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author:("Chou, pests")
1.  The safety and immunogenicity of a MF59-adjuvanted H5N1 prepandemic influenza vaccine in healthy adults primed with homologous or heterologous H5N1 vaccines: an observational study 
BMC Infectious Diseases  2014;14(1):587.
Background
World Health Organization (WHO) has recommended individuals with increased risk of contracting influenza A H5N1 infection to be immunized against the virus during the inter-pandemic period. Safety and immunogenicity of H5N1 vaccine among participants primed with homologous or heterologous H5N1 vaccines produced by diverse manufactures have not been reported.
Methods
Healthy individuals aged 20 to 60 years old were recruited and stratified into three groups: participants without priming (control group), participants primed with A/Indonesia/05/2005 vaccine, participants primed with A/Vietnam/1194/2004 vaccine and A/Indonesia/05/2005 vaccine. Enrolled participants received two doses of MF59-adjuvanted A/Vietnam/1194/2004 vaccine (study vaccine). Solicited reactions were recorded by vaccine recipients. Blood samples were obtained for hemagglutination inhibition test.
Results
A total of 131 participants were enrolled. No significant adverse events were recorded. Tenderness, fatigue and general muscle ache were the most common solicited reactions which alleviated within one week of immunization. Three weeks after two doses of the study vaccine, 63%, 68% and 88% were in seroprotective status in the control group, A/Indonesia/05/2005 primed group and A/Vietnam/1194/2004 and A/Indonesia/05/2005 primed group, respectively. Participants primed with A/Vietnam/1194/2004 and A/Indonesia/05/2005 showed high immune response after booster with one dose of the study vaccine.
Conclusion
The study vaccine did not cause severe adverse events. It elicited mostly mild to moderate reactions among participants. Participants primed with A/Vietnam/1194/2004 and A/Indonesia/05/2005 vaccine showed higher immune response than those without priming or primed with A/Indonesia/05/2005 vaccine. The report suggested those with an increased risk of influenza A H5N1 virus exposure may benefit from receiving influenza A H5N1 priming during the inter-pandemic period if the antigenicity of the pandemic influenza strain is similar to that of the priming strain.
doi:10.1186/s12879-014-0587-z
PMCID: PMC4236496  PMID: 25394941
A/Vietnam/1194/2004; A/Indonesia/05/2005; H5N1 vaccine; Priming
2.  Nosocomial Neonatal Legionellosis Associated with Water in Infant Formula, Taiwan 
Emerging Infectious Diseases  2014;20(11):1921-1924.
We report 2 cases of neonatal Legionella infection associated with aspiration of contaminated water used in hospitals to make infant formula. The molecular profiles of Legionella strains isolated from samples from the infants and from water dispensers were indistinguishable. Our report highlights the need to consider nosocomial legionellosis among neonates who have respiratory symptoms.
doi:10.3201/eid2011.140542
PMCID: PMC4214307  PMID: 25340315
water; infant formula; Legionella; neonatal legionellosis; neonate; nosocomial infection; Taiwan; bacteria
3.  The Impact of Prior Tonsillitis and Treatment Modality on the Recurrence of Peritonsillar Abscess: A Nationwide Cohort Study 
PLoS ONE  2014;9(10):e109887.
Background
Studies suggest an increased risk of peritonsillar abscess (PTA) recurrence in patients with prior tonsillitis. However, this association is inconsistent and could be confounded by different treatment modalities. This study aimed to assess the risk of recurrence among PTA patients with different degrees of prior tonsillitis and treatment modalities, and the role of tonsillectomy in current practice.
Methods
All in-patients with peritonsillar abscess between January 2001 and December 2009 were identified in a nationwide, retrospective cohort study. Recurrence was defined as the first occurrence of PTA ≧30 days from the initial PTA. Factors independently associated with recurrence were analyzed using Cox proportional hazard model after adjusting for demographic and clinical data.
Results
There were 28,837 patients, with a 5.15% recurrence rate and 4.74 years of follow-up. The recurrence rates were significantly higher among subjects with more than five prior tonsillitis or 1–4 prior tonsillitis compared to those without prior tonsillitis (adjusted hazard ratio, 2.82 [95% confidence interval, 2.39–3.33] and 1.59 [95% CI: 1.38–1.82]). The adjusted HR in patients treated with needle aspiration was 1.08 compared to those treated with incision & drainage (95% CI: 0.85–1.38). After age stratification, the adjusted HRs of more than five prior tonsillitis increased to 2.92 and 3.50 in patients aged ≦18 and 19–29 years respectively. The adjusted HR ofneedle aspiration only increased in patients ≦18 years old (aHR: 1.98 [95% CI: 0.99–3.97]). The overall tonsillectomy rate was 1.48% during our study period.
Conclusions
The risk of PTA recurrence increases with higher degrees of prior tonsillitis in all age groups and management by needle aspiration only in the pediatric population. Patients younger than 30 years old with PTA and more than five prior tonsillitis have the greatest risk of recurrence.
doi:10.1371/journal.pone.0109887
PMCID: PMC4188615  PMID: 25291179
4.  Dental Prophylaxis Decreases the Risk of Esophageal Cancer in Males; A Nationwide Population-Based Study in Taiwan 
PLoS ONE  2014;9(10):e109444.
Background
Periodontal disease (PD) is one of the most common chronic inflammatory diseases. Esophageal cancer (EC) is also a common cause of death due to cancer among males. Systemic inflammatory processes have been shown to increase the risk of cancer. We conducted a retrospective cohort study to investigate the association between PD and EC.
Methods
A total of 718,409 subjects were recruited from the Taiwan National Health Insurance Research Database (NHIRD) and followed from January 1, 2000 to December 31, 2010. Of these, 519,831 subjects were diagnosed with PD and were grouped according to the most advanced treatment they received: dental prophylaxis, intensive treatment, or no treatment. The IRs of EC were compared among groups.
