E-Da Hospital

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Fecal microbiota transplantation (FMT) is a method to directly change the recipient's gut microbiota to normalize the composition and gain a therapeutic benefit. The history of FMT has been traced back to the 4th century and has been highly regarded since 2013, when the United States Food and Drug Administration approved FMT for treating recurrent and refractory Clostridium difficile infection. Since then, the range of FMT applications extended rapidly and broadly not only in gastrointestinal disorders, but also in extra-gastrointestinal diseases. Donor selection with questionnaire, interview, blood tests, and stool examinations should be strictly performed before FMT to reduce and prevent occurrence of any adverse events. Step-by-step cautious fecal and recipient preparation along with adequately choosing delivery methods based on individual clinical situations are key points of the FMT process. Although current evidence deems FMT as a generally safe therapeutic method with few adverse effects, the long-term outcomes of FMT have not been completely elucidated. Therefore, establishing periodicity and length of regular follow-up after FMT to monitor the clinical efficacy and long-term adverse events are other essential issues. In the future, we will look forward to personalized FMT for different patients and conditions according to varied hosts and diseases.

BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).

Lipids, as the basic component of cell membranes, play an important role in human health as well as brain function. The brain is highly enriched in lipids, and disruption of lipid homeostasis is related to neurologic disorders as well as neurodegenerative diseases such as Alzheimer's disease (AD). Aging is associated with changes in lipid composition. Alterations of fatty acids at the level of lipid rafts and cerebral lipid peroxidation were found in the early stage of AD. Genetic and environmental factors such as apolipoprotein and lipid transporter carrying status and dietary lipid content are associated with AD. Insight into the connection between lipids and AD is crucial to unraveling the metabolic aspects of this puzzling disease. Recent advances in lipid analytical methodology have led us to gain an in-depth understanding on lipids. As a result, lipidomics have becoming a hot topic of investigation in AD, in order to find biomarkers for disease prediction, diagnosis, and prevention, with the ultimate goal of discovering novel therapeutics.

OBJECTIVE: Emerging evidence suggests that gut microbiome composition alterations affect neurodegeneration through neuroinflammation in the pathogenesis of Parkinson's disease (PD). Here, we evaluate gut microbiota alterations and host cytokine responses in a population of Taiwanese patients with PD. METHODS: Fecal microbiota communities from 80 patients with PD and 77 age and gender-matched controls were assessed by sequencing the V3-V4 region of the 16S ribosomal RNA gene. Diet and comorbidities were controlled in the analyses. Plasma concentrations of IL-1β, IL-2, IL-4, IL-6, IL-13, IL-18, GM-CSF, IFNγ, and TNFα were measured by a multiplex immunoassay and relationships between microbiota, clinical characteristics, and cytokine levels were analyzed in the PD group. We further examined the cytokine changes associated with the altered gut microbiota seen in patients with PD in another independent cohort of 120 PD patients and 120 controls. RESULTS: Microbiota from patients with PD was altered relative to controls and dominated by Verrucomicrobia, Mucispirillum, Porphyromonas, Lactobacillus, and Parabacteroides. In contrast, Prevotella was more abundant in controls. The abundances of Bacteroides were more increased in patients with non-tremor PD subtype than patients with tremor subtype. Bacteroides abundance was correlated with motor symptom severity defined by UPDRS part III motor scores (rho = 0.637 [95% confidence interval 0.474 to 0.758], P < 0.01). Altered microbiota was correlated with plasma concentrations of IFNγ and TNFα. There was a correlation between Bacteroides and plasma level of TNFα (rho = 0.638 [95% CI: 0.102-0.887], P = 0.02); and a correlation between Verrucomicrobia abundance and plasma concentrations of IFNγ (rho = 0.545 [95% CI - 0.043-0.852], P = 0.05). The elevated plasma cytokine responses were confirmed in an additional independent 120 patients with PD and 120 controls (TNFα: PD vs. control 8.51 ± 4.63 pg/ml vs. 4.82 ± 2.23 pg/ml, P < 0.01; and IFNγ: PD vs. control: 38.45 ± 7.12 pg/ml vs. 32.79 ± 8.03 pg/ml, P = 0.03). CONCLUSIONS: This study reveals altered gut microbiota in PD and its correlation with clinical phenotypes and severity in our population. The altered plasma cytokine profiles associated with gut microbiome composition alterations suggest aberrant immune responses may contribute to inflammatory processes in PD.

