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Ching-Yu Ho,1,2,&ast; Yuan-Pin Hung,3– 5,&ast; Po-Lin Chen,3,5 Chih-Chia Hsieh,3,6 Chung-Hsun Lee,3,6 Ching-Chi Lee,3,7 Wen-Chien Ko3,5 1Department of Adult Critical Care Medicine, Tainan Sin-Lau Hospital, Tainan, 70142, Taiwan; 2Department of Nursing, National Tainan Junior College of Nursing, Tainan, 700007, Taiwan; 3Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70403, Taiwan; 4Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, 70043, Taiwan; 5Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; 6Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70403, Taiwan; 7Clinical Medicine Research Centre, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70403, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ching-Chi Lee, Clinical Medicine Research Centre, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138, Sheng Li Road, Tainan, 70403, Taiwan, Tel +886 6-2353535 ext. 6058, Fax +886 6-2380239, Email chichingbm85@gmail.com Wen-Chien Ko, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138, Sheng Li Road, Tainan, 70403, Taiwan, Tel +886 6-2353535 ext. 3596, Fax +886 6-2752038, Email winston3415@gmail.comPurpose: To investigate the different impact of delayed administration of appropriate antimicrobial therapy (AAT) on short-term mortality of bacteraemia patients initially presenting with various body temperatures (BTs).Materials and Methods: A six-year, two-center cohort consisting of adults with community-onset bacteraemia in emergency departments (EDs) was retrospectively collected. Through the multivariable analyses, clinical impacts of delayed AAT, assessed by the time gap between the first dose of AAT and ED arrival, on 30-day mortality (primary outcomes) were respectively examined in the different groups of initial BTs (iBTs).Results: Of the 3171 adults, despite the similarities of delayed AAT in six iBT categories, hourly AAT delay was associated with an average increase in 30-day mortality rates of 0.24% in the group of iBT < 36.0℃, 0.40% in the 36.0℃– 36.9℃ group, 0.48% in the 37.0℃– 37.9℃ group, 0.59% in the 38.0℃– 38.9℃ group, 0.58% in the 39.0℃– 39.9℃ group, and 0.71% in the ≥ 40.0℃ group, after respective adjusting independent predictors of mortality. Furthermore, for 589 patients who inappropriately received empirical antimicrobial treatment (ie, delayed AAT ≥ 24 hours), with a cutoff of 34.0℃, each 1℃ increase in iBTs was independently associated with an average increase in 30-day mortality rates of 42%.Conclusion: For adults with community-onset bacteraemia, the iBT-related differences in the prognostic impacts of delayed administration of appropriate antimicrobials might be evident.Keywords: body temperature, empirical, antibiotic, community-onset, bloodstream infection, mortality

Te-Fu Tsai,1,2 Po-Chun Chen,3,4 Yi-Chia Lin,1,2 Kuang-Yu Chou,1,2 Hung-En Chen,1 Chao-Yen Ho,1,5 Ji-Fan Lin,3 Thomas I-Sheng Hwang1,2,6 1Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; 2Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan; 3Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; 4Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan; 5Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 6Department of Urology, Taipei Medical University, Taipei, TaiwanCorrespondence: Thomas I-Sheng HwangDivision of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11102, TaiwanTel +886-2-28332211 Ext 2065Fax +886-2-28389404Email thomashwang0828@gmail.comPo-Chun Chen Email blibra1002@gmail.comPurpose: Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, a transcription factor capable of upregulating antioxidant response element (ARE)-mediated expression and cytoprotective proteins, plays critical roles in chemoprevention, inflammation and aging. NRF2 has recently been proposed as a novel target for cancer chemoprevention. The fungicide miconazole has shown promising antiproliferative effects in cancer cells.Materials and Methods: After miconazole treatment, the p62-KEAP1-NRF2 activation was analyzed by qPCR and Western blot. The nuclear translocation indicating NRF2 activation was further confirmed by immunofluorescence. Finally, the ROS production was detected by CM-H2DCFDA staining.Results: We demonstrate in this study that miconazole dramatically increases NRF2 activation in bladder cancer cells, in a dose- and time-dependent manner. Interestingly, levels of expression of p62, a noncanonical pathway that mediates NRF2 activation, appeared to increase in accordance with NRF2. We also investigated levels of the negative regulator kelch-like ECH-associated protein 1 (KEAP1), which is involved in NRF2 activation. As expected, a decrease in KEAP1 expression was found after miconazole exposure. Confirmation of NRF2 nuclear translocation was monitored by immunofluorescence. Miconazole-induced generation of reactive oxygen species (ROS) promoted NRF2 activation. Pretreatment of bladder cancer cells with ROS scavengers abolished NRF2 expression and nuclear translocation, indicating that miconazole activates the noncanonical p62-KEAP1-NRF2 pathway, which is regulated by ROS production.Conclusion: Our study elucidates the mechanisms through which miconazole stimulates NRF2 which may contribute to cancer chemopreventive effects.Keywords: miconazole, NRF2, p62, KEAP1, bladder cancer

Qin Xiang Ng,1,2 Michelle Lee Zhi Qing De Deyn,3 Nandini Venkatanarayanan,4 Collin Yih Xian Ho,2 Wee-Song Yeo,5 1Department of Medicine, National University Hospital, National University Health System, Singapore; 2MOH Holdings Pte Ltd, Singapore; 3Department of Medicine, James Cook University Hospital, Middlesbrough, UK; 4Department of Medicine, Nottingham University Hospitals NHS Trust, Queen’s Medical Centre, Nottingham, UK; 5Department of Paediatrics, National University Hospital, National University Health System, Singapore Background: Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are dermatologic emergencies with high morbidity and mortality risk. Cyclosporine, an immunomodulatory agent, is sometimes used off-label, and its role continues to be debated. This meta-analysis aimed to provide an update of current evidence and to clarify the role of cyclosporine in SJS/TEN treatment better.Methods: Using the keywords [cyclosporine OR cyclosporine OR ciclosporin OR CsA] AND [Steven-Johnson OR SJS OR toxic epidermal OR epidermal necrolysis OR TEN OR hypersensitivity OR dermatologic OR burns], a preliminary search on the PubMed, Ovid, Web of Science, and Google Scholar Database yielded 615 papers published in English between January 1, 1960 and July 1, 2017. The inclusion criteria for this review were: 1) published retrospective or prospective study (excluding single case reports); 2) patients with clinical diagnosis of SJS or TEN; 3) trial of cyclosporine treatment; and 4) available survival/mortality data.Results: A total of 12 studies, with a total of 358 SJS/TEN patients were reviewed. Two studies were excluded from the meta-analysis as they did not report SCORe of toxic epidermal necrosis/predicted mortality data; one was excluded because of possible data irregularities. Meta-analysis of nine studies revealed a significant reduction in mortality risk with cyclosporine therapy (standardized mortality ratio 0.320; 95% CI: 0.119–0.522; P=0.002). Cyclosporine was also generally well tolerated with little adverse effects or increased infection, albeit the patients tended to be critically ill. Publication bias was observed in the funnel plot and Egger test (P=0.0467).Conclusion: Currently available evidence are predominantly open trials and retrospective studies with a significant risk of bias, perhaps owing to the rarity and life-threatening nature of the condition. Given its immunomodulatory actions, cyclosporine could be a potential treatment option for SJS/TEN in addition to best supportive measures. Further confirmation with robust randomized, controlled trials or larger case series is necessary and should be encouraged. Keywords: SJS, TEN, epidermal necrolysis, cyclosporine, CsA, meta-analysis