Results
A total of 682 patients developed EC, resulting in an overall IR of 0.11 case-number per 1000 person-years (‰/y). The dental prophylaxis group had a significantly lower IR of EC (0.06‰/y) than other groups (p<0.001). Multivariable Cox regression analysis further revealed that male subjects [hazard ratio (HR) = 10.04, 95% confidence interval (CI)  = 7.58–13.30], as well as a history of esophageal ulcers (HR = 7.10, 95% CI = 5.03–10.01), alcohol abuse (HR = 5.46, 95% CI = 2.26–13.18), or esophageal reflux (HR = 1.86, 95% CI = 1.02–3.52), were factors associated with a higher risk of EC. And the dental prophylaxis group showed a significantly lower risk for EC (HR = 0.53, 95% CI = 0.44–0.65). Further subgroup analysis showed that the dental prophylaxis group among males had a significant lower risk (HR = 0.54, 95% CI = 0.44–0.66) for EC, while that of the females did not has statistically significant difference.
Conclusion
For this cohort, subjects received dental prophylaxis reduced the risk of EC compared to all PD and no PD groups among males.
doi:10.1371/journal.pone.0109444
PMCID: PMC4184879  PMID: 25279666
5.  Anxiety and Depression Mediate the Health-Related Quality of Life Differently in Patients with Cardiovascular Disease and Stroke–Preliminary Report of the Yilan Study: A Population-Based Community Health Survey 
PLoS ONE  2014;9(9):e107609.
Background
Cardiovascular disease and stroke have emerged as substantial and growing health challenges to populations around the world. Besides for the survival and medical prognosis, how to improve the health-related quality of life (HRQoL) might also become one of the goals of treatment programs. There are multiple factors that influence HRQol, including comorbidity, mental function and lifestyle. However, substantial research and investigation have still not clarified these underlying pathways, which merit further attention. The purpose of this study was to determine how psychological factors affect the link between cardiovascular disease and stroke with HRQoL.
Methods and Result
A total of 1,285 elder subjects at least 65 years of age (47.2% male) were enrolled. The mental function and HRQol of each patient was then measured using the Hospital Anxiety and Depression Scale and Short Form-12. After multiple regression analysis, anxiety, depression, cardiovascular disease, stroke, education level and age were shown to be associated with both mental component score (MCS) and physical component score (PCS). In the mediation analysis using the SPSS macro provided by Preacher and Hayes, cardiovascular disease and stroke affected HRQoL via anxiety and depression, respectively.
Conclusions
These results suggest that cardiovascular disease and stroke have negative impacts on patient MCS and PCS through different underlying pathways. Cardiovascular disease influences the HRQoL both directly and indirectly with the mediation of anxiety, and stroke influences the HRQoL by way of depression. These findings support the proposition that different combinations of both physical and psychological support are necessary to best manage these diseases.
doi:10.1371/journal.pone.0107609
PMCID: PMC4166664  PMID: 25226168
6.  The Incidence of Japanese Encephalitis in Taiwan—A Population-Based Study 
Background
A mass Japanese encephalitis (JE) vaccination program targeting children was launched in Taiwan in 1968, and the number of pediatric JE cases substantially decreased thereafter. The aim of this study was to elucidate the long-term trend of JE incidence, and to investigate the age-specific seroprevalence of JE-neutralizing antibodies.
Methodology/Principal Findings
A total of 2,948 laboratory-confirmed JE cases that occurred between 1966 and 2012 were analyzed using a mandatory notification system managed by the Centers for Disease Control, Taiwan. A total of 6,594 randomly-sampled serum specimens obtained in a nationwide population-based survey in 2002 were analyzed to estimate the seroprevalence of JE-neutralizing antibodies in the general population. The average annual JE incidence rate of the group aged 30 years and older was 0.167 cases per 100,000 people between 2001 and 2012, which was higher than the 0.052 cases per 100,000 people among those aged under 30 years. These seroepidemiological findings indicate that the cohort born between 1963 and 1975, who generally received two or three doses of the vaccine and were administered the last booster dose more than 20 years ago, exhibited the lowest positive rate of JE-neutralizing antibodies (54%). The highest and second highest antibody rates were observed, respectively, in the oldest unvaccinated cohort (86%) and in the youngest cohort born between 1981 and 1986, who received four doses 10–15 years ago (74%).
Conclusion/Significance
Over the past decade, the main age group of the confirmed JE cases in Taiwan shifted from young children to adults over 30 years of age. People who were born between 1963 and 1975 exhibited the lowest seroprevalence of JE-neutralizing antibodies. Thus, the key issue for JE control in Taiwan is to reduce adult JE cases through a cost-effective analysis of various immunization strategies.
Author Summary
JE is one of the major public health problems in Asian and the Western Pacific regions, and most cases occur in children under the age of 14 years. A JE virus infection can cause severe sequelae such as an impairment of language ability, cognitive ability, or movement. Because humans are a dead-end host of the JE virus, the disease cannot be transmitted among people. Vaccination is currently the most effective method for preventing JE, and children in most endemic areas are vaccinated. After decades of mass vaccination, the number of confirmed JE cases has considerably declined in Taiwan, Japan, and South Korea. Most JE cases have occurred in adults rather than children in these countries, thus, the disease must be controlled by reducing the number of adult JE cases. Therefore, a prevention policy for the adult and elderly population should be implemented in the near future.
doi:10.1371/journal.pntd.0003030
PMCID: PMC4109885  PMID: 25058573
7.  Prevalence and factors associated with HIV infection among injection drug users at methadone clinics in Taipei, Taiwan 
BMC Public Health  2014;14:682.
