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Influenza vaccine effectively reduced risks for in-hospital death or hospitalization, regardless of statin use., Debates on whether statin use reduces the effectiveness of influenza vaccines against critical illness and death among persons >65 years of age continue. We conducted a study of 9,427,392 persons >65 years of age who did and did not receive influenza vaccinations during 12 consecutive influenza seasons, 2000–01 through 2011–12. Using data from Taiwan’s National Health Insurance Research Database, we performed propensity score-matching to compare vaccinated persons with unvaccinated controls. After propensity score-matching, the vaccinated group had lower risks for in-hospital death from influenza and pneumonia and for hospitalization for pneumonia and influenza, circulatory conditions, and critical illnesses compared with the unvaccinated group. We stratified the 2 groups by statin use and analyzed data by interaction analysis and saw no statistically significant difference. We found that influenza vaccine effectively reduced risks for hospitalization and death in persons >65 years of age, regardless of statin use.

This study was conducted to determine the protective effect of influenza vaccine against primary major adverse cardiovascular events (MACEs) in elderly patients, especially those with influenza-like illness (ILI).This retrospective, population-based case-control study of an elderly population (age≥65 years) was conducted using Taiwan's National Health Insurance Research Database (2000-2013). One control was selected for each MACE case (n=80,363 each), matched according to age, year of study entry, and predisposing factors for MACEs. ILI and MACEs (myocardial infarction [MI] and ischemic stroke) were defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Odds ratios (ORs) were calculated for the association between MACEs and vaccination.Influenza vaccination received in the previous year was associated with reduced risks of primary MACEs overall (adjusted OR [aOR] 0.80, 95% CI 0.78-0.82, P.001), MI (aOR 0.80, 95% CI 0.76-0.84, P.001), and ischemic stroke (aOR 0.80, 95% CI 0.77-0.82, P.001). ILI diagnosed in the previous year was associated with increased risks of MACEs (aOR 1.24, 95% CI 1.18-1.29, P.001), MI (aOR 1.46, 95% CI 1.34-1.59, P.001), and ischemic stroke (aOR 1.16, 95% CI 1.10-1.22, P.001). Vaccination attenuated the heightened risks associated with ILI (MACEs: aOR 0.99, 95% CI 0.92-1.07, P=.834; MI: aOR 1.05, 95% CI 0.92-1.21, P=.440; ischemic stroke: aOR 0.96, 95% CI 0.89-1.05, P=.398).Results of this study suggest that influenza vaccination is associated with reduced primary MACE risks in the elderly population, including those with ILI.

Background Although theophylline has been shown to have anti-inflammatory effects, the therapeutic use of theophylline before sepsis is unknown. The aim of our study was to determine the effect of theophylline on COPD patients presenting with sepsis. Methods This nationwide, population-based, propensity score-matched analysis used data from the linked administrative databases of Taiwan's National Health Insurance program. Patients with COPD who were hospitalized for sepsis between 2000 and 2011 were divided into theophylline users and non-users. The primary outcome was 30-day mortality. The secondary outcome was in-hospital death, intensive care unit admission, and need for mechanical ventilation. Cox proportional hazard model and conditional logistic regression were used to calculate the risk between groups. Results A propensity score-matched cohort of 51,801 theophylline users and 51,801 non-users was included. Compared with non-users, the 30-day (HR 0.931, 95% CI 0.910–0.953), 180-day (HR 0.930, 95% CI 0.914–0.946), 365-day (HR 0.944, 95% CI 0.929–0.960) and overall mortality (HR 0.965, 95% CI 0.952–0.979) were all significantly lower in theophylline users. Additionally, the theophylline users also had lower risk of in-hospital death (OR 0.895, 95% CI 0.873–0.918) and need for mechanical ventilation (OR 0.972, 95% CI 0.949–0.997). Conclusions Theophylline use is associated with a lower risk of sepsis-related mortality in COPD patients. Pre-hospital theophylline use may be protective to COPD patients with sepsis.

Background Although recent clinical trials raised concerns about the risk for heart failure (HF) in dipeptidyl peptidase-4 (DPP-4) inhibitor use, data on the cardiovascular risks in the patients with pre-existing HF are still lacking. Methods We used Taiwan9s National Health Insurance Research Database to identify 196 986 patients diagnosed with type 2 diabetes mellitus (T2DM) who had previous history of HF between 2009 and 2013. This population included 30 204 DPP-4 inhibitor users and 166 782 propensity score-matched DPP-4 inhibitor non-users. The outcomes of interest were all-cause mortality, combination of myocardial infarction (MI) and ischaemic stroke, and hospitalisation for HF. Results The incidence in DPP-4 users compared with non-users was 67.02 vs 102.85 per 1000 person-years for all-cause mortality, 37.89 vs 47.54 per 1000 person-years for the combination of MI and ischaemic stroke, 12.70 vs 16.18 per 1000 person-years for MI and 26.37 vs 32.46 per 1000 person-years for ischaemic stroke. The risk of all-cause mortality was lower in DPP-4 inhibitor users (HR 0.67, 95% CI 0.64 to 0.70), combination of MI and stroke (HR 0.81, 95% CI 0.76 to 0.87), MI (HR 0.80, 95% CI 0.71 to 0.89) and ischaemic stroke (HR 0.83, 95% CI 0.76 to 0.89) than in non-users. Notably, the risk of hospitalisation for HF did not differ significantly between groups. The results were similar after accounting for death as a competing risk. Conclusions In this nationwide T2DM cohort, the risks of mortality and the combination of MI and ischaemic stroke were lower for patients receiving DPP-4 inhibitors than for those who did not receive such treatment. DPP-4 inhibitor use was not associated with a higher risk of hospitalisation for HF even in patients with pre-existing HF.

