Genome-wide association study of primary dysmenorrhea in the Taiwan Biobank validates associations near the NGF and IL1 gene loci.

Using the Taiwan Biobank, we aimed to identify traits and genetic variations that could predispose Han Chinese women to primary dysmenorrhea. Cases of primary dysmenorrhea included those who self-reported "frequent dysmenorrhea" in a dysmenorrhea-related Taiwan Biobank questionnaire, and those who have been diagnosed with severe dysmenorrhea by a physician. Controls were those without self-reported dysmenorrhea. Customized Axiom-Taiwan Biobank Array Plates were used to perform whole-genome genotyping, PLINK was used to perform association tests, and HaploReg was used to conduct functional annotations of SNPs and bioinformatic analyses. The GWAS analysis included 1186 cases and 24,020 controls. We identified 53 SNPs that achieved genome-wide significance (P < 5 × 10-8, which clustered in 2 regions. The first SNP cluster was on chromosome 1, and included 24 high LD (R2 > 0.88) variants around the NGF gene (lowest P value of 3.83 × 10-13 for rs2982742). Most SNPs occurred within NGF introns, and were predicted to alter regulatory binding motifs. The second SNP cluster was on chromosome 2, including 7 high LD (R2 > 0.94) variants around the IL1A and IL1B loci (lowest P value of 7.43 × 10-10 for rs11676014) and 22 SNPs that did not reach significance after conditional analysis. Most of these SNPs resided within IL1A and IL1B introns, while 2 SNPs may be in the promoter histone marks or promoter flanking regions of IL1B. To conclude, data from this study suggest that NGF, IL1A, and IL1B may be involved in the pathogenesis of primary dysmenorrhea in the Han Chinese in Taiwan.

Risk Factors for Myocardial Infarction and Stroke Among Sepsis Survivors: A Competing Risks Analysis.

OBJECTIVES: Predictors for post-sepsis myocardial infarction (MI) and stroke are yet to be identified due to the competing risk of death. METHODS: This study included all hospitalized patients with sepsis from National Health Insurance Research Database of Taiwan between 2000 and 2011. The primary outcome was the first occurrence of MI and stroke requiring hospitalization within 180 days following hospital discharge from the index sepsis episode. The association between predictors and post-sepsis MI and stroke were analyzed using cumulative incidence competing risk model that controlled for the competing risk of death. RESULTS: Among 42 316 patients with sepsis, 1012 (2.4%) patients developed MI and stroke within 180 days of hospital discharge. The leading 5 predictors for post-sepsis MI and stroke are prior cerebrovascular diseases (hazard ratio [HR]: 2.02, 95% confidence interval [CI]: 1.74-2.32), intra-abdominal infection (HR: 1.94, 95% CI: 1.71-2.20), previous MI (HR: 1.81, 95% CI: 1.53-2.15), lower respiratory tract infection (HR: 1.62, 95% CI: 1.43-1.85), and septic encephalopathy (HR: 1.61, 95% CI: 1.26-2.06). CONCLUSIONS: Baseline comorbidities and sources of infection were associated with an increased risk of post-sepsis MI and stroke. The identified risk factors may help physicians select a group of patients with sepsis who may benefit from preventive measures, antiplatelet treatment, and other preventive measures for post-sepsis MI and stroke.

Impact of post-sepsis cardiovascular complications on mortality in sepsis survivors: a population-based study.