Background
Methadone treatment was introduced in Taiwan in 2006 as a harm-reduction program for injection drug users (IDUs), among whom HIV was endemic. We examined the association of HIV serostatus with demographic characteristics, substance use, and sexual behaviors among IDUs at methadone clinics in Taipei, Taiwan.
Methods
During 2012–2013, IDUs at methadone clinics in Taipei were recruited to complete a risk assessment interview and undergo serologic testing for HIV infection. Correlates of HIV infection were identified by multivariate logistic regression.
Results
Of the 827 eligible participants, 85.9% were male, median age was 45 years, and mean years of injecting was 18.0 (range 1–56). The prevalence of HIV infection was 17.7%. In multivariate analysis, HIV infection was significantly associated with age ≤45 years (adjusted odds ratio [AOR] = 1.62, 95% confidence interval [CI] 1.01–2.62), being divorced (AOR = 1.67, 95% CI 1.06–2.62), deriving the majority of income during the previous 6 months from temporary jobs or other noncriminal sources (AOR = 1.53, 95% CI 1.02–2.30), unstable housing during the previous 6 months (AOR = 1.47, 95% CI 1.003–2.15), higher number of incarcerations (AOR = 1.14, 95% CI 1.03–1.26), and a history of overdose (AOR = 1.51, 95% CI 1.01–2.28).
Conclusions
Taiwanese IDUs at methadone clinics have a relatively high HIV prevalence, which was associated with younger age and history of overdose. It is imperative to educate IDUs’ about HIV transmission, particularly for the younger and overdosed IDUs.
doi:10.1186/1471-2458-14-682
PMCID: PMC4098925  PMID: 24996558
HIV; Taiwan; Injection drug use; Methadone
8.  The Protective Effect of Adenoidectomy on Pediatric Tympanostomy Tube Re-Insertions: A Population-Based Birth Cohort Study 
PLoS ONE  2014;9(7):e101175.
Objectives
Adenoidectomy in conjunction with tympanostomy tube insertion for treating pediatric otitis media with effusion and recurrent acute otitis media has been debated for decades. Practice differed surgeon from surgeon. This study used population-based data to determine the protective effect of adenoidectomy in preventing tympanostomy tube re-insertion and tried to provide more evidence based information for surgeons when they do decision making.
Study Design
Retrospective birth cohort study.
Methods
This study used the National Health Insurance Research Database for the period 2000–2009 in Taiwan. The tube reinsertion rate and time to tube re-insertion among children who received tympanostomy tubes with or without adenoidectomy were compared. Age stratification analysis was also done to explore the effects of age.
Results
Adenoidectomy showed protective effects on preventing tube re-insertion compared to tympanostomy tubes alone in children who needed tubes for the first time (tube re-insertion rate 9% versus 5.1%, p = 0.002 and longer time to re-insertions, p = 0.01), especially those aged over 4 years when they had their first tube surgery. After controlling the effect of age, adenoidectomy reduced the rate of re-insertion by 40% compared to tympanostomy tubes alone (aHR: 0.60; 95% CI: 0.41–0.89). However, the protective effect of conjunction adenoidectomy was not obvious among children with a second tympanostomy tube insertion. Children who needed their first tube surgery at the age 2–4 years were most prone to have tube re-insertions, followed by the age group of 4–6 years.
Conclusions
Adenoidectomy has protective effect in preventing tympanostomy tube re-insertions compared to tympanostomy tubes alone, especially for children older than 4 years old and who needed tubes for the first time. Nonetheless, clinicians should still weigh the pros and cons of the procedure for their pediatric patients.
doi:10.1371/journal.pone.0101175
PMCID: PMC4077749  PMID: 24983459
9.  Increased Risk of Ischemic Stroke after Hyperosmolar Hyperglycemic State: A Population-Based Follow-Up Study 
PLoS ONE  2014;9(4):e94155.
Background
Although much attention has been focused on the association between chronic hyperglycemia and cerebrovascular diseases in type 2 diabetes mellitus (DM) patients, there is no data regarding the risk of ischemic stroke after a hyperosmolar hyperglycemic state (HHS) attack. The objective of this study was to investigate the risk of ischemic stroke in type 2 DM patients after an HHS attack.
Methods
From 2004 to 2008, this retrospective observational study was conducted on a large cohort of Taiwanese using Taiwan’s National Health Insurance Research Database (NHIRD). We identified 19,031 type 2 DM patients who were discharged with a diagnosis of HHS and 521,229 type 2 DM patients without an HHS diagnosis. Using the propensity score generated from logistic regression models, conditional on baseline covariates, we matched 19,031 type 2 DM patients with an HHS diagnosis with the same number from the comparison cohort. The one-year cumulative rate for ischemic stroke was estimated using the Kaplan-Meier method. After adjusting covariates, Cox proportional hazard regression was used to compute the adjusted one-year rate of ischemic stroke.
Results
Of the patients sampled, 1,810 (9.5%) of the type 2 DM patients with HHS and 996 (5.2%) of the comparison cohort developed ischemic stroke during the one-year follow-up period. After adjusting for covariates, the adjusted HR for developing ischemic stroke during the one-year follow-up period was 1.8 (95% C.I., 1.67 to 1.95, P<0.001) for type 2 DM patients with HHS compared with those without HHS.
Conclusion
Although DM is a well-recognized risk factor for atherosclerosis, type 2 DM patients that have suffered a HHS attacks are at an increased risk of developing ischemic stroke compared with those without HHS.
doi:10.1371/journal.pone.0094155
PMCID: PMC3979762  PMID: 24714221
10.  Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes 
Diabetes Care  2013;36(4):894-900.