Objective To examine the risk of acute kidney injury (AKI) in a nationwide cohort of patients with type 2 diabetes initiating dipeptidyl peptidase-4 (DPP-4) inhibitors. Patients and Methods This nested case-control study of a cohort of adult DPP-4 inhibitor users with type 2 diabetes who were hospitalized for AKI between January 1, 2010, and December 31, 2013, was conducted using Taiwan's National Health Insurance Research Database. Each AKI case was matched with one control subject according to duration of follow-up, age, sex, urbanization level, monthly income, comorbidity severity, and well-known predisposing factors for AKI. Odds ratios (ORs) for AKI were calculated according to current, recent, or past use of DPP-4 inhibitors. Results A total of 6752 cases with AKI and 6752 matched controls were analyzed. The exposure prevalence of DPP-4 inhibitor use in the previous year was higher among patients with AKI (adjusted OR, 1.20; 95% CI, 1.05-1.36; P =.006). In a stratified analysis, the association was significant for current DPP-4 inhibitor use (adjusted OR, 1.26; 95% CI, 1.08-1.48; P =.004), but not for recent or past use. Conclusion In this large contemporary cohort, DPP-4 inhibitor users had an increased risk of AKI development compared with nonusers. Further research is warranted to investigate the mechanism underlying this association.

Renin-angiotensin-aldosterone system blockers are the preferred antihypertensive medications in patients with diabetes and prior stroke. This study aimed to compare the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in terms of major adverse cardiac events (MACEs) in patients with diabetes who survived ischemic stroke.We conducted an observational, nationwide, propensity score-matched cohort study using Taiwan's National Health Insurance Research Database. Patients aged at least 20 years with type 2 diabetes who initiated ACEI (n = 15,959) or ARB (n = 23,929) use within 90 days after discharge for first ischemic stroke between January 2000 and December 2011 were allocated to ACEI and ARB groups, respectively. The primary outcomes were MACEs (myocardial infarction, ischemic stroke, and cardiovascular mortality). The secondary outcomes were hospitalization for acute kidney injury and hyperkalemia. Intention-to-treat and as-treated models were used.Intention-to-treat analysis showed no significant difference between the ACEI and ARB groups in the outcomes of MACEs [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.95-1.04], including ischemic stroke (HR, 1.01; 95% CI, 0.97-1.06), myocardial infarction (HR, 1.06; 95% CI, 0.95-1.18), and cardiovascular mortality (HR, 0.98; 95% CI, 0.91-1.06). As-treated analysis produced similar results. Additionally, the groups showed no difference in the risk of hospitalization for acute kidney injury or hyperkalemia.Our study supports the hypothesis that the risks of MACEs and two additional secondary outcomes in patients with diabetes who survived ischemic stroke did not differ according to ACEI versus ARB use.

Background and objective Recent observational studies have shown that sleep apnoea (SA) is associated with increased risk of incident CKD. However, the contribution of SA relative to common traditional CKD risk factors remains unknown. The aims of this study were to investigate the long-term risk of incident CKD events following SA diagnosis and compare the relative contributions of SA, diabetes and hypertension. Methods Data were retrieved from Taiwan's National Health Insurance Research Database during the period between 2000 and 2010 for this retrospective cohort study. The cohorts are composed of patients (age ≥ 20 years) newly diagnosed with SA and matched subjects without SA. The two cohorts were followed until the occurrence of CKD, death or the end of 2010. Results The sample is composed of 43 434 individuals (8687 patients with SA and 34 747 matched non-SA subjects). A total of 157 new CKD events in patients with SA and 298 events in the matched non-SA cohort were recorded during a mean follow-up period of 3.9 years (incidence rates, 4.5 and 2.2/per 1000 person-years). The risk of CKD development was greater among patients with SA than in the matched non-SA cohort (adjusted hazard ratio (aHR) 1.58, 95% confidence interval ( CI): 1.29–1.94). The contribution of SA to the CKD hazard was similar to that of hypertension (aHR 1.17, 95% CI: 0.68–2.01, P = 0.56), whereas that of diabetes remained significantly higher (aHR 2.17, 95% CI: 1.21–3.90, P = 0.01). Conclusion SA was associated with an increase in the risk of CKD incidence similar to that of hypertension. See Editorial, page 578

Background Previous studies have demonstrated that high estimated glomerular filtration rate (eGFR) is paradoxically associated with an increased risk of mortality, and the association becomes more predominant in older people. However, the role of malnutrition–inflammation–cachexia syndrome (MICS) in the association between eGFR and mortality has never been explored. Methods We conducted a community-based cohort study using data from the Taipei City Elderly Health Examination Database, collected during the period 2001–10. All participants aged ≥65 years were included and stratified by the absence or presence of MICS, which is defined as the presence of at least one of the following markers: body mass index

In a large observational database study of add-on treatments to metformin, the addition of dipeptidyl peptidase-4 (DPP-4) inhibitors was associated with a lower risk for all-cause mortality, stroke...

Background The link between elevated serum uric acid ( SUA ) levels and cardiovascular disease ( CVD )–related mortality in the elderly population remains inconclusive. Nutritional status influences both SUA and CVD outcomes. Therefore, we investigated whether SUA ‐predicted mortality and the effect‐modifying roles of malnourishment in older people. Methods and Results A longitudinal Taiwanese cohort including 127 771 adults 65 years and older participating in the Taipei City Elderly Health Examination Program from 2001 to 2010 were stratified by 1‐mg/dL increment of SUA . Low SUA (2 . Study outcomes were all‐cause and CVD ‐related mortality. Cox models were used to estimate hazard ratios ( HRs ) of mortality, after adjusting for 20 demographic and comorbid covariates. Over a median follow‐up of 5.8 years, there were 16 439 all‐cause and 3877 CVD ‐related deaths. Compared with the reference SUA strata of 4 to SUA HR , 1.16; 95% confidence interval, 1.07–1.25) and ≥8 mg/dL ( HR , 1.13; confidence interval, 1.06–1.21), with progressively elevated risks at both extremes. Similarly, increasingly higher CVD ‐related mortality was found at the SUA level HR , 1.19; confidence interval, 1.00–1.40) and ≥7 mg/dL ( HR , 1.17; confidence interval, 1.04–1.32). Remarkably, among the low SUA (CVD ‐related mortality. This modifying effect of malnourishment remained consistent across subgroups. Conclusions SUA ≥8 or CVD ‐related mortality in the elderly, particularly in those with malnourishment.

