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Yen-Hao Chen,1– 4 Wan-Ting Huang,5 Wen-Chin Lee,6 Ching-Mei Chen,5 Fu-Jen Cheng,7 Chia-Te Kung,7 Chin-Chou Wang,8 Liang-Jen Wang,9 Yu-Che Ou,10 Shau-Hsuan Li1 1Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 2School of Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 3School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan; 4Department of Nursing, School of Nursing, Fooyin University, Kaohsiung, 831, Taiwan; 5Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 6Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 7Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 8Department of Occupational Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 9Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 10Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, TaiwanCorrespondence: Shau-Hsuan Li, Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City, 833, Taiwan, Email lee.a0928@msa.hinet.netBackground: The aim of this study was to investigate the role of phthalate in patients with esophageal squamous cell carcinoma (ESCC).Methods: A total of 116 ESCC patients and 58 controls without any known histories of malignancies were enrolled. All eight urine phthalate metabolites were measured to assess phthalate levels. Clinical and urine phthalate metabolite profiles were compared between subgroups to identify differences, and the effects of phthalates on clinical ESCC outcomes were also examined.Results: The concentrations of some urine phthalate metabolites were higher in the ESCC group than in the control group, including mono-(3-carboxypropyl) phthalate (MCPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MnBP). Higher concentrations of urine phthalate metabolites were associated with clinical T3–T4 status. Patients with higher concentration of mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-2-ethylhexyl phthalate (MEHP), and MEOHP had lower 1-year and 2-year overall survival (OS) rates than those with lower concentrations of these metabolites in our univariate analysis. Multivariate analysis showed that urinary MEHP of ≥ 3 μg/L and clinical stage IVB were independent prognostic factors for worse OS.Conclusion: The results of our study showed that urine phthalate metabolites are elevated in ESCC patients and associated with advanced tumor stage, and that a high urinary concentration of MEHP is an independent prognostic factor of worse OS.Keywords: phthalate, esophageal cancer, squamous cell carcinoma, survival

Kuo-Feng Hua,1,2,* Hsien-Ta Hsu,3,4,* May-Shu Huang,5,6 Hsiao-Wen Chiu,1 Wei-Ting Wong,1 Chien-Hsiu Peng,1 Yu-Bei Lin,1 Ann Chen,7 Chien-Chun Wang,8,9 Chung-Hua Hsu,10,11 Chun-Hsien Wu,12 Wen-Yu Lin,1,12 Chen-Lung Ho,13 Lan-Hui Li14 1Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan; 2Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; 3Division of Neurosurgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; 4School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan; 5Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 6Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 7Department of Pathology, Hualien Tzu Chi Hospital, Hualien, Taiwan; 8Infectious Disease Division, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan; 9Kunming Prevention and Control Center, Taipei City Hospital, Taipei, Taiwan; 10Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan; 11Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 12Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 13Division of Wood Cellulose, Taiwan Forestry Research Institute, Taipei, Taiwan; 14Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Lan-Hui Li, Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, 100, Kunming Street, Wanhua District, Taipei City, 108203, Taiwan, Tel +886-2-23703739 # 1438, Fax +886-2-23885259, Email A1525@tpech.gov.twPurpose: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, crucial in infectious and inflammatory diseases by regulating IL-1β, presents a target for disease management. Neisseria gonorrhoeae causes gonorrhea in over 87 million people annually, with previous research revealing NLRP3 inflammasome activation in infected macrophages. No natural products have been reported to counteract this activation. Exploring honokiol, a phenolic compound from Chinese herbal medicine, we