OBJECTIVE
Hypoglycemia is associated with serious health outcomes for patients treated for diabetes. However, the outcome of outpatients with type 2 diabetes who have experienced hypoglycemia episodes is largely unknown.
RESEARCH DESIGN AND METHODS
The study population, derived from the National Health Insurance Research Database released by the Taiwan National Health Research Institutes during 1998–2009, comprised 77,611 patients with newly diagnosed type 2 diabetes. We designed a prospective study consisting of randomly selected hypoglycemic type 2 diabetic patients and matched type 2 diabetic patients without hypoglycemia. We investigated the relationships of hypoglycemia with total mortality and cardiovascular events, including stroke, coronary heart disease, cardiovascular diseases, and all-cause hospitalization.
RESULTS
There were 1,844 hypoglycemic events (500 inpatients and 1,344 outpatients) among the 77,611 patients. Both mild (outpatient) and severe (inpatient) hypoglycemia cases had a higher percentage of comorbidities, including hypertension, renal diseases, cancer, stroke, and heart disease. In multivariate Cox regression models, including diabetes treatment adjustment, diabetic patients with hypoglycemia had a significantly higher risk of cardiovascular events during clinical treatment periods. After constructing a model adjusted with propensity scores, mild and severe hypoglycemia still demonstrated higher hazard ratios (HRs) for cardiovascular diseases (HR 2.09 [95% CI 1.63–2.67]), all-cause hospitalization (2.51 [2.00–3.16]), and total mortality (2.48 [1.41–4.38]).
CONCLUSIONS
Symptomatic hypoglycemia, whether clinically mild or severe, is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality. More attention may be needed for diabetic patients with hypoglycemic episodes.
doi:10.2337/dc12-0916
PMCID: PMC3609481  PMID: 23223349
11.  The Association of Socioeconomic Status and Access to Low-Volume Service Providers in Breast Cancer 
PLoS ONE  2013;8(12):e81801.
Background
No large-scale study has explored the combined effect of patients’ individual and neighborhood socioeconomic status (SES) on their access to a low-volume provider for breast cancer surgery. The purpose of this study was to explore under a nationwide universal health insurance system whether breast cancer patients from a lower individual and neighborhood SES are disproportionately receiving breast cancer surgery from low-volume providers.
Methods
5,750 patients who underwent breast cancer surgery in 2006 were identified from the Taiwan National Health Insurance Research Database. The Cox proportional hazards model was used to compare the access to a low-volume provider between the different individual and neighborhood SES groups after adjusting for possible confounding and risk factors. Hosmer-Lemeshow goodness-of-fit statistic was used to determine how well the model fit the data.
Results
Univariate analysis data shows that patients in disadvantaged neighborhood were more likely to receive breast cancer surgery at low-volume hospitals; and lower-SES patients were more likely to receive surgery from low-volume surgeons. In multivariate analysis, after adjusting for patient characteristics, the odds ratios of moderate- and low-SES patients in disadvantaged neighborhood receiving surgery at low-volume hospitals was 1.47 (95% confidence interval=1.19-1.81) and 1.31 (95% confidence interval=1.05-1.64) respectively compared with high-SES patients in advantaged neighborhood. Moderate- and low-SES patients from either advantaged or disadvantaged neighborhood had an odds ratios ranging from 1.51 to 1.80 (p<0.001) to receiving surgery from low-volume surgeons. In Hosmer-Lemeshow goodness-of-fit test, p>0.05 that shows the model has a good fit.
Conclusions
In this population-based cross-sectional study, even under a nationwide universal health insurance system, disparities in access to healthcare existed. Breast cancer patients from a lower individual and neighborhood SES are more likely to receive breast cancer surgery from low-volume providers. The authorities and public health policies should keep focusing on these vulnerable groups.
doi:10.1371/journal.pone.0081801
PMCID: PMC3846901  PMID: 24312589
12.  Directly Observed Therapy Reduces Tuberculosis-Specific Mortality: A Population-Based Follow-Up Study in Taipei, Taiwan 
PLoS ONE  2013;8(11):e79644.
Objectives
To determine the effect of directly observed therapy (DOT) on tuberculosis-specific mortality and non-TB-specific mortality and identify prognostic factors associated with mortality among adults with culture-positive pulmonary TB (PTB).
Methods
All adult Taiwanese with PTB in Taipei, Taiwan were included in a retrospective cohort study in 2006–2010. Backward stepwise multinomial logistic regression was used to identify risk factors associated with each mortality outcome.
Results
Mean age of the 3,487 patients was 64.2 years and 70.4% were male. Among 2471 patients on DOT, 4.2% (105) died of TB-specific causes and 15.4% (381) died of non-TB-specific causes. Among 1016 patients on SAT, 4.4% (45) died of TB-specific causes and 11.8% (120) died of non-TB-specific causes. , After adjustment for potential confounders, the odds ratio for TB-specific mortality was 0.45 (95% CI: 0.30–0.69) among patients treated with DOT as compared with those on self-administered treatment. Independent predictors of TB-specific and non-TB-specific mortality included older age (ie, 65–79 and ≥80 years vs. 18–49 years), being unemployed, a positive sputum smear for acid-fast bacilli, and TB notification from a general ward or intensive care unit (reference: outpatient services). Male sex, end-stage renal disease requiring dialysis, malignancy, and pleural effusion on chest radiography were associated with increased risk of non-TB-specific mortality, while presence of lung cavities on chest radiography was associated with lower risk.
Conclusions
DOT reduced TB-specific mortality by 55% among patients with PTB, after controlling for confounders. DOT should be given to all TB patients to further reduce TB-specific mortality.
doi:10.1371/journal.pone.0079644
PMCID: PMC3838349  PMID: 24278152
13.  Impact of Young Age on the Prognosis for Oral Cancer: A Population-Based Study in Taiwan 
PLoS ONE  2013;8(9):e75855.