Background The association between periodontal disease and chronic kidney disease in older people is controversial, and evidence for a causal link between kidney function decline and subsequent mortality risk is limited. Study Design Longitudinal, observational, community-based cohort study. Setting & Participants Participants were citizens 65 years or older who received the Taipei City Government–sponsored Annual Elderly Health Examination Program during 2005 to 2010, including dental status assessment and biochemical examinations. Predictors Participants with periodontal disease defined by the World Health Organization Community Periodontal Index of Treatment Need criteria. Outcomes All-cause and cardiovascular mortality and estimated glomerular filtration rate (eGFR) decline ≥ 30% over 2 years. Results Of 100,263 study participants, 13,749 (13.7%) had periodontal disease. In a mean follow-up of 3.8 years, all-cause and cardiovascular mortality rates in those with periodontal disease (11.5% and 2.6%, respectively) were higher compared with those without periodontal disease (6.7% and 1.6%, respectively). After adjustment for demographic characteristics, comorbid conditions, and biochemistry data, adjusted HRs for all-cause and cardiovascular mortality were 1.34 (95% CI, 1.26-1.42) and 1.25 (95% CI, 1.13-1.41), respectively. The frequency of eGFR decline ≥ 30% over 1-, 2-, and 3-years' follow-up in those with periodontal disease was 1.8%, 3.7%, and 4.0%, respectively. In a logistic regression model, adjusted ORs of the detrimental effect of periodontal disease on 30% eGFR decline in participants over 1-, 2-, or 3-years' follow-up were 1.03 (95% CI, 0.85-1.25), 1.62 (95% CI, 1.41-1.87), and 1.59 (95% CI, 1.37-1.86), respectively. In subgroup analyses according to age, sex, and comorbid conditions, risks for eGFR decline and mortality remained consistent. Limitations Results may not be generalizable to other non-Asian ethnic populations. Conclusions The results indicate that periodontal disease is a risk factor for all-cause and cardiovascular mortality and eGFR decline ≥ 30% over 2 to 3 years in older people.

Background Retinal vein occlusion (RVO) is the second most common retinal vascular disease, with peak incidence at 70years of age. However, the bidirectional association between the risk of comorbidities and the diagnosis of RVO in this population is uncertain. Methods A population-based cohort of 1,784,960 patients 70years of age and older retrieved from the Taiwan National Health Insurance Research Database between 2000 and 2010. Risks of comorbidities were assessed 5years before and after the diagnosis of RVO. Results In our study, 3393 subjects had central RVO (CRVO) and 6688 subjects had branch RVO (BRVO). Before the diagnosis of RVO, patients showed increased risks for the following comorbidities: hypertension (odds ratio [OR]=1.83, 95% confidence interval [CI], 1.74–1.93), dyslipidemia (OR=1.29, [1.23–1.35]), DM (OR=1.29, [1.23–1.35]), liver disease (OR=1.22, [1.16–1.29]), renal disease (OR=1.30, [1.23–1.37]), and cerebrovascular disease (OR=1.16, [1.11–1.21]). After the diagnosis of RVO, patients were at greater risk of developing DM (adjusted hazard ratio [AHR]=1.12, [1.06–1.19]), PAD (AHR=1.17, [1.08–1.27]), and MACE (AHR=1.35, [1.25–1.46]); however, the risk of all-cause mortality was unchanged. Elderly patients with CRVO had a significantly higher risk of all-cause mortality (AHR=1.09, [1.02–1.17]), whereas patients with BRVO showed no significant differences in mortality. Conclusion This study suggests bidirectional association between the risk of comorbidities and the diagnosis of RVO in an elderly population.

Background— Substantial infective endocarditis (IE)–related morbidity and mortality may occur even after successful treatment. However, no previous study has explored long-term hard end points (ie, stroke, myocardial infarction, heart failure, cardiovascular death) in addition to all-cause mortality in IE survivors. Methods and Results— A nationwide population-based cohort study was conducted among IE survivors identified with the use of the Taiwan National Health Insurance Research Database during 2000 to 2009. IE survivors were defined as those who survived after discharge from first hospitalization with a diagnosis of IE. A total of 10 116 IE survivors were identified. IE survivors were matched to control subjects without IE at a 1:1 ratio through the use of propensity scores. The primary outcomes were stroke, myocardial infarction, readmission for heart failure, and sudden cardiac death or ventricular arrhythmia. The secondary outcomes were repeat IE and all-cause mortality. Compared with the matched cohort, IE survivors had higher risks of ischemic stroke (adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.40–1.80), hemorrhagic stroke (aHR, 2.37; 95% CI, 1.90–2.96), myocardial infarction (aHR, 1.44; 95% CI, 1.17–1.79), readmission for heart failure (aHR, 2.24; 95% CI, 2.05–2.43), sudden death or ventricular arrhythmia (aHR, 1.69; 95% CI, 1.44–1.98), and all-cause death (aHR, 2.27; 95% CI, 2.14–2.40). Risk factors for repeat IE were older age, male sex, drug abuse, and valvular replacement after an initial episode of IE. Conclusion— Despite treatment, the risk of long-term major adverse cardiac events was substantially increased in IE survivors.