investigated its impact on NLRP3 inflammasome activation in N. gonorrhoeae-infected macrophages.Methods: Honokiol’s impact on the protein expression of pro-inflammatory mediators was analyzed using ELISA and Western blotting. The generation of intracellular H2O2 and mitochondrial reactive oxygen species (ROS) was detected through specific fluorescent probes (CM-H2DCFDA and MitoSOX, respectively) and analyzed by flow cytometry. Mitochondrial membrane integrity was assessed using specific fluorescent probes (MitoTracker and DiOC2(3)) and analyzed by flow cytometry. Additionally, the effect of honokiol on the viability of N. gonorrhoeae was examined through an in vitro colony-forming units assay.Results: Honokiol effectively inhibits caspase-1, caspase-11 and GSDMD activation and reduces the extracellular release of IL-1β, NLRP3, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in N. gonorrhoeae-infected macrophages. Detailed investigations have demonstrated that honokiol lowers the production of H2O2 and the phosphorylation of ERK1/2 in N. gonorrhoeae-infected macrophages. Importantly, the phosphorylation of JNK1/2 and p38 and the activation of NF-κB remain unaffected. Moreover, honokiol reduces the N. gonorrhoeae-mediated generation of reactive oxygen species within the mitochondria, preserving their integrity. Additionally, honokiol suppresses the expression of the pro-inflammatory mediator IL-6 and inducible nitric oxide synthase induced by N. gonorrhoeae independently of NLRP3. Impressively, honokiol exhibits in vitro anti-gonococcal activity against N. gonorrhoeae.Conclusion: Honokiol inhibits the NLRP3 inflammasome in N. gonorrhoeae-infected macrophages and holds great promise for further development as an active ingredient in the prevention and treatment of symptoms associated with gonorrhea.Keywords: Neisseria gonorrhoeae, honokiol, NLRP3 inflammasome, mitochondria, bactericiide

Xin-Mei Hu,1,* Can-Can Wang,1,* Yu Xiao,1 Yu Liu,1 Hong-Ri Huang,2 Peng Jiang,1 Ying-Kai Wang,1 Yun-Jin Lin,1 Liang-Cheng Li,3 Zhong-Quan Qi1 1Medical College, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Research and Development, Guangxi Taimei Rensheng Biotechnology Co., Ltd, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhong-Quan Qi, Guangxi University, Da-Xue-Dong Road No. 100, Xixiangtang District, Nanning, Guangxi Zhuang Autonomous Region, 530004, People’s Republic of China, Tel +8613806001271, Email yxyyz@gxu.edu.cn Liang-Cheng Li, Xiamen University, No. 4221-115, Rm 355, Xiang’an District, Xiang’an, Xiamen Fujian Province, 361102, People’s Republic of China, Tel +8618359206906, Email lchli2013@xmu.edu.cnPurpose: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future.Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection.Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group.Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.Keywords: exosomes, cynomolgus monkeys, safety, immunotoxicity

Hsiao-Mei Hsu,1 Hsin-I Tsai,2– 4 Wei-Chen Lee,4,5 Chih-Chi Wang,6,7 Ming-Chin Yu,3,4,8 Shi-Ming Lin,4,9 Chun-Yen Lin,4,9 Chi-Huan Wu,4,9 Chao-Wei Lee3– 5 1Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2Department of Anesthesiology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 3Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan; 4College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Division of General Surgery, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 7Division of General Surgery, Department of Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan; 8Department of Surgery, New Taipei Municipal Tu-Cheng Hospital (Built and Operated by Chang Gung Medical Foundation), New Taipei City, Taiwan; 9Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan, TaiwanCorrespondence: Chao-Wei Lee, Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou Medical Center, Guishan, No. 5, Fuxing St., Guishan District, Taoyuan City, 33305, Taiwan, Tel +886-975366192, Email alanchaoweilee@hotmail.comAbstract: Surgical resection remains one of the most effective curative therapies for HCC. However, the majority of patients have advanced unresectable diseases upon presentation. It is of paramount importance to raise the resectability of patients with HCC. The remarkable objective response rate reported by Phase III IMbrave150 trial has led to the concept of “Atezo/Bev followed by curative conversion (ABC conversion)” for initially unresectable HCC. With this revolutionary treatment strategy, the concept of surgical resection for HCC should be amended. The current opinion illustrated three extended surgical concepts, which could be integrated into clinical practice in the era of immune checkpoint inhibitors (ICI).Keywords: hepatocellular carcinoma, liver resection, surgery, immune checkpoint inhibitors, immunotherapy