OBJECTIVE: Type 2 diabetes mellitus is associated with a higher risk of hepatocellular carcinoma (HCC), which is attenuated by the use of metformin. However, there are no studies addressing the effect of metformin on hepatocarcinoma cells from the antitumoural perspective. DESIGN: In the nationwide case-control study, the authors recruited 97,430 HCC patients and 19,860 age-, gender- and physician visit date-matched controls. The chemopreventive effects of metformin were examined by multivariate analysis and stratified analysis. The in vitro effects of metformin on cell proliferation and cell cycle were studied in HepG2 and Hep3B hepatoma cell lines. RESULTS: The OR of diabetes in HCC patients was 2.29 (95% CI 2.25 to 2.35, p<0.001). Each incremental year increase in metformin use resulted in 7% reduction in the risk of HCC in diabetic patients (adjusted OR=0.93, 95% CI 0.91 to 0.94, p<0.0001). In the multivariate stratified analysis, metformin use was associated with a reduced risk of HCC in diabetic patients in nearly all subgroups. Cell line studies showed that metformin inhibits hepatocyte proliferation and induces cell cycle arrest at G0/G1 phase via AMP-activated protein kinase and its upstream kinase LKB1 to upregulate p21/Cip1 and p27/Kip1 and downregulate cyclin D1 in a dose-dependent manner, but independent of p53. Combined treatment of oral metformin with doxorubicin functioned more efficiently than either agent alone, in vivo. CONCLUSIONS: Use of metformin is associated with a decreased risk of HCC in diabetic patients in a dose-dependent manner, via inhibition of hepatoma cells proliferation and induction of cell cycle arrest at G0/G1 phase.

BACKGROUND: Obese and overweight people have a higher risk of both chronic physical illness and mental illness. Obesity is reported to be positively associated with psychiatric disorders, especially in people who seek obesity treatment. At the same time, obesity treatment may be influenced by psychological factors or personality characteristics. This study aimed to understand the prevalence of mental disorders among ethnic Chinese who sought obesity treatment. METHODS: Subjects were retrospectively recruited from an obesity treatment center in Taiwan. The obesity treatments included bariatric surgery and non-surgery treatment. All subjects underwent a standardized clinical evaluation with two questionnaires and a psychiatric referral when needed. The psychiatric diagnosis was made thorough psychiatric clinic interviews using the SCID. A total of 841 patients were recruited. We compared the difference in psychiatric disorder prevalence between patients with surgical and non-surgical treatment. RESULTS: Of the 841 patients, 42% had at least one psychiatric disorder. Mood disorders, anxiety disorders and eating disorders were the most prevalent categories of psychiatric disorders. Females had more mood disorders and eating disorders than males. The surgical group had more binge-eating disorder, adjustment disorder, and sleep disorders than the non-surgical group. CONCLUSION: A high prevalence of psychiatric disorders was found among ethnic Chinese seeking obesity treatment. This is consistent with study results in the US and Europe.