End-stage renal disease (ESRD) patients are more prone to infectious disease because of their immunocompromised status. However, the association between pyogenic liver abscess (PLA) and ESRD remains not clear. The aim of our study is to evaluate the incidence, risk factors, and outcomes of PLA in ESRD patients. We recruited all incident ESRD patients from the Taiwan National Health Insurance database from 1998 to 2006. The incidence rate of PLA in ESRD patients was compared with that of a randomly selected non-ESRD control group matched for age, sex gender, Charlson comorbidity score, diabetes mellitus, and cirrhosis. Among the 57,761 incident dialysis patients, there were 538 cases of PLA. The incidence rate of PLA was 18.20 per 10,000 person-years in the ESRD cohort and 6.34 per 10,000 person-years in matched control cohort. The rate of PLA was significantly higher in the ESRD cohort (hazard ratio 3.63, 95% confidence interval 2.83–4.65, P

Introduction Due to lifelong immunosuppression, renal transplant recipients (RTRs) are at risk of infectious complications such as pneumonia. Severe pneumonia results in respiratory failure and is life‑threatening. We aimed to examine the influence of immunosuppressant dose reduction on RTRs with bacterial pneumonia and respiratory failure. Methods From January 2001 to January 2011, 33 of 1,146 RTRs at a single centre developed bacterial pneumonia with respiratory failure. All patients were treated using mechanical ventilation and aggressive therapies in the intensive care unit. Results Average time from kidney transplantation to pneumonia with respiratory failure was 6.8 years. In-hospital mortality rate was 45.5% despite intensive care and aggressive therapies. Logistic regression analysis indicated that a high serum creatinine level at the time of admission to the intensive care unit (odds ratio 1.77 per mg/dL, 95% confidence interval 1.01-3.09; p = 0.045) was a mortality determinant. Out of the 33 patients, immunosuppressive agents were reduced in 17 (51.5%). We found that although immunosuppressant dose reduction tended to improve in-hospital mortality, this was not statistically significant. Nevertheless, during a mean follow-up period of two years, none of the survivors (n = 18) developed acute rejection or allograft necrosis. Conclusion In RTRs with bacterial pneumonia and respiratory failure, higher serum creatinine levels were a mortality determinant. Although temporary immunosuppressant dose reduction might not reduce mortality, it was associated with a minimal risk of acute rejection during the two-year follow-up. Our results suggest that early immunosuppressant reduction in RTRs with severe pneumonia of indeterminate microbiology may be safe even when pathogens are bacterial in nature.

Background and objectives We aimed to investigate the benefits and risks of dual antiplatelet therapy (DAPT) after coronary drug-eluting stent (DES) implantation in patients undergoing hemodialysis. Design, setting, participants, & measurements A nested case-control analysis of patients on hemodialysis after receipt of DES and DAPT treatment was conducted using data from Taiwan’s National Health Insurance Research Database for the period 2007–2011. Cases of myocardial infarction or death within 1 year after DES implantation were matched one-to-one with control patients. Odds ratios were calculated to compare DAPT continuation with discontinuation. Additionally, a propensity score–adjusted 6-month landmark cohort analysis was also conducted to evaluate the long-term benefits and risks of prolonged (>6 months) compared with ≤6 months of DAPT use. The primary outcomes were death and myocardial infarction. The secondary outcomes were ischemic stroke, revascularization, and major bleeding. Results In the nested case-control analysis, patients who continued DAPT had a lower rate of death or myocardial infarction within 1 year after receipt of a DES (adjusted odds ratio, 0.54; 95% confidence interval, 0.36 to 0.81; P =0.003), whereas this association became statistically nonsignificant when compared with patients who discontinued DAPT for the period between 6 and 12 months after receipt of a DES (adjusted odds ratio, 1.51; 95% confidence interval, 0.75 to 3.04). In the propensity score–adjusted cohort analysis, >6 months of DAPT use was not associated with different primary or secondary outcomes than shorter-term use. Conclusions Our findings support that the clinical effectiveness of extended DAPT in a hemodialysis population may be tempered after 6 months post-DES implantation.

Background: Secondary hyperparathyroidism is associated with vascular calcification and arterial stiffness in patients with end-stage renal disease. The aim of this study was to analyze the frequency of intradialytic hypotension (IDH) and cardiovascular function before and after parathyroidectomy (PTX) in maintenance hemodialysis patients. Methods: We compared predialytic and intradialytic blood pressure, left and right ventricular ejection fraction (LVEF and RVEF), and cardiothoracic ratio 1 month before PTX, and 6 and 12 months after PTX. IDH was defined as a decrease in systolic blood pressure ≥ 20 mmHg or a decrease in mean arterial pressure ≥ 10 mmHg. Results: At the time of PTX, the mean age of the patients was 57.4 ± 12.0 years, and the mean dialysis vintage was 12.2 ± 5.8 years. At baseline, 6 months, and 12 months after PTX, the average numbers of sessions disturbed by IDH during 13 dialysis sessions (1 month) were 6.4, 3.9 (p < 0.016 vs. baseline), and 4.0 sessions (p < 0.037 vs. baseline, p = 0.801 vs. 6 months), respectively. LVEF and RVEF were improved significantly after PTX. Furthermore, volume status was also improved, as evidenced by the significantly greater ultrafiltration volume and reduced cardiothoracic ratio. Conclusions: Hemodialysis patients with severe secondary hyperparathyroidism are more likely to achieve normotensive and euvolemic status after PTX, probably through improved heart function and reduced IDH episodes.