Yi-Cheng Li,1,2 Yia-Ling Chang,3 Fang-Yih Liaw,2,4 Chih-Chia Wang,2,4 Yaw-Wen Chang2,4 1Department of Family Medicine, Hualien Armed Forces General Hospital, Hualien, Taiwan, Republic of China; 2School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China; 3Department of Nursing, Tri-Service General Hospital Penghu Branch, National Defense Medical Center, Penghu, Taiwan, Republic of China; 4Department of Family and Community Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of ChinaCorrespondence: Yaw-Wen Chang, School of Medicine, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei City, 11490, Taiwan, Republic of China, Email yawwenc@office365.ndmctsgh.edu.twBackground: The Discharge Planning Curriculum (DPC) is a 4-hour course for penultimate-year medical students at a tertiary teaching hospital in Taiwan. The course begins with a 30-minute introduction, followed by the students shadowing discharge planning case managers as they visit patients on the wards. After patient visits, the students engaged in a 1-hour case discussion. Our research assessed the effectiveness of the DPC for medical students.Methods: This mixed methods study recruited medical students participating in family medicine rotations between October 2017 and May 2018. To determine the impact of the DPC, we quantitatively analyzed questionnaire responses to measure changes in self-efficacy, attitude toward discharge planning, and course satisfaction before and after completing the DPC. Additionally, we conducted qualitative focus group interviews to gain insight into the students’ learning experiences and applied thematic analysis to the interview data.Results: Our study found two quantitative results: 1) The DPC significantly improved self-efficacy and attitude toward discharge planning (p < 0.001). 2) The medical students acquired knowledge about home care, assistive device application, long-term care facility referral, home rehabilitation, and home care services, and more than 95% of the students reported being satisfied with the course. In addition, the focus group interviews revealed that medical students learned several aspects of discharge planning through the curriculum, including an understanding of various aspects of discharge planning through the curriculum, the importance of early discharge planning, the roles of doctors and case managers, and the challenges faced in the process.Conclusion: The DPC helped medical students understand different team members’ roles in discharge planning and appreciate the challenges that case managers face in this process. The DPC improved medical students’ attitudes toward discharge planning. The curriculum can be a valuable tool in training future healthcare providers in effective transitional care.Keywords: continuity of patient care, curriculum evaluation, interdisciplinary training, patient discharge, undergraduate medical education

Jade Winjei Hwang,1 Shao Ju Chien,2 Chih-Chi Wang,3 Kuang-Che Kuo,4 Kuo-Shu Tang,5 Yu Lee,1 Yi-Chun Chen,6 Mao-Hung Lo,2 Ing-Kit Lee,6 Seng-Kee Chuah,7 Chien-Te Lee,8 Chia-Te Kung,9 Liang-Jen Wang10 1Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 2Division of Pediatric Cardiology, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung, 83301, Taiwan; 3Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 4Division of Pediatric Infection, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan; 5Division of Pediatric Emergency, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan; 6Division of Infectious Disease, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 7Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 8Department of Nephrology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 9Department of Emergency, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 10Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, TaiwanCorrespondence: Liang-Jen