BACKGROUND: Reactive oxygen species are important mediators exerting toxic effects on various organs during ischemia-reperfusion (IR) injury. We hypothesized that adipose-derived mesenchymal stem cells (ADMSCs) protect the kidney against oxidative stress and inflammatory stimuli in rat during renal IR injury. METHODS: Adult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus immediate intra-renal administration of 1.0 × 106 autologous ADMSCs, followed by intravenous ADMSCs at 6 h and 24 h after IR). The duration of ischemia was 1 h, followed by 72 hours of reperfusion before the animals were sacrificed. RESULTS: Serum creatinine and blood urea nitrogen levels and the degree of histological abnormalities were markedly lower in group 3 than in group 2 (all p < 0.03). The mRNA expressions of inflammatory, oxidative stress, and apoptotic biomarkers were lower, whereas the anti-inflammatory, anti-oxidative, and anti-apoptotic biomarkers were higher in group 3 than in group 2 (all p < 0.03). Immunofluorescent staining showed a higher number of CD31+, von Willebrand Factor+, and heme oxygenase (HO)-1+ cells in group 3 than in group 2 (all p < 0.05). Western blot showed notably higher NAD(P)H quinone oxidoreductase 1 and HO-1 activities, two indicators of anti-oxidative capacity, in group 3 than those in group 2 (all p < 0.04). Immunohistochemical staining showed higher glutathione peroxidase and glutathione reductase activities in group 3 than in group 2 (all p < 0.02) CONCLUSION: ADMSC therapy minimized kidney damage after IR injury through suppressing oxidative stress and inflammatory response.

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known. METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo. CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

BACKGROUND: Discrimination between neoplastic and non-neoplastic lesions is crucial in colorectal cancer screening. Application of narrow-band imaging (NBI) in colonoscopy visualises mucosal vascular networks in neoplastic lesions and may improve diagnostic accuracy. AIM: To compare the diagnostic efficacy of NBI in differentiating neoplastic from non-neoplastic colorectal lesions with diagnostic efficacies of standard modalities, conventional colonoscopy, and chromoendoscopy. METHODS: In this prospective study, 180 colorectal lesions from 133 patients were observed with conventional colonoscopy, and under low-magnification and high-magnification NBI and chromoendoscopy. Lesions were resected for histopathological analysis. Endoscopic images were stored electronically and randomly allocated to two readers for evaluation. Sensitivity, specificity and diagnostic accuracy of each endoscopic modality were assessed by reference to histopathology. RESULTS: NBI and chromoendoscopy scored better under high magnification than under low magnification in comparison with conventional colonoscopy. The diagnostic accuracy of NBI with low or high magnification was significantly higher than that of conventional colonoscopy (low magnification: p = 0.0434 for reader 1 and p = 0.004 for reader 2; high magnification: p<0.001 for both readers) and was comparable to that of chromoendoscopy. CONCLUSION: Both low-magnification and high-magnification NBI were capable of distinguishing neoplastic from non-neoplastic colorectal lesions; the diagnostic accuracy of NBI was better than that of conventional colonoscopy and equivalent to that of chromoendoscopy. The role of NBI in screening colonoscopy needs further evaluation.

CONTEXT: The occupational health literature has long been dominated by stress-related topics. A more contemporary perspective suggests using a positive approach in the form of a health model focused on what is right with people, such as feelings of well-being and satisfaction. OBJECTIVES: Using a positive perspective and multi-source data collection, this study investigated the inter-relationships among emotional intelligence (EI), patient satisfaction, doctor burnout and job satisfaction. METHODS: In this observational study, 110 internists and 2872 out-patients were surveyed in face-to-face interviews. RESULTS: Higher self-rated EI was significantly associated with less burnout (p<0.001) and higher job satisfaction (p<0.001). Higher patient satisfaction was correlated with less burnout (p<0.01). Less burnout was found to be associated with higher job satisfaction (p<0.001). CONCLUSIONS: This study identified EI as a factor in understanding doctors' work-related issues. Given the multi-dimensional nature of EI, refinement of the definition of EI and the construct validity of EI as rated by others require further examination.