Background
Oral cancer leads to a considerable use of health care resources. Wide resection of the tumor and reconstruction with a pedicle flap/ free flap is widely used. This study was conducted to investigate if young age at the time of diagnosis of oral cancer requiring this treatment confers a worse prognosis.
Methods
A total of 2339 patients who underwent resections for oral cancer from 2004 to 2005 were identified from The Taiwan National Health Insurance Research Database. Survival analysis, Cox proportional regression model, propensity scores, and sensitivity test were used to evaluate the association between 5-year survival rates and age.
Results
In the Cox proportional regression model, the older age group (>65 years) had the worst survival rate (hazard ratio [HR], 1.80; 95% confidence interval [CI], 1.45-2.22; P<0.001). When analyzed using the propensity scores, the adjusted 5-year survival rates were also poorer for oral cancer patients with older age (>65 years), compared to those with younger age (<45 years) (P<0.001). In sensitivity test, the adjusted hazard ratio remained no statistically elevated in the younger age group (<45 years).
Conclusions
For those oral cancer patients who underwent wide excision and reconstruction, young age did not confer a worse prognosis using a Cox proportional regression model, propensity scores or sensitivity test. Young oral cancer patients may be treated using general guidelines and do not require more aggressive treatment.
doi:10.1371/journal.pone.0075855
PMCID: PMC3784390  PMID: 24086646
14.  Differential Impact of Statin on New-Onset Diabetes in Different Age Groups: A Population-Based Case-Control Study in Women from an Asian Country 
PLoS ONE  2013;8(8):e71817.
Background
Statins reduce cardiovascular risks but increase the risk of new-onset diabetes (NOD). The aim of this study is to determine what effect, if any, statins have on the risk of NOD events in a population-based case-control study. An evaluation of the relationship between age and statin-exposure on NOD risks was further examined in a female Asian population.
Method
In a nationwide case-controlled study, the authors assessed 1065 female NOD patients and 10650 controls with matching ages, genders and physician visit dates. The impact of statin-exposure on NOD was examined through multiple logistic regression models. Subgroup analysis for exploring the risk of NOD and statin-exposure in different age groups was performed.
Results
Statin-exposure was statistically significantly associated with increased new-onset diabetes risks using multivariate analysis. Interaction effect between age and statin-exposure on NOD risk was noted. For atorvastatin, the risk of cDDDs>60 was highest among the 55–64 year-olds (adjusted odds ratio [OR], 8.0; 95% confidence interval [CI], 2.57–24.90). For rosuvastatin, the risk of cDDDs>60 was highest among the 40–54 year-olds (adjusted OR, 14.8; 95% CI, 2.27–96.15). For simvastatin, the risk of cDDDs>60 was highest among the 55–64 year-olds (adjusted OR, 15.8; 95% CI, 5.77–43.26). For pravastatin, the risk of cDDDs>60 was highest among the 55–64 year-olds (adjusted OR, 14.0; 95% CI, 1.56–125.18).
Conclusions
This population-based study found that statin use is associated with an increased risk of NOD in women. The risk of statin-related NOD was more evident for women aged 40–64 years compared to women aged 65 or more, and was cumulative-dose dependent. The use of statins should always be determined by weighing the clinical benefits and potential risks for NOD, and the patients should be continuously monitored for adverse effects.
doi:10.1371/journal.pone.0071817
PMCID: PMC3741277  PMID: 23951249
15.  Disparities in Oral Cancer Survival among Mentally Ill Patients 
PLoS ONE  2013;8(8):e70883.
Background
Many studies have reported excess cancer mortality in patients with mental illness. However, scant studies evaluated the differences in cancer treatment and its impact on survival rates among mentally ill patients. Oral cancer is one of the ten most common cancers in the world. We investigated differences in treatment type and survival rates between oral cancer patients with mental illness and without mental illness.
Methods
Using the National Health Insurance (NHI) database, we compared the type of treatment and survival rates in 16687 oral cancer patients from 2002 to 2006. The utilization rate of surgery for oral cancer was compared between patients with mental illness and without mental illness using logistic regression. The Cox proportional hazards model was used for survival analysis.
Results
Oral cancer patients with mental disorder conferred a grave prognosis, compared with patients without mental illness (hazard ratios [HR] = 1.58; 95% confidence interval [CI] = 1.30–1.93; P<0.001). After adjusting for patients’ characteristics and hospital characteristics, patients with mental illness were less likely to receive surgery with or without adjuvant therapy (odds ratio [OR] = 0.47; 95% CI = 0.34–0.65; P<0.001). In multivariate analysis, oral cancer patients with mental illness carried a 1.58-times risk of death (95% CI = 1.30–1.93; P<0.001).
Conclusions
Oral cancer patients with mental illness were less likely to undergo surgery with or without adjuvant therapy than those without mental illness. Patients with mental illness have a poor prognosis compared to those without mental illness. To reduce disparities in physical health, public health strategies and welfare policies must continue to focus on this vulnerable group.
doi:10.1371/journal.pone.0070883
PMCID: PMC3737269  PMID: 23951029
16.  Epidemiology of Idiopathic Central Serous Chorioretinopathy in Taiwan, 2001–2006: A Population-based Study 
PLoS ONE  2013;8(6):e66858.
Objectives
The epidemiology of idiopathic central serous chorioretinopathy (CSCR) is not well understood in an Asian population. The present study aimed to investigate the incidence and risk factors for corticosteroid-unrelated CSCR using Taiwan’s National Health Insurance Research Database.