Wang, Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta-Pei Road, Kaohsiung, Taiwan, Tel +886-7-7317123 Ext 8753, Fax +886-7-7326817, Email wangliangjen@gmail.comBackground: Vaccinating adolescents is a vital strategy to enhance population protection without imposing overly restrictive measures on our daily lives during the COVID-19 pandemic. As teenagers gain more independence, their willingness to get vaccinated may depend on their own understanding of the pandemic, vaccines, and mental well-being, as well as that of their caregivers. Our study aimed to examine how Taiwanese adolescents and their caregivers perceive COVID-19 vaccination and assess their mental health status.Methods: We invited a total of 138 vaccinated adolescents and their caregivers to complete several questionnaires, including the Drivers of COVID-19 Vaccination Acceptance Scale (DrVac-COVID19S), Impact of Event Scale (IES), and Chinese Health Questionnaire (CHQ).Results: Among the adolescents, 76.8% considered the BNT162b2 vaccine (Pfizer-BioNTech) as the ideal option for COVID-19 vaccination, while 27.5% of caregivers expressed acceptance of any available vaccine. Adolescents scored higher than caregivers in terms of vaccine value (p< 0.001) and autonomy (p< 0.001), but lower in knowledge (p< 0.001), as assessed by the DrVac-COVID19S subscales. The adolescents’ intention to get vaccinated against COVID-19 (DrVac-COVID19S total score) showed a positive correlation with their perception of the pandemic’s impact (IES scores, r=0.214, p=0.012) and their caregivers’ vaccination intention (r=0.371, p< 0.001). Furthermore, adolescents’ mental health demonstrated a positive association with the mental health of their caregiver (CHQ total scores, r=0.481, p< 0.001).Conclusion: During the COVID-19 outbreak, caregivers have encountered heightened levels of mental stress, and this stress has been found to be positively correlated with the mental stress experienced by adolescents and their intentions regarding vaccination. These findings can serve as crucial references for healthcare providers and governments when formulating vaccination policies for adolescents in the future.Keywords: adolescent, autonomy, caregivers, vaccine, psychosomatic, SARS-Cov-2

Hong-Xia Yu,1,&ast; Guo-Shuai Lin,1,&ast; Ji-Fan Zhang,2 Cong-Cong Wang,1 Xiang-Jun Long,1 Mao-Mao Zhao1 1Department of Infection, Yuhuangding Hospital, Yantai, People’s Republic of China; 2Department of Critical Care Medicine, Liaocheng People’s Hospital, Liaocheng, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mao-Mao Zhao, Department of Infection, Yuhuangding Hospital, No. 20 of Yuhuangding East Road, Zhifu District, Yantai, People’s Republic of China, Tel +86 13863872227, Fax +86 6240341, Email zhaomm295@126.comObjective: This study was designed to analyze the clinical characteristics, etiological characteristics, drug resistance, and empirical use of antibiotics for community-acquired pyogenic liver abscess (PLA) to provide a basis for rational and effective empirical treatment of PLA in the local area.Methods: The clinical data, etiological characteristics, drug resistance, and empirical anti-infective therapy schemes of 606 patients with PLA were collected and analyzed retrospectively.Results: The included patients were mainly males, with a male-to-female ratio of 1.3:1. The average age of the patients was 60.3 ± 14.1 years. The underlying diseases were diabetes and biliary tract disease, accounting for 38.7% and 22.3%, respectively. The main clinical manifestations were fever (92.9%), abdominal pain (44.7%), and nausea (33.3%). Imaging findings: the proportion of patients with a single lesion was 74.7%, and 67% of the patients had involvement in the right lobe of the liver. The main pathogen was Klebsiella pneumoniae accounted for 74.9% in blood culture and 84.1% in pus culture, mainly extended-spectrum β-lactamase. In 272 strains negative for extended-spectrum β-lactamase (ESBLs), 100% were resistant to ampicillin and less than 50% were sensitive to nitrofurantoin. Only 36 ESBL-positive strains had higher than 80% sensitivity to carbapenems, β-lactamase inhibitor compound, and amikacin. Patients treated with different treatment methods showed significantly different average length of hospital stay (14 [9– 21] vs 13 [8– 18]). Empirical anti-infective therapy: Beta-lactamase complex, carbapenems, cephalosporins, and quinolones were used in 280 (37.6%), 180 (29.7%), 180 (29.7%), and 147 (24.3%) patients, respectively.Conclusion: Patients with community-acquired PLA in this area are mainly males, and the underlying diseases are mainly diabetes and hepatobiliary system disease. The main clinical manifestation is fever, so patients with fever of unknown cause should pay attention to possible liver abscesses. Based on drug sensitivity tests, the empirical use of antibiotics is somewhat unreasonable.Keywords: liver abscess, Klebsiella pneumoniae, epidemiological, community