Hemodialysis (HD) is the most commonly-used renal replacement therapy for patients with end-stage renal disease worldwide. Arterio-venous fistula (AVF) is the vascular access of choice for HD patients with lowest risk of infection and thrombosis. In addition to environmental factors, genetic factors may also contribute to malfunction of AVF. Previous studies have demonstrated the effect of genotype polymorphisms of angiotensin converting enzyme on vascular access malfunction. We conducted a multicenter, cross-sectional study to evaluate the association between genetic polymorphisms of renin-angiotensin-aldosterone system and AVF malfunction. Totally, 577 patients were enrolled. Their mean age was 60 years old and 53% were male. HD patients with AVF malfunction had longer duration of HD (92.5 ± 68.1 vs. 61.2 ± 51.9 months, p < 0.001), lower prevalence of hypertension (44.8% vs. 55.3%, p = 0.025), right-sided (31.8% vs. 18.4%, p = 0.002) and upper arm AVF (26.6% vs. 9.7%, p < 0.001), and higher mean dynamic venous pressure (DVP) (147.8 ± 28.3 vs. 139.8 ± 30.0, p = 0.021). In subgroup analysis of different genders, location of AVF and DVP remained significant clinical risk factors of AVF malfunction in univariate and multivariate binary logistic regression in female HD patients. Among male HD patients, univariate binary logistic regression analysis revealed that right-side AVF and upper arm location are two important clinical risk factors. In addition, two single nucleotide polymorphisms (SNPs), rs275653 (Odds ratio 1.90, p = 0.038) and rs1492099 (Odds ratio 2.29, p = 0.017) of angiotensin II receptor 1 (AGTR1), were associated with increased risk of AVF malfunction. After adjustment for age and other clinical factors, minor allele-containing genotype polymorphisms (AA and CA) of rs1492099 still remained to be a significant risk factor of AVF malfunction (Odds ratio 3.63, p = 0.005). In conclusion, we demonstrated that rs1492099, a SNP of AGTR1 gene, could be a potential genetic risk factor of AVF malfunction in male HD patients.

Background Recent clinical trials have evaluated the cardiovascular outcomes of dipeptidyl peptidase-4 ( DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM), but those with end-stage renal disease (ESRD) were ineligible for participation in these trials. We aimed to characterize the impact of DPP-4 inhibitors on major adverse cardiovascular events (MACEs) in patients with T2DM and ESRD undergoing chronic dialysis. Methods This nationwide observational study utilized data from 3556 patients aged ≥20years with T2DM and ESRD who initiated treatment with DPP-4 inhibitors between 1 March 2009 and 31 June 2013, retrieved from Taiwan's National Health Insurance Research Database. Each DPP-4 inhibitor user was matched to a non-user control subject using propensity scores. The primary outcomes were all-cause mortality and MACEs (ischemic stroke and myocardial infarction). The secondary outcomes were hospitalization for heart failure and hypoglycemia. All subjects were followed until death or 31 December 2013. Results Compared with non-users, DPP-4 inhibitor users had lower risks of all-cause mortality (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.39–0.47), MACEs (HR 0.76, 95% CI 0.65–0.90), and ischemic stroke (HR 0.77, 95% CI 0.61–0.97); the risks of myocardial infarction and hospitalization for heart failure and hypoglycemia did not differ. This treatment effect remained consistent in subgroup analyses according to age, sex, comorbidities, dialysis modality, and insulin use. Conclusions In this nationwide ESRD cohort, DPP-4 inhibitor use was associated with reduced risks of all-cause mortality and ischemic stroke.

Background: Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective treatments for diabetic retinopathy, but randomized trials and meta-analyses comparing their effects on macrovascular complications have yielded conflicting results. We compared the effectiveness of these drugs in patients with pre-existing diabetic retinopathy in a large population-based cohort. Methods: We conducted a propensity score–matched cohort study using Taiwan’s National Health Insurance Research Database. We included adult patients prescribed an ACE inhibitor or ARB within 90 days after diagnosis of diabetic retinopathy between 2000 and 2010. Primary outcomes were all-cause death and major adverse cardiovascular events (myocardial infarction, ischemic stroke or cardiovascular death). Secondary outcomes were hospital admissions with acute kidney injury or hyperkalemia. Results: We identified 11 246 patients receiving ACE inhibitors and 15 173 receiving ARBs, of whom 9769 patients in each group were matched successfully by propensity scores. In the intention-to-treat analyses, ARBs were similar to ACE inhibitors in risk of all-cause death (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.87–1.01) and major adverse cardiovascular events (HR 0.95, 95% CI 0.87–1.04), including myocardial infarction (HR 1.03, 95% CI 0.88–1.20), ischemic stroke (HR 0.94, 95% CI 0.85–1.04) and cardiovascular death (HR 1.01, 95% CI 0.88–1.16). They also did not differ from ACE inhibitors in risk of hospital admission with acute kidney injury (HR 1.01, 95% CI 0.91–1.13) and hospital admission with hyperkalemia (HR 1.01, 95% CI 0.86–1.18). Results were similar in as-treated analyses. Interpretation: Our study showed that ACE inhibitors were similar to ARBs in risk of all-cause death, major adverse cardiovascular events and adverse effects among patients with pre-existing diabetic retinopathy.

Objectives Pneumocystis jiroveci pneumonia is a rare but lethal complication in renal transplant recipients. Dose reduction of immunosuppressive agents in such situations is recommended, but its quantity and safety are unclear. Materials and methods From January 2001 to January 2011, twenty of one thousand forty-six renal transplant recipients in a single center developed Pneumocystis jiroveci pneumonia, which was diagnosed by the Giemsa and Gomori methenamine silver stains from a specimen of bronchoalveolar lavage. Results We found that timing of the first immunosuppressant reduction of the Pneumocystis jiroveci pneumonia survivor (mean, 1.4 days after admission) was significantly earlier than that of the deceased patient (mean, 5.1 days after admission). Logistic regression analysis indicated that for those whose immunosuppressants were reduced more aggressively (either 1 of the immunosuppressants was reduced by more than 50% within 2 days of hospitalization) were significantly more likely to survive (mortality risk, OR, 0.074 [95% CI, 0.01-0.84]; P = .035). In addition, none of the survivors developed acute rejection or allograft necrosis during a mean follow-up of 2 years. Conclusions Dosage reduction of immunosuppressive agents in renal transplant recipients with Pneumocystis jiroveci pneumonia should be prompt and sufficient. Aggressive immuno-suppressant dosage reduction is safe in such circumstance and is associated with minimal risk of in-hospital and long-term acute allograft rejection.