BACKGROUND: It remains unclear whether sepsis-related cardiovascular complications have an adverse impact on survival independent of pre-existing comorbidities. To investigate the survival impact of post-sepsis cardiovascular complications among sepsis survivors, we conducted a population-based study using the National Health Insurance Database of Taiwan. METHODS: We identified sepsis patients from the National Health Insurance Research Database of Taiwan using ICD-9-CM codes involving infection and organ dysfunction between 2000 and 2011. Post-sepsis incident myocardial infarction (MI) and stroke were ascertained by ICD-9-CM codes and antiplatelet treatment. We constructed a non-sepsis comparison cohort using propensity score matching to ascertain the association between sepsis and cardiovascular complications. Furthermore, we compared the 180-day mortality and 365-day mortality between patients surviving sepsis with or without post-sepsis MI or stroke within 70 days of hospital discharge. We constructed Cox regression models adjusting for pre-existing comorbidities to evaluate the independent survival impact of post-sepsis MI or stroke among sepsis survivors. RESULTS: We identified 42,316 patients hospitalized for sepsis, from which we matched 42,151 patients 1:1 with 42,151 patients hospitalized without sepsis. Compared to patients hospitalized without sepsis, patients hospitalized with sepsis had an increased risk of MI or stroke (adjusted odds ratio 1.72, 95% CI 1.60-1.85). Among 42,316 patients hospitalized for sepsis, 486 (1.15%) patients developed incident stroke and 108 (0.26%) developed incident MI within 70 days of hospital discharge. Compared to sepsis survivors without cardiovascular complications, sepsis survivors with incident MI or stroke had a higher mortality rate at 180 days (11.68% vs. 4.44%, P = 0.003) and at 365 days (16.75% vs. 7.11%, P = 0.005). Adjusting for age, sex, and comorbidities, post-sepsis MI or stroke was independently associated with increased 180-day (adjusted hazard ratio [HR] 2.16, 95% CI 1.69-2.76) and 365-day (adjusted HR 1.90, 95% CI 1.54-2.32) mortality. CONCLUSIONS: Compared to sepsis patients without incident MI or stroke, sepsis patients with incident MI or stroke following hospital discharge had an increased risk of mortality for up to 365 days of follow-up. This increased risk cannot be explained by pre-sepsis comorbidities.

Comparison of outcome and cost between the open, laparoscopic, and robotic surgical treatments for colon cancer: a propensity score-matched analysis using nationwide hospital record database.

BACKGROUND: There are limited studies that compare the cost and outcome of robotic-assisted surgery to open and laparoscopic surgery for colon cancer treatment. We aimed to compare the three surgical modalities for colon cancer treatment. METHODS: We performed a cohort study using the population-based Nationwide Inpatient Sample database. Patients with a primary diagnosis of colon cancer who underwent robotic, laparoscopic, or open surgeries between 2008 and 2014 were eligible for enrollment. We compared in-hospital mortality, complications, length of hospital stay, and cost for patients undergoing one of these three procedures using a multivariate adjusted logistic regression analysis and propensity score matching. RESULTS: Of the 531,536 patients undergoing surgical treatment for colon cancer during the study period, 348,645 (65.6%) patients underwent open surgeries, 174,748 (32.9%) underwent laparoscopic surgeries, and 8143 (1.5%) underwent robotic surgeries. In-hospital mortality, length of hospital stay, wound complications, general medical complications, general surgical complications, and costs of the three surgical treatment modalities. Compared to those undergoing laparoscopic surgery, patients undergoing open surgery had a higher mortality rate (OR 2.98, 95% CI 2.61-3.40), more general medical complications (OR 1.77, 95% CI 1.67-1.87), a longer length of hospital stay (6.60 vs. 4.36 days), and higher total cost ($18,541 vs. $14,487) in the propensity score matched cohort. Mortality rate and general medical complications were equivalent in the laparoscopic and robotic surgery groups, but the median cost was lower in the laparoscopic group ($14641 vs. $16,628 USD). CONCLUSIONS: Laparoscopic colon cancer surgery was associated with a favourable short-term outcome and lower cost compared with open surgery. Robot-assisted surgery had comparable outcomes but higher cost as compared to laparoscopic surgery.

Nationwide Trend of Sepsis: A Comparison Among Octogenarians, Elderly, and Young Adults.