Chiung-Zuei Chen,1 Chau-Chyun Sheu,2 Shih-Lung Cheng,3,4 Hao-Chien Wang,5 Meng-Chih Lin,6 Wu-Huei Hsu,7 Kang-Yun Lee,8 Diahn-Warng Perng,9 Hen-I Lin,10 Ming-Shian Lin,11 Sheng-Hao Lin,12 Jong-Rung Tsai,13 Chin-Chou Wang,6 Cheng-Yi Wang,10 Tsung-Ming Yang,14 Ching-Lung Liu,15 Tsai-Yu Wang,16 Ching-Hsiung Lin12,17,18 1Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan; 3Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 220, Taiwan; 4Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli, Taoyuan, 320, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 8Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 110, Taiwan; 9Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan; 10Department of Internal Medicine, Cardinal Tien Hospital, Fu-Jen Catholic University, Taipei, 242, Taiwan; 11Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 600, Taiwan; 12Division of Chest Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan; 13Division of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 14Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan City, Taiwan; 15Division of Chest Medicine, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, 104, Taiwan; 16Pulmonary Disease Research Centre, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taipei, Taiwan; 17Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; 18Department of Recreation and Holistic Wellness, MingDao University, Changhua, 523, TaiwanCorrespondence: Ching-Hsiung LinDivision of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, TaiwanTel +886-4-7238595Fax +886-4-7232942Email 47822@cch.org.twBackground and Aim: Chronic obstructive pulmonary disease (COPD) is frequently underdiagnosed because of the unavailability of spirometers, especially in resource-limited outpatient settings. This study provides real-world evidence to identify optimal approaches for COPD case finding in outpatient settings.Methods: This retrospective study enrolled individuals who were at risk of COPD (age ≥ 40 years, ≥ 10 pack-years, and ≥ 1 respiratory symptom). Eligible participants were examined using various COPD case-finding tools, namely the COPD Population Screener (COPD-PS) questionnaire, a COPD prediction (PCOPD) model, and a microspirometer, Spirobank Smart; subsequently, the participants underwent confirmatory spirometry. The definition and confirmation of COPD were based on conventional spirometry. Receiver operating characteristic curve (ROC), area under the curve (AUC), and decision curve analyses were conducted, and a clinical impact curve was constructed.Results: In total, 385 participants took part in the study [284 without COPD (73.77%) and 101 with COPD (26.23%)]. The microspirometer exhibited a higher AUC value than did the COPD-PS questionnaire and the PCOPD model. The AUC for microspirometry was 0.908 (95% confidence interval [CI] = 0.87– 0.95), that for the PCOPD model was 0.788 (95% CI = 0.74– 0.84), and that for the COPD-PS questionnaire was 0.726 (95% CI = 0.67– 0.78). Decision and clinical impact curve analyses revealed that a microspirometry-derived FEV1/FVC ratio of < 74% had superior clinical utility to the other measurement tools.Conclusion: The PCOPD model and COPD-PS questionnaire were useful for identifying symptomatic patients likely to have COPD, but microspirometry was more accurate and had higher clinical utility. This study provides real-world evidence to identify optimal practices for COPD case finding; such practices ensure that physicians have convenient access to up-to-date evidence when they encounter a symptomatic patient likely to have COPD.Keywords: COPD, COPD case-finding, PCOPD model, COPD-PS questionnaire, microspirometry, spirometry