Purpose Sepsis is a major health burden worldwide. Preclinical investigations in animals and retrospective studies in patients have suggested that inhibition of platelets may improve the outcome of sepsis. In this study we investigated whether chronic antiplatelet therapy impacts on the presentation and outcome of sepsis, and the host response. Methods We performed a prospective observational study in 972 patients admitted with sepsis to the mixed intensive care units (ICUs) of two hospitals in the Netherlands between January 2011 and July 2013. Of them, 267 patients (27.5 %) were on antiplatelet therapy (95.9 % acetylsalicylic acid) before admission. To account for differential likelihoods of receiving antiplatelet therapy, a propensity score was constructed, including variables associated with use of antiplatelet therapy. Cox proportional hazards regression was used to estimate the association of antiplatelet therapy with mortality. Results Antiplatelet therapy was not associated with sepsis severity at presentation, the primary source of infection, causative pathogens, the development of organ failure or shock during ICU stay, or mortality up to 90 days after admission, in either unmatched or propensity-matched analyses. Antiplatelet therapy did not modify the values of 19 biomarkers providing insight into hallmark host responses to sepsis, including activation of the coagulation system, the vascular endothelium, the cytokine network, and renal function, during the first 4 days after ICU admission. Conclusions Pre-existing antiplatelet therapy is not associated with alterations in the presentation or outcome of sepsis, or the host response. Electronic supplementary material The online version of this article (doi:10.1007/s00134-015-4171-9) contains supplementary material, which is available to authorized users.

Objectives The elderly (aged ≥65 years) population with type 2 diabetes (T2D) is growing substantially, but evidence for associations between the use of dipeptidyl peptidase-4 inhibitors (DPP-4is), novel incretin-based antidiabetic drugs, and clinical hard endpoints in this group remains inconclusive. We aimed to assess the safety and cardiovascular effects of DPP-4i use in a nationally representative sample of elderly adults with T2D. Design, setting, and participants We conducted a nationwide, observational, propensity score–matched study using Taiwan's National Health Insurance Research Database. Of a total of 414,213 patients aged ≥65 years with T2D, 58,485 patients receiving initial DPP-4i prescriptions between March 1, 2009, and June 31, 2013, were included. Each DPP-4i user was matched with a nonuser control using propensity scores. The endpoints were all-cause mortality and major adverse cardiovascular events (MACEs), including ischemic stroke and myocardial infarction. Potential adverse effects of hospitalization for heart failure and hypoglycemia were also evaluated. Results Compared with the matched control cohort, the risks of all-cause mortality (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.52–0.56), MACEs (HR 0.79, 95% CI 0.75–0.83), myocardial infarction (HR 0.79, 95% CI 0.72–0.87), and ischemic stroke (HR 0.79, 95% CI 0.75–0.84) were lower in the DPP-4i cohort. DPP-4i use did not affect the risks of hospitalization for heart failure and hypoglycemia. Stratified analyses produced consistent results across age, sex, and comorbidity subgroups. Conclusions Prescription of DPP-4is was associated with reduced risks of all-cause mortality and MACEs in patients aged ≥65 years with T2D.

Although oral antidiabetic drugs (OADs) have been associated with immunomodulation in preclinical studies, little is still known about the association between the use of OADs and the risk of sepsis. Using a cohort of patients, extracted from Taiwan’s National Health Insurance Research Database, with type 2 diabetes who were newly diagnosed between 2010 and 2012 and treated with OADs, we conducted a nested case-control study involving 43,015 cases (patients who were first hospitalized for sepsis) and 43,015 matched controls. Compared with non-use, metformin use was associated with a decreased risk of developing sepsis (adjusted odds ratio [OR] 0.80, 95% confidence interval [CI] 0.77–0.83, P P

article i nfo Background:Guidelinesforhypertensionmanagementrecommendeitherangiotensin-convertingenzymeinhib- itors (ACEIs) or angiotensin II receptor blockers (ARBs) as first-line therapies for diabetes population. No head- to-head trial has been conducted to determine the priority of ACEI/ARB use for major adverse cardiac events (MACEs) in diabetes mellitus. Methods: Data on patients with newly diagnosed diabetes treated with ACEIs or ARBs were collected from Taiwan's National Health Insurance Research Database for the period 2000-2010. A total of 30,777 ARB users and 21,436 ACEI users were identified. One ARB user was matched to one ACEI user by propensity score. Intention-to-treat (ITT) and as-treated (AT) models were used. The primary outcomes were myocardial infarc- tion, ischemic stroke, and all-cause mortality. The secondary outcomes were hospitalization for acute kidney in- jury and hyperkalemia. Findings: Compared with ACEI users (n = 21,436), ARB users (n = 30,777) showed no significant difference in the outcomes of myocardial infarction (hazard ratio (HR): 0.92; 95% confidence interval (CI): 0.80 to 1.07), ische- mic stroke (HR: 0.95; 95% CI: 0.87 to 1.04), or all-cause mortality (HR: 0.95; 95% CI: 0.89 to 1.01) in the ITT anal- ysis. The risks of hospitalization for acute kidney injury and hyperkalemia also did not differ between groups. ACEI and ARB use also had similar effects on MACEs and adverse effects in the AT analysis. Conclusions: This large cohort study supports the comparative effectiveness of ACEIs and ARBs in terms of MACE outcomes in patients with incident diabetes.