OBJECTIVE: We aimed to compare the sepsis incidence, mortality rates, and primary sites of infection among adult, elderly, and octogenarian patients with sepsis. DESIGN: Population-based cohort study. SETTING: The entire health insurance claims data of Taiwan, which enrolled 99.8% of the 23 million Taiwanese population. PATIENTS: Sepsis patients were identified by International Classification of Diseases, 9th Edition, Clinical Modification codes for both infection and organ dysfunction from January 1, 2002, to December 31, 2012. Patients were categorized into three age groups: 1) adults (18-64 yr); 2) elderly (65-84 yr); and 3) oldest old (≥ 85 yr). The 30-day all-cause mortality was verified by a linked national death certificate database. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From 2002 to 2012, we identified 1,259,578 patients with sepsis, of which 417,328 (33.1%) were adults, 652,618 (51.8%) were elderly, and 189,632 (15.1%) were oldest old. We determined that the incidence of sepsis in the oldest old was 9,414 cases per 100,000 population on 2012, which was 31-fold greater than the adult incidence (303 cases per 100,000 population) and three-fold greater than the elderly incidence (2,908 cases per 100,000 population). Despite the increasing trend in incidence, the mortality decreased by 34% for adults, 24% for elderly, and 22% for oldest old. However, systemic fungal infection was disproportionately increased in oldest old patients (1.76% annual increase) and the elderly patients (1.00% annual increase). CONCLUSION: The incidence of sepsis is disproportionately increased in elderly and oldest old patients. Despite the increasing trend in incidence, the mortality rate in geriatric patients with sepsis has decreased. However, the increased incidence of fungal infections in the geriatric population warrants further attention.

Susceptible period for cardiovascular complications in patients recovering from sepsis.

BACKGROUND: Patients are at increased risk of cardiovascular complications while recovering from sepsis. We aimed to study the temporal change and susceptible periods for cardiovascular complications in patients recovering from sepsis by using a national database. METHODS: In this retrospective population-based cohort study, patients with sepsis were identified from the National Health Insurance Research Database in Taiwan. We estimated the risk of myocardial infarction (MI) and stroke following sepsis by comparing a sepsis cohort to a matched population and hospital control cohort. The primary outcome was first occurrence of MI or stroke requiring admission to hospital during the 180-day period following discharge from hospital after sepsis. To delineate the risk profile over time, we plotted the weekly risk of MI and stroke against time using the Cox proportional hazards model. We determined the susceptible period by fitting the 2 phases of time-dependent risk curves with free-knot splines, which highlights the turning point of the risk of MI and stroke after discharge from the hospital. RESULTS: We included 42 316 patients with sepsis; stroke developed in 831 of these patients and MI developed in 184 within 180 days of discharge from hospital. Compared with population controls, patients recovering from sepsis had the highest risk for MI or stroke in the first week after discharge (hazard ratio [HR] 4.78, 95% confidence interval [CI] 3.19 to 7.17; risk difference 0.0028, 95% CI 0.0021 to 0.0034), with the risk decreasing rapidly until the 28th day (HR 2.38, 95% CI 1.94 to 2.92; risk difference 0.0045, 95% CI 0.0035 to 0.0056) when the risk stabilized. In a repeated analysis comparing the sepsis cohort with the nonsepsis hospital control cohort, we found an attenuated but still marked elevated risk before day 36 after discharge (HR 1.32, 95% CI 1.15 to 1.52; risk difference 0.0026, 95% CI 0.0013 to 0.0039). The risk of MI or stroke was found to interact with age, with younger patients being associated with a higher risk than older patients (interaction p = 0.0004). INTERPRETATION: Compared with the general population with similar characteristics, patients recovering from sepsis had a markedly elevated risk of MI or stroke in the first 4 weeks after discharge from hospital. More close monitoring and pharmacologic prevention may be required for these patients at the specified time.

Preadmission Use of Calcium Channel Blocking Agents Is Associated With Improved Outcomes in Patients With Sepsis: A Population-Based Propensity Score-Matched Cohort Study.

OBJECTIVES: Use of calcium channel blockers has been found to improve sepsis outcomes in animal studies and one clinical study. This study determines whether the use of calcium channel blockers is associated with a decreased risk of mortality in patients with sepsis. DESIGN: Population-based matched cohort study. SETTING: National Health Insurance Research Database of Taiwan. PATIENTS: Hospitalized severe sepsis patients identified from National Health Insurance Research Database by International Classification of Diseases, Ninth Revision, Clinical Modification codes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The association between calcium channel blocker use and sepsis outcome was determined by multivariate-adjusted Cox proportional hazard models and propensity score analysis. To examine the influence of healthy user bias, beta-blocker was used as an active comparator. Our study identified 51,078 patients with sepsis, of which, 19,742 received calcium channel blocker treatments prior to the admission. Use of calcium channel blocker was associated with a reduced 30-day mortality after propensity score adjustment (hazard ratio, 0.94; 95% CI, 0.89-0.99), and the beneficial effect could extend to 90-day mortality (hazard ratio, 0.95; 95% CI, 0.89-1.00). In contrast, use of beta-blocker was not associated with an improved 30-day (hazard ratio, 1.06; 95% CI, 0.97-1.15) or 90-day mortality (hazard ratio, 1.00; 95% CI, 0.90-1.11). On subgroup analysis, calcium channel blockers tend to be more beneficial to patients with male gender, between 40 and 79 years old, with a low comorbidity burden, and to patients with cardiovascular diseases, diabetes, or renal diseases. CONCLUSIONS: In this national cohort study, preadmission calcium channel blocker therapy before sepsis development was associated with a 6% reduction in mortality when compared with patients who have never received calcium channel blockers.