Victor C Kok,1,2 Charles CN Wang,2,3 Szu-Han Liao,2 De-Lun Chen2 1Division of Medical Oncology, Kuang Tien General Hospital Cancer Center, Taichung, 43303, Taiwan; 2Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan; 3Center for Artificial Intelligence and Precision Medicine Research, Asia University, Taichung, 41354, TaiwanCorrespondence: Victor C Kok; Charles CN Wang, Email vkok@alumni.harvard.edu; cnwang@asia.edu.twIntroduction: Only a proportion of triple-negative breast cancer (TNBC) is immunotherapy-responsive. We hypothesized that the tumor microenvironment (TME) influences the outcomes of TNBC and investigated the relevant signaling pathways.Materials and Methods: Immune score (IS) and stromal score (SS) were calculated using the ESTIMATE and correlated with the overall survival (OS) in TNBC. RNA-seq data from 115 TNBC samples and 112 normal adjacent tissues were retrieved. Validations in the methylation levels in 10 TNBC and five non-TNBC cell lines were obtained. Cox model overall survival (OS) validated the derived transcription factor (TF) genes in cBioPortal breast cancer patients.Results: SS-low predicts a higher OS compared with SS-high patients (P = 0.0081 IS-high/SS-low patients had better OS (P = 0.045) than IS-low/SS-high patients. More macrophages were polarized to the M2 state in patients with IS-low/SS-high patients (P < 0.001). Moreover, CIBERSORTx showed more CD8+ cytotoxic T-cells in IS-high/SS-low patients (p = 0.0286) and more resting NK cells in the IS-low/SS-high TME (P = 0.0108). KEGG pathway analysis revealed that overexpressed genes were enriched in the IL-17 and cytokine-cytokine receptor interaction pathways. The lncRNA DRAIC, a tumor suppressor, was consistently deactivated in the 10 TNBC cell lines. On the cBioPortal platform, we validated that 13% of ER-negative, HER2-unamplified BC harbored IL17RA deep deletion and 25% harbored TRAF3IP2 amplification. On cBioPortal datasets, the nine altered TF genes derived from the X2K analysis showed significantly worse relapse-free survival in 2377 patients and OS in 4819 invasive BC patients than in the unaltered cohort.Conclusion: Of note, the results of this integrated in silico study can only be generalized to approximately 17% of patients with TNBC, in which infiltrating stromal cells and immune cells play a determinant prognostic role.Keywords: triple-negative breast cancer, immune cells, tumor microenvironment, IL-17 signaling pathway, immune evasion, in silico study

Dolutegravir (DLG) has become a distinctive first-line antiretroviral therapy for the treatment of HIV in most countries due to its affordability, high efficacy, and low drug-drug interactions. However, the evaluation of genotoxic impurities (GTIs) in DLG and their toxicity assessment has not been explored thoroughly. Thus, in this study, a simple, fast, and selective analytical methodology was developed for the identification and determination of 7 GTIs in the comprehensive, explicit route of synthesis for the dolutegravir sodium (DLG-Na) drug. A facile, fast ultrasonication-assisted liquid-liquid extraction procedure was adapted to isolate the GTIs in DLG-Na and then analyzed using the gas chromatography (GC)-electron impact (EI)/mass spectrometer (MS) quantification (using selective ion monitoring mode) technique. This EI-GC/MS method was validated as per the current requirements of ICH Q2 (R1) guidelines. Under optimal method conditions, excellent linearities were achieved with R between 0.9959 and 0.9995, and high sensitivity was obtained in terms of detection limits (LOD) between 0.15 to 0.63 µg/g, and quantification limits (LOQ) between 0.45 to 1.66 µg/g for the seven GTIs in DLG. The obtained recoveries ranged from 98.2 to 104.3 % at LOQ, 15 µg/g, and 18 µg/g concentration levels (maximum daily dose of 100 mg). This developed and validated method is rapid, easy to adopt, specific, sensitive, and accurate in estimating the seven GTIs in a relatively complex sodium matrix of the DLG-Na drug moiety. As a method application, two different manufactured samples of DLG-Na drug substances were analyzed for the fate of the GTIs and drug safety for the intended dosage applications. Moreover, an in-silico QSAR toxicity prediction assessment was carried out to prove scientifically the potential GTI nature of each impurity from the alerting functional groups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Microbes