Nontyphoid salmonellosis (NTS) is one of the most common foodborne diseases worldwide, affecting millions of persons each year [1, 2]. Usually acquired by consumption of contaminated food, especially eggs and poultry products, NTS may cause gastroenteritis, bacteremia, and focal infections [3]. Predisposing host factors include gastric hypoacidity [1], diabetes [3, 4], autoimmune diseases [1, 4], cancer [5], hepatic cirrhosis [3], gallstones [1], previous gastrointestinal surgery [6], AIDS [7, 8], and prior use of antimicrobial agents [3, 7, 8]. Proton pump inhibitors (PPIs) have also been associated with NTS [9–11]. This association is thought to be due to disruption of the natural gut microbial ecology [12] caused by inhibition of gastric acid secretion, mucosal permeability [13], and neutrophil bactericidal activity [14]. Most studies have shown an association between PPI use and susceptibility to NTS but failed to consider the confounding effects of host factors that enhance susceptibility to NTS [9–11]. A recent study, which controlled for individual confounding factors by using the patients as their own control over a 12-month period, found no association between PPIs use and NTS, suggesting that predisposing factors other than PPIs may contribute to the increased rate of NTS [15]. Because of the conflicting results in the literature, problems of selection bias [16], and differences in the intervals of time between the use of a PPI and onset of NTS we believed that a large, community-based study was needed to adjust for the effect of predisposing host factors and to determine the critical interval between use of a PPI and the onset of NTS. To accomplish this we conducted a nested case-control study, matching for demographic and predisposing host factors for NTS. The Taiwan National Health Insurance Research Database (NHIRD) 2000–2010 was used to identify a large number of case patients and controls during an 11-year period.

Background There is substantial debate regarding the development of acute coronary syndrome in patients using proton pump inhibitors (PPIs) combined with clopidogrel. However, data remain limited to address the effect of PPIs alone on the subsequent risk of myocardial infarction (MI). We aimed to explore the subsequent risk of MI in PPI users who had no previous history of MI. Methods The records of inpatients and outpatients with PPI prescriptions were retrieved from the Taiwan National Health Insurance Research Database between 2000 and 2009. We conducted two different study designs, the first using propensity score (PS)-matching analyses and the second using case-crossover analyses. The risk of developing MI for PPI users was analyzed in the PS-matched study. The association between risk of MI and prior PPI exposure was further validated in the case-crossover study. Results In the PS-matched study, we included 126,367 PPI users and 126,367 PS-matched PPI non-users. After 120days of follow-up, PPI use was associated with a 1.58-fold greater risk of MI (adjusted hazard ratio [HR]=1.58, 95% confidence interval [CI]=1.11 to 2.25). In the case-crossover study, adjusted odds ratios of PPI for MI risk were 4.61 (95% CI=1.76 to 12.07) for the 7-day window and 3.47 (95% CI=1.76 to 6.83) for the 14-day window. Conclusions Use of PPIs may be independently associated with an increased risk of MI. However, the benefits of PPIs may greatly outweigh the risks of adverse cardiovascular effects, with number needed to harm of 4357.

Background Older patients with advanced chronic kidney disease (CKD) face the decision of whether to undergo dialysis. Currently available data on this issue are limited because they were generated by small, short-term studies with statistical drawbacks. Further research is urgently needed to provide objective information for dialysis decision making in older patients with advanced CKD. Methods This nationwide population-based cohort study was conducted using Taiwan’s National Health Insurance Research Database. Data from 2000 to 2010 were extracted. A total of 8,341 patients ≥70 years old with advanced CKD and serum creatinine levels >6 mg/dl, who had been treated with erythropoiesis-stimulating agents were included. Cox proportional hazard models in which initiation of chronic dialysis was defined as the time-dependent covariate were used to calculate adjusted hazard ratios for mortality. The endpoint was all-cause mortality. Results During a median follow-up period of 2.7 years, 6,292 (75.4%) older patients chose dialysis therapy and 2,049 (24.6%) received conservative care. Dialysis was initiated to treat kidney failure a median of 6.4 months after enrollment. Dialysis was associated with a 1.4-fold increased risk of mortality compared with conservative care (adjusted hazard ratio 1.39, 95% confidence interval 1.30 to 1.49). In subgroup analyses, the risk of mortality remained consistently increased, independent of age, sex and comorbidities. Conclusions In older patients, dialysis may be associated with increased mortality risk and healthcare cost compared with conservative care. For patients who are ≥70 years old with advanced CKD, decision making about whether to undergo dialysis should be weighted by consideration of risks and benefits. Electronic supplementary material The online version of this article (doi:10.1186/s12916-014-0169-3) contains supplementary material, which is available to authorized users.

The aim of our study was to determine whether pre-emptive statin therapy was associated with improved outcome of infective endocarditis (IE). We conducted a nationwide, population-based, propensity score-matched cohort study with the Taiwan's National Health Insurance Research Database. All patients with IE between January 2000 and December 2010 were enrolled. The primary outcome was in-hospital mortality. The secondary outcome included all-cause mortality within the first 3 months, 6 months, and one year after the diagnosis of IE. Among 13,584 patients with IE, we applied propensity score-matching on a 1:4 ratio, in which 370 statin users were matched to 1,480 statin non-users. Compared with statin non-users, statin users had a significantly lower risk of in-hospital mortality (adjusted hazard ratio [aHR] 0.65, 95% confidence interval [CI], 0.49–0.86). The reduction in mortality from IE remained significant for follow-up 3 months (aHR 0.68, 95% CI, 0.53–0.88), 6 months (aHR 0.73, 95% CI, 0.58–0.91), and 12 months (aHR 0.68, 95% CI, 0.55–0.84). Statin therapy was associated with a reduced risk of ICU admission rates, shock events, the need for mechanical ventilation, but not significantly with the need for heart valvular replacement surgery. In conclusion, our study found that statin therapy is associated with a reduced risk of in-hospital and subsequent mortality of IE.