Methods and Results
From 2001 to 2006, a total of 786 patients (500 [63.6%] males) who were newly diagnosed with CSCR, aged from 20 to 64 years and had no history of corticosteroid prescription were identified as incident cases of idiopathic CSCR. 3606 age-, gender-, and enrollment time-matched subjects were randomly selected as the control group. The mean annual incidence was 0.21‰ (0.27‰ for males, and 0.15‰ for females; P<0.001), with a male/female ratio of 1.74. The peak incidence was in the 35- to 39-year-old age group (0.30‰), followed by the 40- to 44-year-old age group (0.26‰). Males had a significantly higher mean annual incidence than female only in the middle age groups. Conditional logistic regression was used to estimate the odds ratios (ORs) for potential risk factors of idiopathic CSCR. Only exposure to anti-anxiety drugs (OR, 1.63; 95% confidence interval, 1.09–2.44) was found to be independently associated with idiopathic CSCR among males. No risk factors of idiopathic CSCR were found for females.
Conclusions
This study provides the nationwide, population-based data on the incidence of idiopathic CSCR in adult Asians, and suggests that exposure to anti-anxiety drugs is an independent risk factor for idiopathic CSCR among males.
doi:10.1371/journal.pone.0066858
PMCID: PMC3691239  PMID: 23826160
17.  Association between Provider Volume and Healthcare Expenditures of Patients with Oral Cancer in Taiwan: A Population-Based Study 
PLoS ONE  2013;8(6):e65077.
Background
Oral cancer requires considerable utilization of healthcare services. Wide resection of the tumor and reconstruction with free flap are widely used. Due to high recurrence rate, close follow-up is mandatory. This study was conducted to explore the relationship between the healthcare expenditure of oncological surgery and one-year follow up and provider volume.
Methods
From the National Health Insurance Research Database published by the Taiwanese National Health Research Institute, the authors selected a total of 1300 oral cancer patients who underwent tumor resection and free flap reconstruction in 2008. Hierarchical linear regression analysis was subsequently performed to explore the relationship between provider volume and expenditures of oncological surgery and one-year follow-up period. Emergency department (ED) visits and 30-day readmission rates were also analyzed.
Results
The mean expenditure for oncological surgery was $11080±4645 (all costs are given in U.S. dollars) and $10129±9248 for one-year follow up. For oncological surgery expenditure, oral cancer patients treated by low-volume surgeons had an additional $845 than those in high-volume surgeons in mixed model. For one-year follow-up expenditure, patients in low-volume hospitals had an additional $3439 than those in high-volume hospitals; patient in low-volume surgeons and medium-volume surgeons incurred an additional expenditure of $2065 and $1811 than those in high-volume surgeons. Oral cancer patients treated in low-volume hospitals incurred higher risk of 30-day readmission rate (odds ratio, 6.6; 95% confidence interval, 1.6–27).
Conclusions
After adjusting for physician, hospital, and patient characteristics, low-volume provider performing wide excision with reconstructive surgery in oral cancer patients incurred significantly higher expenditure for oncological surgery and one-year healthcare per patient than did others with higher volumes. Treatment strategies adapted by high-volume providers should be further analyzed.
doi:10.1371/journal.pone.0065077
PMCID: PMC3672134  PMID: 23750234
18.  The Role of Secondary Cytoreductive Surgery in Patients with Recurrent Epithelial Ovarian, Tubal, and Peritoneal Cancers: A Comparative Effectiveness Analysis 
The Oncologist  2012;17(6):847-855.
This study aims to provide supportive evidence for previous reports that secondary cytoreductive surgery may increase overall survival for patients with recurrent epithelial, tubal, and peritoneal cancers by using comparative effectiveness methods to adjust for confounding.
Background.
All published reports concerning secondary cytoreductive surgery for relapsed ovarian cancer have essentially been observational studies. However, the validity of observational studies is usually threatened from confounding by indication. We sought to address this issue by using comparative effectiveness methods to adjust for confounding.
Methods.
Using a prospectively collected administrative health care database in a single institution, we identified 1,124 patients diagnosed with recurrent epithelial, tubal, and peritoneal cancers between 1990 and 2009. Effectiveness of secondary cytoreductive surgery using the conventional Cox proportional hazard model, propensity score, and instrumental variable were compared. Sensitivity analyses for residual confounding were explored using an array approach.
Results.
Secondary cytoreductive surgery prolonged overall survival with a hazard ratio (95% confidence interval) of 0.76 (range 0.66–0.87), using the Cox proportional hazard model. Propensity score methods produced comparable results: 0.75 (range 0.64–0.86) by nearest matching, 0.73 (0.65–0.82) by quintile stratification, 0.71 (0.65–0.77) by weighting, and 0.72 (0.63–0.83) by covariate adjustment. The instrumental variable method also produced a comparable estimate: 0.75 (range 0.65–0.86). Sensitivity analyses revealed that the true treatment effects may approach the null hypothesis if the association between unmeasured confounders and disease outcome is high.
Conclusions.
This comparative effectiveness study provides supportive evidence for previous reports that secondary cytoreductive surgery may increase overall survival for patients with recurrent epithelial, tubal, and peritoneal cancers.
doi:10.1634/theoncologist.2011-0373
PMCID: PMC3380884  PMID: 22591974
Instrumental variable; Ovarian cancer; Propensity score; Secondary cytoreductive surgery
19.  Dental prosthetic treatment needs of inpatients with schizophrenia in Taiwan: a cross-sectional study 
BMC Oral Health  2013;13:8.
Background
The need to obtain information on the dental prosthetic treatment needs (DPTNs) of inpatients with schizophrenia is unrecognized. This study aims to assess the DPTNs of this population and investigate the association between these needs and related factors.
