ratio of changing to a non-income earner was 2.06 (95% CI, 1.82-2.33) in patients with bipolar disorder. Male sex, ages 18 to 25 years, lower payroll bracket (< NT$50,001 [US $1,489]), and living in an urban area and insured area in the Northern region were associated with the risk of changing to a non-income earner in patients with bipolar disorder.

Conclusions: Patients with bipolar disorder had poorer employment outcomes than the controls, with greater risks of occupational deterioration before and after the bipolar episodes. Employment status should be incorporated as a measure of functioning and of treatment and intervention effectiveness in clinical practices and research.
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http://dx.doi.org/10.4088/JCP.14m09576DOI Listing
April 2016

Aspirin has limited ability to modulate shear-mediated platelet activation associated with elevated shear stress of ventricular assist devices.

Thromb Res 2016 Apr 1;140:110-117. Epub 2016 Feb 1.

Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA; Department of Medicine, Sarver Heart Center, University of Arizona, Tucson, AZ, USA; Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.

Continuous flow ventricular assist devices (cfVADs) while effective in advanced heart failure, remain plagued by thrombosis related to abnormal flows and elevated shear stress. To limit cfVAD thrombosis, patients utilize complex anti-thrombotic regimens built upon a foundation of aspirin (ASA). While much data exists on ASA as a modulator of biochemically-mediated platelet activation, limited data exists as to the efficacy of ASA as a means of limiting shear-mediated platelet activation, particularly under elevated shear stress common within cfVADs. We investigated the ability of ASA (20, 25 and 125 μM) to limit shear-mediated platelet activation under conditions of: 1) constant shear stress (30 dynes/cm(2) and 70 dynes/cm(2)); 2) dynamic shear stress, and 3) initial high shear exposure (70 dynes/cm(2)) followed by low shear exposure - i.e. a platelet sensitization protocol, utilizing a hemodynamic shearing device providing uniform shear stress in vitro. The efficacy of ASA to limit platelet activation mediated via passage through a clinical cfVAD system (DeBakey Micromed) in vitro was also studied. ASA reduced platelet activation only under conditions of low shear stress (38% reduction compared to control, n=10, p<0.004), with minimal protection at higher shear stress and under dynamic conditions (n=10, p>0.5) with no limitation of platelet sensitization. ASA had limited ability (25.6% reduction in platelet activation rate) to modulate shear-mediated platelet activation induced via cfVAD passage. These findings, while performed under "deconstructed" non-clinical conditions by utilizing purified platelets alone in vitro, provide a potential contributory mechanistic explanation for the persistent thrombosis rates experienced clinically in cfVAD patients despite ASA therapy. An opportunity exists to develop enhanced pharmacologic strategies to limit shear-mediated platelet activation at elevated shear levels associated with mechanical circulatory support devices.
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http://dx.doi.org/10.1016/j.thromres.2016.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924614PMC
April 2016

Antidepressants and Gastric Cancer: A Nationwide Population-Based Nested Case-Control Study.

PLoS One 2015 25;10(11):e0143668. Epub 2015 Nov 25.

Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.

Background: To our knowledge, no epidemiological study has reported on whether an association between antidepressant exposure and gastric cancer exists. Herein, we aim to investigate the possible association between antidepressant exposure and gastric cancer incidence.

Methods: Using a nested case-control design, we identified 26289 cases with gastric cancer and 127984 controls from Taiwan's National Health Insurance Research Database (NHIRD). The data were analyzed using a conditional logistic regression model adjusting for possible confounding variables.

Results: We found antidepressant use did not increase the risk of gastric cancer. The lack of an association between antidepressant prescription and elevated gastric cancer incidence was apparent for across selective serotonin-reuptake inhibitors (SSRIs), tricyclic agents (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), reversible inhibitors of monoamine oxidase A (RIMA), trazodone, mirtazapine and bupropion. There were slightly decreased gastric cancer risks of SSRIs use (≧28 DDD group, adjusted OR = 0.87; 95% CI = 0.78-0.96). Sensitive analysis showed SSRIs, TCAs, and SNRIs did not increase gastric cancer risks significantly even in the group with peptic ulcer history.

Conclusions: An association between antidepressant exposure and gastric cancer was not apparent in this analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143668PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659600PMC
June 2016

Microfluidic emulation of mechanical circulatory support device shear-mediated platelet activation.

Biomed Microdevices 2015 Dec;17(6):117

Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, 20133, Italy.

Thrombosis of ventricular assist devices (VADs) compromises their performance, with associated risks of systemic embolization, stroke, pump stop and possible death. Anti-thrombotic (AT) drugs, utilized to limit thrombosis, are largely dosed empirically, with limited testing of their efficacy. Further, such testing, if performed, typically examines efficacy under static conditions, which is not reflective of actual shear-mediated flow. Here we adopted our previously developed Device Thrombogenicity Emulation methodology to design microfluidic platforms able to emulate representative shear stress profiles of mechanical circulatory support (MCS) devices. Our long-term goal is to utilize these systems for point-of-care (POC) personalized testing of AT efficacy under specific, individual shear profiles. First, we designed different types of microfluidic channels able to replicate sample shear stress patterns observed in MCS devices. Second, we explored the flexibility of microfluidic technology in generating dynamic shear stress profiles by modulating the geometrical features of the channels. Finally, we designed microfluidic channel systems able to emulate the shear stress profiles of two commercial VADs. From CFD analyses, the VAD-emulating microfluidic systems were able to replicate the main characteristics of the shear stress waveforms of the macroscale VADs (i.e., shear stress peaks and duration). Our results establish the basis for development of a lab-on-chip POC system able to perform device-specific and patient-specific platelet activation state assays.
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http://dx.doi.org/10.1007/s10544-015-0015-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855287PMC
December 2015

Response to the Letter by Sacerdote A., et al.

J Clin Endocrinol Metab 2015 Nov;100(11):L114-5

Institute of Occupational Medicine and Industrial Hygiene (W.-C.C., Y.-H.T., P.-C.C.) and Department of Public Health (P.-C.C.), National Taiwan University College of Public Health, Taipei 10055, Taiwan; Department of Psychiatry (W.-C.C.), Cathay General Hospital, Taipei 10630, Taiwan; School of Medicine (W.-C.C.), Fu Jen Catholic University, Taipei 24205, Taiwan; Division of Endocrinology and Metabolism (Y.-H.T.), Department of Internal Medicine, and Division of Geriatrics (Y.-H.T.), Puli Branch, Nantou County 545, Taichung Veterans General Hospital, Taichung 40705, Taiwan; and Department of Environmental and Occupational Medicine (P.-C.C.), National Taiwan University and Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.

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http://dx.doi.org/10.1210/jc.2015-3629DOI Listing
November 2015