Administration of Hypertonic Solutions for Hemorrhagic Shock: A Systematic Review and Meta-analysis of Clinical Trials.

BACKGROUND: Several clinical trials on hypertonic fluid administration have been completed, but the results have been inconclusive. The objective of this study is to summarize current evidence for treating hypovolemic patients with hypertonic solutions by performing a systematic review and meta-analysis. METHODS: Major electronic databases were searched from inception through June 2014. We included only randomized controlled trials involving hemorrhagic shock patients treated with hypertonic solutions. After screening 570 trials, 12 were eligible for the final analysis. Pooled effect estimates were calculated with a random effect model. RESULTS: The 12 studies included 6 trials comparing 7.5% hypertonic saline (HS) with 0.9% saline or Ringer's lactate solution and 11 trials comparing 7.5% hypertonic saline with dextran (HSD) with isotonic saline or Ringer's lactate. Overall, there were no statistically significant survival benefits for patients treated with HS (relative risk [RR], 0.96; 95% confidence interval [CI], 0.82-1.12) or HSD (RR, 0.92; 95% CI, 0.80-1.06). Treatment with hypertonic solutions was also not associated with increased complications (RR, 1.03; 95% CI, 0.78-1.36). Subgroup analysis on trauma patients in the prehospital or emergency department settings did not change these conclusions. There was no evidence of significant publication bias. Meta-regression analysis did not find any significant sources of heterogeneity. CONCLUSIONS: Current evidence does not reveal increased mortality when the administration of isotonic solutions is compared to HS or HSD in trauma patients with hemorrhagic shock. HS or HSD may be a viable alternative resuscitation fluid in the prehospital setting. Further studies are needed to determine the optimum volume and regimen of intravenous fluids for the treatment of trauma patients.

Risk of incident active tuberculosis disease in patients treated with non-steroidal anti-inflammatory drugs: a population-based study.

BACKGROUND: Mycobacterium tuberculosis (TB) is one of the world's most devastating public health threats. Our goal is to evaluate whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) affect the risk of new incident active TB disease. METHODS: We conducted a nested case-control analysis by using a 1 million longitudinally followed cohort, from Taiwan's national health insurance research database. Effects of NSAIDs on active TB were estimated by conditional logistic regression and adjusted using a TB-specific disease risk score (DRS). NSAIDs exposures were defined as having a prescription record of NSAIDs ≧ 7 days that ended between 31 and 90 days prior to the index date. RESULTS: A total of 123,419 users of traditional NSAIDs, 16,392 users of cyclooxygenase-2 selective inhibitor (Coxibs), and 4706 incident cases of active TB were identified. Compared with nonusers, use of traditional NSAIDs was associated with an increased risk of TB in the unadjusted analysis ([RR], 1.39; 95% [CI], 1.24 - 1.57 and DRS adjusted analysis ([ARR], 1.30; 95% [CI], 1.15- 1.47). However, use of Coxibs was not associated with a significant increase in the risk of TB after DRS adjustment ([ARR], 1.23; 95% [CI], 0.89 - 1.70). CONCLUSIONS: In this large population-based study, we found that subjects using traditional NSAIDs were associated with increased risk for active TB. We did not find evidence for a causative mechanism between traditional NSAIDs and TB, and more research is required to verify whether the association between traditional NSAIDs and TB is causal, or simply reflects an increased use of anti-inflammatory drugs in the early phases of TB onset.