Methods
The results of an oral health survey involving 1,103 schizophrenic adult inpatients in a long-term care institution in Taiwan were used. Chi-square tests and multiple logistic analyses were used to measure the independent effects of the characteristics of each subject on their DPTNs.
Results
Of the subjects, 805 (73.0%) were men and 298 (27.0%) were women. The mean age was 50.8 years. A total of 414 (37.5%) required fixed prosthesis, whereas 700 (63.5%) needed removable prosthesis. Multivariate analyses show that fixed prosthesis is associated with age only after adjusting for other potential independent variables. Older subjects who had a lower educational attainment or a longer length of stay required removable prosthesis.
Conclusions
The findings of this study show that the DPTNs of schizophrenic inpatients are not being met. Therefore, a special approach to the dental prosthetic treatment of these patients should be developed.
doi:10.1186/1472-6831-13-8
PMCID: PMC3554600  PMID: 23331491
Fixed prosthesis; Removable prosthesis; Treatment needs; Schizophrenia
20.  Pneumococcal Pneumonia and the Risk of Stroke: A Population-Based Follow-Up Study 
PLoS ONE  2012;7(12):e51452.
Background
To investigate the risk of developing stroke in patients hospitalized following a diagnosis of pneumococcal pneumonia.
Methods
The study cohorts comprised of patients hospitalized with a principal diagnosis of pneumococcal pneumonia (n  = 745), with a random sampling of control individuals in 2004 (n  = 1490). The Cox proportional hazard model was used to compare the stroke-free survival rate between the cohorts after adjusting for possible confounding and risk factors for a two-year follow up. Instrumental variable analysis (IVA) was used to address potential biases associated with measured and unmeasured confounding variables.
Results
Of the 153 patients with stroke, 80 (10.7%) were from the pneumococcal pneumonia cohort, and 73 (4.9%) were from the control group. The risk of stroke was 3.65 times higher (95% confidence interval, 2.25–5.90; P<0.001) in patients with pneumococcal pneumonia after adjusting for patient characteristics, co-morbidities, geographic region, urbanization level of residence, and socioeconomic status during the first year. IVA showed an additional 14% risk of stroke for pneumococcal pneumonia patients (odds ratio = 1.14; 95% CI, 1.02–1.26, P = 0.032).
Conclusions
Patients with pneumococcal pneumonia carry an increased risk for stroke than the general population. Further studies are warranted for developing better diagnostic and follow-up strategies for patients with increased risk.
doi:10.1371/journal.pone.0051452
PMCID: PMC3520842  PMID: 23251538
21.  The Impact of Influenza Vaccinations on the Adverse Effects and Hospitalization Rate in the Elderly: A National Based Study in an Asian Country 
PLoS ONE  2012;7(11):e50337.
Objectives
To examine the risk of adverse effects of special interest in persons vaccinated against seasonal influenza compared with unvaccinated persons aged 65 and above.
Methods
We retrospectively observed 41,986 vaccinated elderly persons and 50,973 unvaccinated elderly persons in Taiwan from October 1, 2008, through September 30, 2009, using the National Health Insurance database. Neurological and autoimmune disorders and one-year hospitalization rates and in-hospital mortality rates were analyzed according to the vaccination status. Propensity score analysis was used to assess the relationship between adverse outcomes, hospitalization rates, and vaccination status.
Results
45% of the elderly received influenza vaccination. Multiple logistic regression showed that the probability of being vaccinated was related to more patients visiting for URI symptoms (odds ratio (OR), 1.03; 95% CI, 1.02–1.03), men (OR, 1.15; 95% CI, 1.12–1.17), increased age (OR, 1.02; 95% CI, 1.02–1.03), and more comorbidities (OR, 1.2; 95% CI, 1.17–1.23). There were no statistical differences in neurological and autoimmune diseases between the vaccinated and unvaccinated individuals using propensity score analysis, but vaccinated persons had a reduced hospitalization rate of 19% (odds ratio [OR], 0.81; 95% CI, 0.77–0.84) for the first six-months and 13% for one-year of follow-up (OR, 0.87; 95% CI, 0.85–0.9).
Conclusions
Based on data from the one-year follow-ups among 93,049 elderly persons in Taiwan, reassuring results for selected neurological and autoimmune diseases were found among the vaccinated individuals after adjusting other factors. Influenza vaccination decreased the risk for hospitalization. Public health strategies must continue to improve the influenza vaccination rate among the elderly with information based upon tangible evidence.
doi:10.1371/journal.pone.0050337
PMCID: PMC3508921  PMID: 23209714
22.  Infectious Complications in Head and Neck Cancer Patients Treated with Cetuximab: Propensity Score and Instrumental Variable Analysis 
PLoS ONE  2012;7(11):e50163.
Background
To compare the infection rates between cetuximab-treated patients with head and neck cancers (HNC) and untreated patients.
Methodology
A national cohort of 1083 HNC patients identified in 2010 from the Taiwan National Health Insurance Research Database was established. After patients were followed for one year, propensity score analysis and instrumental variable analysis were performed to assess the association between cetuximab therapy and the infection rates.
Results
HNC patients receiving cetuximab (n = 158) were older, had lower SES, and resided more frequently in rural areas as compared to those without cetuximab therapy. 125 patients, 32 (20.3%) in the group using cetuximab and 93 (10.1%) in the group not using it presented infections. The propensity score analysis revealed a 2.3-fold (adjusted odds ratio [OR] = 2.27; 95% CI, 1.46–3.54; P = 0.001) increased risk for infection in HNC patients treated with cetuximab. However, using IVA, the average treatment effect of cetuximab was not statistically associated with increased risk of infection (OR, 0.87; 95% CI, 0.61–1.14).