BACKGROUND: The use of ultrasound-guided ablation procedures to treat both benign and malignant thyroid conditions is gaining increasing interest. This document has been developed as an international interdisciplinary evidence-based statement with a primary focus on radiofrequency ablation and is intended to serve as a manual for best practice application of ablation technologies. METHODS: A comprehensive literature review was conducted to guide statement development and generation of best practice recommendations. Modified Delphi method was applied to assess whether statements met consensus among the entire author panel. RESULTS: A review of the current state of ultrasound-guided ablation procedures for the treatment of benign and malignant thyroid conditions is presented. Eighteen best practice recommendations in topic areas of preprocedural evaluation, technique, postprocedural management, efficacy, potential complications, and implementation are provided. CONCLUSIONS: As ultrasound-guided ablation procedures are increasingly utilized in benign and malignant thyroid disease, evidence-based and thoughtful application of best practices is warranted.

UNLABELLED: Hepatitis C virus (HCV) infection is causally associated with insulin resistance and diabetes mellitus. This population-based cohort study aimed to investigate whether antiviral therapy for HCV infection was associated with improved clinical outcomes related to diabetes. From the Taiwan National Health Insurance Research Database, 2,267,270 Taiwanese residents diagnosed with diabetes mellitus were screened for eligibility. HCV infection was defined by a specific diagnosis code and measurement of serum antibody. After excluding patients with serious comorbidity, we enrolled a total of 1,411 eligible patients who received pegylated interferon plus ribavirin (treated cohort), and matched them 1:1 with 1,411 untreated controls by propensity scores (untreated cohort). We also matched the treated cohort 1:4 with 5,644 diabetic patients without HCV infection (uninfected cohort). Participants were followed up for the occurrence of endstage renal disease (ESRD), ischemic stroke, and acute coronary syndrome (ACS) after receiving antiviral treatment or the corresponding calendar date. From 2003 to 2011, the 8-year cumulative incidences of ESRD in the treated, untreated, and uninfected cohorts were 1.1% (95% confidence interval [CI], 0.3-2.0%), 9.3% (95% CI, 5.9-12.7%), and 3.3% (95% CI, 2.3-4.3%), respectively (P < 0.001); those of stroke were 3.1% (95% CI, 1.1-5.0%), 5.3% (95% CI, 3.0-7.5%), and 6.1% (95% CI, 4.8-7.4%), respectively (P = 0.01); and those for ACS were 4.1% (95% CI, 2.1-6.1%), 6.6% (95% CI, 3.7-9.5%), and 7.4% (95% CI, 5.9-9.0%), respectively (P = 0.05). As compared with the untreated cohort, antiviral treatment was associated with multivariate-adjusted hazard ratios of 0.16 (95% CI, 0.07-0.33%) for ESRD, 0.53 (95% CI, 0.30-0.93) for ischemic stroke, and 0.64 (95% CI, 0.39-1.06) for ACS. CONCLUSION: Antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients.

INTRODUCTION: Currently the treatment of chronic pain is inadequate and compromised by debilitating central nervous system side effects. Here we discuss new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain. Areas covered: The DRGs contain the cell bodies of primary sensory neurons including nociceptive neurons. After painful injuries, primary sensory neurons demonstrate maladaptive molecular changes in DRG cell bodies and in their axons. These changes result in hypersensitivity and hyperexcitability of sensory neurons (peripheral sensitization) and are crucial for the onset and maintenance of chronic pain. We discuss the following new strategies to target DRGs and primary sensory neurons as a means of alleviating chronic pain and minimizing side effects: inhibition of sensory neuron-expressing ion channels such as TRPA1, TRPV1, and Nav1.7, selective blockade of C- and Aβ-afferent fibers, gene therapy, and implantation of bone marrow stem cells. Expert opinion: These peripheral pharmacological treatments, as well as gene and cell therapies, aimed at DRG tissues and primary sensory neurons can offer better and safer treatments for inflammatory, neuropathic, cancer, and other chronic pain states.