Statin treatment is associated with a decreased risk of active tuberculosis: an analysis of a nationally representative cohort.

BACKGROUND: Epidemiological data suggest that statins improve the clinical outcome of respiratory infections. We sought to examine whether statin therapy decreases the risk of active TB. METHODS: We conducted a nested case-control study on data obtained from a national health insurance claims database between 1999 and 2011. The use of statins was classified as current, recent, past or chronic use. Three conditional logistic regression models were used to estimate the incidence rate ratios (RRs). The first assessed the effect of statin use without further adjustment; the second adjusted (individually) for 75 potential confounders; and the third adjusted for the Disease Risk Score (DRS). RESULTS: A total of 8098 new TB cases and 809 800 control patients were examined. All four types of statin users showed a decreased risk of active TB. Chronic use (>90 days in a calendar year) of statins was associated with the lowest unadjusted risk of TB (RR 0.74; 95% CI 0.63 to 0.87). The protective effect of active TB remained after adjusting for individual confounders (RR 0.66; 95% CI 0.56 to 0.78) and after DRS adjustment (RR 0.62; 95% CI 0.53 to 0.72). The effect estimates obtained for chronic and current use of statins were very similar. We also found that the active TB protection increased with increasing length of statin prescription. CONCLUSIONS: We found that statin therapy was associated with a decreased risk of active TB, and the length of statin therapy affected the TB protection. Given the observational nature of this study, the protective effect against active TB must be confirmed in future randomised trials.

Does procalcitonin, C-reactive protein, or interleukin-6 test have a role in the diagnosis of severe infection in patients with febrile neutropenia? A systematic review and meta-analysis.

PURPOSE: The study aims to determine the usefulness of procalcitonin (PCT) and other blood markers for identification of bacterial infection among patients with febrile neutropenia (FN). METHODS: The Medline, EMBASE, and Cochrane databases were searched for articles from 1966 to December 2012. We performed a search to identify articles that examined the diagnostic accuracy of PCT in patients with FN. Statistical analyses (fixed- or random-effect models) were conducted to summarize and calculate the sensitivity, specificity, likelihood ratios, and 95 % confidence intervals (CIs). RESULTS: Twenty-seven studies were included (1960 febrile episodes) for PCT analysis, 13 (1712 febrile episodes) for C-reactive protein (CRP) analysis, and five (314 febrile episodes) for interleukin (IL)-6 analysis. Increased PCT levels (odds ratio [OR] 11.5; 95 % CI 7.6 to 17.3), raised CRP levels (3.3; 2.7 to 4.2), and raised IL-6 levels (10.0; 5.5 to 18.0) were significantly associated with bacterial infection. Overall positive likelihood ratio was 5.49 (4.04-7.45) for PCT, 1.82 (1.42-2.33) for CRP, and 3.68 (2.41-5.60) for IL-6. Overall negative likelihood ratio was 0.40 (0.31-0.51) for PCT, 0.40 (0.26-0.61) for CRP, and 0.33 (0.23-0.46) for IL-6. CONCLUSIONS: Of the three potentially useful markers, PCT had the best positive likelihood ratio and can be used to confirm the diagnosis of bacterial infections in patients with FN. Due to unacceptably high negative likelihood ratio, medical decision for stopping antibiotics based on PCT alone in this high-risk population may not be possible.

Prognostic determinants of community-acquired bloodstream infection in type 2 diabetic patients in ED.