To investigate the association between the use of nonselective or cyclooxygenase (COX)-2-selective nonsteroidal antiinflammatory drugs (NSAIDs) and risk of acute kidney injury (AKI) in a general Asian population. We conducted an observational, nationwide, nested case-control cohort study using Taiwan's National Health Insurance Research Database between 2010 and 2012. AKI cases were defined as hospitalization with a principle diagnosis of AKI. Each case was matched to 4 randomly selected controls based on age, sex, and the month and year of cohort entry. Odds ratios (ORs) were used to demonstrate the association between hospitalization for AKI and current, recent, or past use of an oral NSAID. During the study period, we identified 6199 patients with AKI and 24,796 matched controls. Overall, current users (adjusted OR 2.73, 95% confidence interval [CI] 2.28-3.28) and recent users (adjusted OR 1.17, 95% CI 1.01-1.35) were associated with increased risk of hospitalization for AKI. The risk was also similar for nonselective NSAIDs. However, neither current nor recent use of COX-2 inhibitors was significantly associated with AKI events. Our study supported that the initiation of nonselective NSAIDs rather than COX-2 inhibitors is associated with an increased risk of AKI requiring hospitalization. Future randomized trials are needed to elucidate these findings.

Renin and aldosterone activity levels are low in elderly patients, raising concerns about the benefits and risks of angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARB) use. However, data from direct comparisons of the effects of ACEIs on ARBs in the elderly population remain inconclusive. In this nationwide study, all patients aged ≥ 70 years were retrieved from the Taiwan National Health Insurance database for the period 2000 to 2009 and were followed up until the end of 2010. The ARB cohort (12,347 patients who continuously used ARBs for ≥ 90 days) was matched to ACEI cohort using high-dimensional propensity score (hdPS). Intention-to-treat (ITT) and as-treated (AT) analyses were conducted. In the ITT analysis, after considering death as a competing risk, the ACEI cohort had similar risks of myocardial infarction (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79–1.06), ischemic stroke (HR 0.98, 95% CI 0.90–1.07), and heart failure (HR 0.93, 95% CI 0.83–1.04) compared with the ARB cohort. No difference in adverse effects, such as acute kidney injury (HR 0.99, 95% CI 0.89–1.09) and hyperkalemia (HR 1.02, 95% CI 0.87–1.20), was observed between cohorts. AT analysis produced similar results to those of ITT analysis. We were unable to demonstrate a survival difference between cohorts (HR 1.03, 95% CI 0.88–1.21) after considering drug discontinuation as a competing risk in AT analysis. Our study supports the notion that ACEI and ARB users have similar risks of major adverse cardiovascular events (MACE), even in elderly populations.

Background The usage of urine protein/creatinine ratio to estimate daily urine protein excretion is prevalent, but relatively little attention has been paid to the influence of urine concentration and its impact on test accuracy. We took advantage of 24-hour urine collection to examine both urine protein/creatinine ratio (UPCR) and daily urine protein excretion, with the latter as the reference standard. Specific gravity from a concomitant urinalysis of the same urine sample was used to indicate the urine concentration. Methods During 2010 to 2014, there were 540 adequately collected 24h urine samples with protein concentration, creatinine concentration, total volume, and a concomitant urinalysis of the same sample. Variables associated with an accurate UPCR estimation were determined by multivariate linear regression analysis. Receiver operating characteristic (ROC) curves were generated to determine the discriminant cut-off values of urine creatinine concentration for predicting an accurate UPCR estimation in either dilute or concentrated urine samples. Results Our findings indicated that for dilute urine, as indicated by a low urine specific gravity, UPCR is more likely to overestimate the actual daily urine protein excretion. On the contrary, UPCR of concentrated urine is more likely to result in an underestimation. By ROC curve analysis, the best cut-off value of urine creatinine concentration for predicting overestimation by UPCR of dilute urine (specific gravity ≦ 1.005) was ≦ 38.8 mg/dL, whereas the best cut-off values of urine creatinine for predicting underestimation by UPCR of thick urine were ≧ 63.6 mg/dL (specific gravity ≧ 1.015), ≧ 62.1 mg/dL (specific gravity ≧ 1.020), ≧ 61.5 mg/dL (specific gravity ≧ 1.025), respectively. We also compared distribution patterns of urine creatinine concentration of 24h urine cohort with a concurrent spot urine cohort and found that the underestimation might be more profound in single voided samples. Conclusions The UPCR in samples with low or high specific gravity is more likely to overestimate or underestimate actual daily urine protein amount, respectively, especially in a dilute urine sample with its creatinine below 38.8 mg/dL or a concentrated sample with its creatinine above 61.5 mg/dL. In particular, UPCR results should be interpreted with caution in cases that involve dilute urine samples because its overestimation may lead to an erroneous diagnosis of proteinuric renal disease or an incorrect staging of chronic kidney disease.

Previous studies have shown that urinary calculi are associated with increased risks of urinary tract cancers. However, the association between urinary calculi and overall cancers is a largely undefined body of knowledge. We conducted a nationwide population-based cohort study using Taiwan's National Health Insurance Research Database from 2000 and 2009. Patients were excluded if they had antecedent cancers or urinary calculi before the enrollment. All study subjects were followed until the occurrence of cancer, dropout from the NHI program, death, or the end of 2010. Patterns of cancer incidence in patients with urinary calculi were compared with those of the general population using standardized incidence ratio (SIR). A total of 43,516 patients with urinary calculi were included. After a median follow-up of 5.3 years, 1891 patients developed cancer. The risk of overall cancers was significantly increased (SIR, 1.75; 95% confidence interval [CI], 1.68–1.83). We observed that urinary calculi was associated with higher risk of cancers of kidney (4.24; 95% CI, 3.47–5.13), bladder (3.30; 95% CI, 2.69–4.00), thyroid (2.50; 95% CI, 1.78–3.40), hematologic origin (2.41; 95% CI, 1.92–2.99), breast (1.84; 95% CI, 1.54–2.20), lung (1.82; 95% CI, 1.59–2.07), digestive tract (1.69; 95% CI, 1.57–1.82), and head and neck (1.54; 95% CI, 1.32–1.79), respectively. Our study shows that urinary calculi are associated with higher risk of systemic cancers in addition to urinary tract cancers. Further study is required to validate this association.