BACKGROUND: Primary liver abscess caused by Klebsiella pneumoniae is an infection that is emerging worldwide and that is associated with severe morbidity and considerable mortality. METHODS: A retrospective analysis of 110 episodes of primary liver abscess caused by K. pneumoniae that required hospitalization during 2001-2002 was conducted to identify predictors of metastatic infection, mortality, and the efficacy of first-generation cephalosporins and percutaneous drainage. The potential role of Klebsiella rmpA and magA genes was also evaluated. RESULTS: The study included 59 men and 51 women, with a mean age of 61.8 years. Diabetes was noted in 67 patients (60.9%). Metastatic infection occurred in 17 patients (15.5%), with meningitis accounting for 11 patients (64.7%) and endophthalmitis accounting for 4 patients (23.5%). The overall mortality rate was 10.0% (11 patients). Most of the severe complications occurred within the first 3 days after hospital admission. Ninety-two patients (83.6%) received treatment with cefazolin for >3 days. Four patients (4.3%) of the group who received cefazolin had metastatic infection, 1 patient (1.1%) experienced septic shock, and 3 (3.3%) experienced acute respiratory failure. Five (5.4%) of those 92 patients died. Multivariable analysis revealed that rmpA (odds ratio [OR], 28.85), Acute Physiologic and Chronic Health Evaluation (APACHE) II score >or=20 (OR, 8.08), and septic shock (OR, 4.33) were statistically significant predictors of metastatic infection. Metastatic infection (OR, 6.73), severity of disease (APACHE II score >or=16; OR, 11.82), septic shock (OR, 8.30), acute respiratory failure (OR, 69.92), and gas formation revealed on imaging (OR, 13.26) predicted mortality. Pigtail drainage protected against both metastatic infection (OR, 0.25) and mortality (OR, 0.14). CONCLUSION: Management of primary liver abscess caused by K. pneumoniae with use of first-generation cephalosporins and percutaneous drainage was associated with low rates of mortality, metastatic infection, and complications. These rates are comparable to those reported for third-generation cephalosporins.

OBJECTIVE: Epicardial adipose tissue (EAT) is a part of visceral fat deposited around the heart between the pericardium and myocardium along the distribution of coronary arteries. EAT thickness is reported to be associated with coronary atherosclerosis; however, no study has measured EAT volume in patients with type 2 diabetes or investigate its association with coronary artery disease. DESIGN: A hospital-based case control study. PATIENTS: A total of 49 patients with type 2 diabetes mellitus (T2DM) and 78 nondiabetic controls were studied. MEASUREMENTS: Cardiac multislice computed tomography was used to measure EAT volume, Gensini score, coronary artery calcium score and, coronary lesions. The relationships between EAT volume, markers of coronary atherosclerosis and anthropometric and biochemical parameters of metabolic syndrome (MetS) were investigated. RESULTS: EAT volume was significantly higher in patients with T2DM than in nondiabetic subjects (166.1 +/- 60.6 cm(3) vs. 123.4 +/- 41.8 cm(3), P < 0.0001). Logistic regression analysis revealed independent and significant associations between EAT and diabetic status. EAT volume was significantly associated with components of MetS (BMI, waist circumference, fasting serum glucose, total cholesterol, HDL-cholesterol, and triglycerides levels), Gensini score, coronary lesions, coronary disease and coronary calcium scores. Univariate, multivariate and trend analyses confirmed that EAT volume was associated with MetS component clustering and the coronary atherosclerosis index. CONCLUSIONS: The analytical results indicate that EAT volume is increased in T2DM patients and is associated with unfavourable components of MetS and coronary atherosclerosis. The close anatomical relationship between EAT and the coronary arteries, combined with other evidence indicating that EAT is a biologically active adipokine-secreting tissue, suggest that EAT participates in the pathogenesis of diabetic coronary atherosclerosis.