OBJECTIVES: The objective of the study is to describe the epidemiology and outcome of community-acquired bloodstream infection (BSI) in type 2 diabetic patients in emergency department (ED). METHODS: All patients admitted to the ED of the university hospital from June 2010 to June 2011 with a history of type 2 diabetes mellitus and microbiologically documented BSI were retrospectively enrolled. Demographic characteristics, Charlson comorbidity index, antibiotic therapy, clinical severity, microbiological etiology, and diabetes-related complications were recorded in a standardized form. The major outcome measure was 30-day survival. χ2 Or Student t test was used for univariate analysis, and Cox proportional hazards models were used for multivariate analysis. RESULTS: Among 250 enrolled emergency patients with BSI, the overall 30-day mortality rate was 15.5%. Twenty-seven patients (10.7%) developed diabetic ketoacidosis (DKA), and 22 patients (8.8%) developed hyperosmolar hyperglycemic state. On univariate analysis, DKA rather than hyperosmolar hyperglycemic state was associated with adverse outcome. Other risk factors include higher mean glycated hemoglobin level, presence of underlying malignancy, long-term use of steroids, lower respiratory tract infection, and higher Charlson scores. Multivariate analysis identified 3 independent risk factors for early mortality when severity, comorbidity, age, and sex were under control: DKA (hazard ratio, 3.89; 95% confidence interval, 1.6-8.9), inappropriate antibiotics (2.25, 1.05-4.82), and chronic use of steroid (3.89, 1.1-13.2). CONCLUSION: In type 2 diabetic patients with BSI, a substantial proportion of patients developed DKA. This condition was probably underrecognized by clinicians and constituted an independent risk factor for short-term mortality. Other identified risk factors are potentially correctable and may allow preventive efforts to individuals at greatest potential benefit.

Use of Calcium Channel Blockers and Risk of Active Tuberculosis Disease: A Population-Based Analysis.

Calcium channel blockers (CCBs) are known to reduce the availability of iron-an important mineral for intracellular pathogens. Nonetheless, whether the use of CCBs modifies the risk of active tuberculosis in the clinical setting remains unclear. To determine whether CCBs may modify the risk of active tuberculosis disease, we conducted a nested case-control study using the National Health Insurance Research Database of Taiwan between January 1999 and December 2011. Conditional logistic regression and disease risk score adjustment were used to calculate the risk of active tuberculosis disease associated with CCB use. Subgroup analyses investigated the effect of different types of CCBs and potential effect modification in different subpopulations. A total of 8164 new active tuberculosis cases and 816 400 controls were examined. Use of CCBs was associated with a 32% decrease in the risk of active tuberculosis (relative risk [RR], 0.68 [95% CI, 0.58-0.78]) after adjustment with disease risk score. Compared with nonuse of CCBs, the use of dihydropyridine CCBs was associated with a lower risk of tuberculosis (RR, 0.63 [95% CI, 0.53-0.79]) than nondihydropyridine CCBs (RR, 0.73 [95% CI, 0.57-0.94]). In contrast, use of ß-blockers (RR, 0.99 [95% CI, 0.83-1.12]) or loop diuretics (RR, 0.88 [95% CI, 0.62-1.26]) was not associated with lower risk of tuberculosis. In subgroup analyses, the risk of tuberculosis associated with the use of CCBs was similar among patients with heart failure or cerebrovascular diseases. Our study confirms that use of dihydropyridine CCBs decreases the risk of active tuberculosis.

Fluoroquinolone use and serious arrhythmias: A nationwide case-crossover study.

AIM: Fluoroquinolones have been associated with life-threatening ventricular arrhythmias and even sudden cardiac death. We aimed to assess the temporal relationship of fluoroquinolone use and serious arrhythmias via a case-crossover analysis of a large cohort of serious arrhythmias patients. METHODS: In a national administrative database, we compare the distributions of fluoroquinolone exposure for the same patient across a 30-day period before the serious arrhythmia event and 5 randomly selected 30-day periods before the serious arrhythmia event. Odds ratios (ORs) and 95% Confidence Intervals (CIs) were estimated using conditional logistic regression analysis. RESULTS: From a total of 2 million participants, 7657 patients with serious arrhythmias were identified. Use of fluoroquinolones within the 30-day period before the event was significantly associated with increased risk for serious arrhythmia (OR:3.03, 95% CI:2.48, 3.71). The risk association was attenuated, but remained significant after adjustment for time-varying confounders (OR:1.48, 95% CI:1.18, 1.86). A consistent increase in risk of serious arrhythmia was observed for all time windows investigated (7 days, 14 days, 30 days, 60 days and 90 days). CONCLUSIONS: Exposure to fluoroquinolones was substantially associated with serious arrhythmic events, independent of the temporal proximity of fluoroquinolone prescription.

Integrative Genome-Wide Association Studies of eQTL and GWAS Data for Gout Disease Susceptibility.