Conclusions
Cetuximab therapy was not statistically associated with infection rate in HNC patients. However, older HNC patients using cetuximab may incur up to 33% infection rate during one year. Particular attention should be given to older HNC patients treated with cetuximab.
doi:10.1371/journal.pone.0050163
PMCID: PMC3509146  PMID: 23209663
23.  Surveillance on secular trends of incidence and mortality for device–associated infection in the intensive care unit setting at a tertiary medical center in Taiwan, 2000–2008: A retrospective observational study 
BMC Infectious Diseases  2012;12:209.
Background
Device–associated infection (DAI) plays an important part in nosocomial infection. Active surveillance and infection control are needed to disclose the specific situation in each hospital and to cope with this problem effectively. We examined the rates of DAI by antimicrobial-resistant pathogens, and 30–day and in–hospital mortality in the intensive care unit (ICU).
Methods
Prospective surveillance was conducted in a mixed medical and surgical ICU at a major teaching hospital from 2000 through 2008. Trend analysis was performed and logistic regression was used to assess prognostic factors of mortality.
Results
The overall rate of DAIs was 3.03 episodes per 1000 device–days. The most common DAI type was catheter–associated urinary tract infection (3.76 per 1000 urinary catheter–days). There was a decrease in DAI rates in 2005 and rates of ventilator–associated pneumonia (VAP, 3.18 per 1000 ventilator–days) have remained low since then (p < 0.001). The crude rates of 30–day (33.6%) and in–hospital (52.3%) mortality, as well as infection by antibiotic-resistant VAP pathogens also decreased. The most common antimicrobial-resistant pathogens were methicillin–resistant Staphylococcus aureus (94.9%) and imipenem–resistant Acinetobacter baumannii (p < 0.001), which also increased at the most rapid rate. The rate of antimicrobial resistance among Enterobacteriaceae also increased significantly (p < 0.05). After controlling for potentially confounding factors, the DAI was an independent prognostic factor for both 30–day mortality (OR 2.51, 95% confidence interval [CI] 1.99–3.17, p = 0.001) and in–hospital mortality (OR 3.61, 95% CI 2.10–3.25, p < 0.001).
Conclusions
The decrease in the rate of DAI and infection by resistant bacteria on the impact of severe acute respiratory syndrome can be attributed to active infection control and improved adherence after 2003.
doi:10.1186/1471-2334-12-209
PMCID: PMC3458996  PMID: 22963041
Surveillance; Secular trend; Device–associated infection; Intensive care unit; Infection control
24.  Cardiac vagal control and theoretical models of co-occurring depression and anxiety: A cross-sectional psychophysiological study of community elderly 
BMC Psychiatry  2012;12:93.
Background
In order to elucidate the complex relationship between co-occurring depression and anxiety with cardiac autonomic function in the elderly, this study examined the correlation between cardiac vagal control (CVC) and pre-defined, theoretical factors from the Hospital Anxiety and Depression Scale (HADS).
Methods
Three hundred fifty-four randomly selected Chinese male subjects aged ≥65 years and living in the community were enrolled. CVC was measured using a frequency-domain index of heart rate variability.
Results
Confirmatory factor analysis showed that the flat tripartite model of HADS provided a modest advantage in model fit when compared with other theoretical factor solutions. In the flat tripartite model, there was a significant negative association between anhedonic depression and CVC. In contrast, autonomic anxiety showed a significant positive correlation with CVC. In the hierarchical tripartite model, negative affectivity was not directly associated with CVC; instead, it had positive and negative indirect effects on CVC via autonomic anxiety and anhedonic depression, respectively. As scores for negative affectivity increased, these specific indirect effects diminished.
Conclusions
Among competing models of co-occurring depression and anxiety, constructs from tripartite models demonstrate fair conformity with the data but unique and distinct correlations with CVC. Negative affectivity may determine the relationship of anhedonic depression and autonomic anxiety with CVC. Separating affective symptoms under the constructs of the tripartite models helps disentangle complex associations between co-occurring depression and anxiety with CVC.
doi:10.1186/1471-244X-12-93
PMCID: PMC3499166  PMID: 22846457
Cardiac vagal control; Co-occurring depression and anxiety; Heart rate variability; The Hospital Anxiety and Depression Scale; Tripartite model
25.  Multivariate Analyses to Assess the Effects of Surgeon and Hospital Volume on Cancer Survival Rates: A Nationwide Population-Based Study in Taiwan 
PLoS ONE  2012;7(7):e40590.
Background
Positive results between caseloads and outcomes have been validated in several procedures and cancer treatments. However, there is limited information available on the combined effects of surgeon and hospital caseloads. We used nationwide population-based data to explore the association between surgeon and hospital caseloads and survival rates for major cancers.
Methodology
A total of 11677 patients with incident cancer diagnosed in 2002 were identified from the Taiwan National Health Insurance Research Database. Survival analysis, the Cox proportional hazards model, and propensity scores were used to assess the relationship between 5-year survival rates and different caseload combinations.
Results
Based on the Cox proportional hazard model, cancer patients treated by low-volume surgeons in low-volume hospitals had poorer survival rates, and hazard ratios ranged from 1.3 in head and neck cancer to 1.8 in lung cancer after adjusting for patients’ demographic variables, co-morbidities, and treatment modality. When analyzed using the propensity scores, the adjusted 5-year survival rates were poorer for patients treated by low-volume surgeons in low-volume hospitals, compared to those treated by high-volume surgeons in high-volume hospitals (P<0.005).
Conclusions
After adjusting for differences in the case mix, cancer patients treated by low-volume surgeons in low-volume hospitals had poorer 5-year survival rates. Payers may implement quality care improvement in low-volume surgeons.
doi:10.1371/journal.pone.0040590
PMCID: PMC3398946  PMID: 22815771

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