OBJECTIVE: To elucidate the association between antiviral therapy and extrahepatic outcomes in individuals infected with HCV. METHODS: This nationwide cohort study screened 293,480 Taiwanese residents with HCV infection and excluded those with substantial comorbidity. A total of 12,384 eligible patients who had received pegylated interferon plus ribavirin between 1 October 2003 and 31 December 2010 were enrolled in the treated cohort; they were matched 1 : 2 with 24,768 untreated controls in the propensity score and post-diagnosis treatment-free period. The incidences of end-stage renal disease (ESRD), acute coronary syndrome (ACS), ischaemic stroke and catastrophic autoimmune diseases were calculated after adjustment for competing mortality. RESULTS: The treated and untreated cohorts were followed up for a mean (±SD) duration of 3.3 (±2.5) and 3.2 (±2.4) years, respectively, until 31 December 2011. The calculated 8-year cumulative incidences of ESRD, ACS, ischaemic stroke and autoimmune catastrophes between treated and untreated patients were 0.15% vs. 1.32% (p<0.001), 2.21% vs. 2.96% (p=0.027), 1.31% vs. 1.76% (p=0.001) and 0.57% vs. 0.49% (p=0.816), respectively. Multivariate-adjusted Cox regression revealed that antiviral treatment was associated with lower risks of ESRD (HR 0.15; 95% CI 0.07 to 0.31; p<0.001), ACS (HR 0.77; 95% CI 0.62 to 0.97; p=0.026) and ischaemic stroke (HR 0.62; 95% CI 0.46 to 0.83; p=0.001), but unrelated to autoimmune catastrophes. These favourable associations were invalid in incompletely treated patients with duration <16 weeks. CONCLUSIONS: Antiviral treatment for HCV is associated with improved renal and circulatory outcomes, but unrelated to catastrophic autoimmune diseases.

INTRODUCTION: Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti-programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and EGFR T790M mutation-positive advanced NSCLC and disease progression after EGFR-TKI therapy. METHODS: Patients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective. RESULTS: CAURAL recruitment was terminated early because of increased incidence of interstitial lung disease-like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% [grade ≥3 in 6% of patients]) in the osimertinib arm and rash (67% [grade ≥3 in 0 patients]) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm. CONCLUSION: Limited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future.

OBJECTIVE: To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment. DESIGN: National prospective cohort study. SETTING: 15 medical centres in different regions of Taiwan, from July 2009 to August 2014. PARTICIPANTS: 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants' peripheral blood was used to assess the presence of HLA-B*58:01. MAIN OUTCOME MEASURES: Incidence of allopurinol induced SCARs with and without screening. RESULTS: Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test). CONCLUSIONS: Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.

OBJECTIVE: To investigate the entire process of autophagy in the left ventricle of septic mice, and the functional significance of autophagy by using pharmacological agents. BACKGROUND: Myocardial dysfunction is a common feature in sepsis and contributes to an increased risk of developing multiple organ failure. Autophagy functions predominantly as a prosurvival pathway in the heart during cellular stress. A dynamic process of autophagy that involves the complete activation of autophagy from autophagosome formation to fusion with lysosomes has driven the development of new approaches to detecting autophagy. METHODS: Male mice were subjected to cecal ligation and puncture (CLP) or sham operation. At 1 hour after CLP operation, mice received either rapamycin (induction of autophagy), bafilomycin A1 (inhibition of autophagosomal degradation), or vehicle. RESULTS: The formation of autophagosomes was increased whereas the degradation of autophagosomes was decreased in the left ventricle at 24 hours after CLP. This was consistent with the morphologic finding that septic hearts revealed an increase in autophagosomes but few autolysosomes, indicating incompletion of the autophagic process. Rapamycin, which induced complete activation of autophagy, restored CLP-induced depressed cardiac performances. This cardioprotective effect was also seen in increased ATP levels, and decreased inflammatory responses. Bafiomycin A1, which resulted in incompletion of the autophagic process, did not show any above beneficial effects in CLP mice. CONCLUSIONS: Incompletion of the autophagic process may contribute to sepsis-induced cardiac dysfunction. Treatment with rapamycin may serve a cardioprotective role in sepsis, possibly through the effect of complete induction of autophagy.