There is a paucity of genome-wide association study on Han Chinese gout patients. We performed a genome-wide association meta-analysis on two Taiwanese cohorts consisting of 758 gout cases and 14166 controls of Han Chinese ancestry. All the participants were recruited from the Taiwan Biobank. For pathway analysis, we applied ICSNPathway (Identify candidate Causal SNPs and Pathways) analysis, and to investigate whether expression-associated genetic variants contribute to gout susceptibility, we systematically integrated lymphoblastoid expression quantitative trait loci (eQTL) and genome-wide association data of gout using Sherlock, a Bayesian statistical frame-work. In the meta-analysis, we found 4 SNPs that reached genome-wide statistical significance (P < 5.0 × 10-8). These SNPs are in or close to ABCG2, PKD2 and NUDT9 gene on chromosome 4. ICSNPathway analysis identified rs2231142 as the candidate causal SNP, and ABCG2 as the candidate gene. Sherlcok analysis identified three genes, which were significantly associated with the risk of gout (PKD2, NUTD9, and NAP1L5). To conclude, we reported novel susceptible loci for gout that has not been previously addressed in the literature.

Epidemiology of Emergency Department Sepsis: A National Cohort Study Between 2001 and 2012.

The aim of this study is to examine the incidence trend of sepsis over 11 years and compared mortality outcomes among Taiwanese patients with sepsis admitted from emergency department (ED) and non-ED routes. We used a nationwide health insurance database from Taiwan, which comprise of 23 million beneficiaries. Patients with sepsis were identified by ICD-9 CM codes for infection and organ dysfunction from 2001 to 2012. We performed propensity score matching and compared mortality rates between ED-admitted and non ED-admitted patients.During the 11-year study period, we identified 1,256,684 patients with sepsis. 493,397 (29.3%) were admitted through the ED, and 763,287 (70.7%) were admitted directly to the floor. For patients with sepsis, mortality in ED-admitted patients decreased from 27.2% in 2002 to 21.1% in 2012 while that in non-ED admitted patients decreased from 35.3% in 2002 to 30.7% in 2012. Although patients with sepsis admitted through the ED had a higher incidence of organ dysfunction than patients who were directly admitted, they had more favorable outcomes in mortality, length of intensive care unit stay, and hospital stay. After propensity score matching, ED-admitted patients had a 7% lower risk of 90-day mortality (HR, 0.93, 95% CI, 0.89-0.97) compared with directly admitted patients. During the study period, mortality declined faster among ED admitted sepsis patients than directly admitted sepsis patients. Results of this study should be interpreted in light of limitations. Like other administrative database studies, treatment details are not available. Further clinical studies evaluating the treatment and outcome difference between ED and non-ED admitted sepsis patients are warranted.

A Population-Based Cohort Study on the Drug-Specific Effect of Statins on Sepsis Outcome.

BACKGROUND: Whether statin treatment, proved by recent experimental studies to have an antimicrobial activity, exerts a drug- or a class-specific effect in sepsis remains unknown. METHODS: Short-term mortality in patients with sepsis was analyzed using data from the National Health Insurance Research Database. Use of statins was defined as the cumulative use of a specific statin (atorvastatin, simvastatin, or rosuvastatin) for > 30 days prior to the index sepsis admission. We determined the association between statin and sepsis outcome by multivariate-adjusted Cox models and propensity score (PS)-matched analysis, using a 1:1:1 PS matching technique. RESULTS: A total of 52,737 patients with sepsis fulfilled the inclusion criteria, of which 1,855 were prescribed atorvastatin, 916 were prescribed simvastatin, and 732 were prescribed rosuvastatin. Compared with nonusers, simvastatin (hazard ratio [HR], 0.72; 95% CI, 0.58-0.90) and atorvastatin (HR, 0.78; 95% CI, 0.68-0.90) were associated with an improved 30-day survival, whereas rosuvastatin was not (HR, 0.87; 95% CI, 0.73-1.04). Using rosuvastatin as the reference, atorvastatin (HR, 0.79; 95% CI, 0.64-0.99) and simvastatin (HR, 0.77; 95% CI, 0.59-0.99) had superior effectiveness in preventing mortality. CONCLUSIONS: Compatible with in vitro experimental findings, our results suggest that the drug-specific effect of statins on sepsis is not correlated to their lipid-lowering potency.

Pentoxifylline decreases post-operative intra-abdominal adhesion formation in an animal model.

BACKGROUND: Intra-abdominal adhesions develop after nearly every abdominal surgery, commonly causing female infertility, chronic pelvic pain, and small bowel obstruction. Pentoxifylline (PTX) is a methylxanthine compound with immunomodulatory and antifibrotic properties. The aim of this study was to investigate whether PTX can reduce post-operative intra-abdominal adhesion formation via collagen deposition, tissue plasminogen activator (tPA) level, inflammation, angiogenesis, and fibrosis. METHODS: Seventy male BALB/c mice were randomized into one of three groups: (1) sham group without peritoneal adhesion model; (2) peritoneal adhesion model (PA group); (3) peritoneal adhesion model with PTX (100 mg/kg/day i.p.) administration was started on preoperative day 2 and continued daily (PA + PTX group). On postoperative day 3 and day 7, adhesions were assessed using the Lauder scoring system. Parietal peritoneum was obtained for histological evaluation with hematoxylin and eosin (HE) and picrosirius red staining. Fibrinolysis was analyzed by tPA protein levels in the peritoneum by ELISA. Immunohistological analysis was also conducted using markers for angiogenesis (ki67+/CD31+), inflammation (F4/80+) and fibrosis (FSP-1+ and α-SMA+). All the comparisons were made by comparing the PA group with the PTX treated PA group, and p < 0.05 was considered statistically significant. RESULTS: Intra-abdominal adhesions were markedly reduced by PTX treatment. Compared with the PA group, PTX treatment had lower adhesion scores than the PA group on both day 3 and day 7 (p < 0.05). Histological evaluations found that PTX treatment reduced collagen deposition and adhesion thickening. ELISA analysis showed that PTX treatment significantly increased the level of tPA in the peritoneum. In addition, in the immunohistological analysis, PTX treatment was found to significantly decrease the number of ki67+/CD31+ cells at the site of adhesion. Finally, we also observed that in the PTX treated group, there was a reduction in the expression of F4/80+, FSP-1+, and α-SMA+ cells at the site of adhesion. CONCLUSION: PTX may decrease intra-abdominal adhesion formation via increasing peritoneal fibrinolytic activity, suppressing angiogenesis, decreasing collagen synthesis, and reducing peritoneal fibrosis. Our findings suggest that PTX can be used to decrease post-operative intra-abdominal adhesion formation.

Oral Fluoroquinolone and the Risk of Aortic Dissection.

BACKGROUND: Previous studies raised safety concerns on the association between fluoroquinolone treatment and serious collagen disorders, aortic aneurysm and dissection (AA/AD). OBJECTIVES: This study sought to evaluate this association via a case-crossover analysis in a large national administrative database. METHODS: A case-crossover design was used to compare the distributions of fluoroquinolone exposure for the same patient across a 60-day period before the AA/AD event (hazard period) and 1 randomly selected 60-day period (referent period) between 60 to 180 days before the AA/AD events. In the sensitivity analysis, the authors repeated the main analysis using a 1:5 ratio of hazard period to referent period, to adjust for the effect of time-variant confounders. A disease-risk score-matched time control analysis was performed to investigate the potential time-trend bias. The risks were calculated by a conditional logistic regression model. RESULTS: A total of 1,213 hospitalized AA/AD patients were identified between 2001 and 2011. In the main case-crossover analysis, exposure to fluoroquinolone was more frequent during the hazard periods than during the referent periods (1.6% vs. 0.6%; odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.14 to 6.46). In the sensitivity analysis, after adjustment for infections and co-medications, the risk remains significant (OR: 2.05; 95% CI: 1.13 to 3.71). An increased risk of AA/AD was observed for prolonged exposure to fluoroquinolones (OR: 2.41 for 3- to 14-day exposure; OR: 2.83 for >14-day exposure). Susceptible period analysis revealed that the use of fluoroquinolone within 60 days was associated with the highest risk of AA/AD. In the case-time-control analysis, there was no evidence that the observed association is due to temporal changes in fluoroquinolone exposure. CONCLUSIONS: Exposure to fluoroquinolone was substantially associated with AA/AD. This risk was modified by the duration of fluoroquinolone use and the length of the hazard period.