in the human body are the determinants of life-long health and disease. Microbiome acquisition starts in utero and matures during early childhood through breastfeeding. However, maternal gut dysbiosis affects the maternal-offspring microbiome interplay. Lines of evidence on dysbiosis-targeted interventions and their effect on maternal-offspring health and gut microbiome are inconsistent and inconclusive. Therefore, this study summarised studies to identify the most common microbiota-targeted intervention during pregnancy and lactation and to comprehensively evaluate its effects on maternal and offspring health., Methods: This umbrella review was conducted by systematically searching databases such as PubMed and the Web of Science from inception to 2 September 2023. The quality was assessed using the Assessment of Multiple Systematic Reviews-2 checklist. The Grading of Recommendations Assessment, Development, and Evaluation was used for grading the strength and certainty of the studies. The overlap of primary studies was quantified by the corrected covered area score., Results: A total of 17 systematic reviews and meta-analyses with 219 randomised controlled trials, 39 113 mothers, and 20 915 infants were included in this study. About 88% of studies had moderate and above certainty of evidence. Probiotics were the most common and effective interventions at reducing gestational diabetes risk (fasting blood glucose with the mean difference (MD) = -2.92, -0.05; I 2  = 45, 98.97), fasting serum insulin (MD = -2.3, -2.06; I 2  = 45, 77), glycated haemoglobin (Hb A1c) = -0.16; I 2  = 0.00)), Homeostatic Model Assessment of insulin resistance (HOMA-IR) (MD = -20.55, -0.16; I 2  = 0.00, 72.00), and lipid metabolism (MD = -5.47, 0.98; I 2  = 0.00, 90.65). It was also effective in preventing and treating mastitis (risk ratio (RR) = 0.49; I 2  = 2.00), relieving anxiety symptoms (MD = -0.99, 0.01; I 2  = 0.00, 70.00), depression in lactation (MD = -0.46, -0.22; I 2  = 0.00, 74.00) and reducing recto-vaginal bacterial colonisation (odds ratio (OR) = 0.62; I 2  = 4.80), and with no adverse events. It also effectively remodelled the infant gut microbiome (MD = 0.89; I 2  = 95.01) and prevented infant allergies. However, studies on pregnancy outcomes and preeclampsia incidences are limited., Conclusions: Our findings from high-quality studies identify that probiotics are the most common microbiome interventions during pregnancy and lactation. Probiotics have a strong impact on maternal and offspring health through maintaining gut microbiome homeostasis. However, further studies are needed on the effect of microbiota-targeted interventions on maternal cardiometabolic health, pregnancy, and neonatal outcomes., Registration: This umbrella review was registered with PROSPERO, CRD42023437098., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Background/aims: The study is to analyze the clinical characteristics and identify prognostic factors as well as evaluate predictive models in patients with acute-on-chronic liver failure (ACLF) from Southern Taiwan., Methods: The cohort study was conducted using the Chang Gung Research Database. We included patients with ACLF based on the definition provided by the Asian-Pacific Association for the Study of the Liver ACLF Research Consortium (AARC)., Results: A total of 231 patients diagnosed with ACLF were included in this study, out of which 26 patients underwent liver transplantation (LT). The primary cause of ACLF was acute exacerbation of hepatitis B virus (HBV) in 68.4% of cases and followed by severe alcoholic hepatitis (20.8%). Among LT-free patients, the 28-day mortality rate was observed to be 31%. Older age, higher INR and ammonia levels, and the presence of severe hepatic encephalopathy on 3-6 days of treatment were independent predictors of 28-day mortality. The CLIF-C ACLF and COSSH-ACLF scores, evaluated on 3-6 days, demonstrated the highest predictive performance for 28-day mortality. The optimal cut-off values for the CLIF-C ACLF and COSSH-ACLF scores were determined to be 47 and 6.3, respectively. Patients with CLIF-C ACLF score >63 or COSSH-ACLF score >8.1 experienced 100% mortality by day 28., Conclusions: The CLIF-C ACLF and COSSH-ACLF scores, evaluated within one week after treatment, exhibit strong predictive capabilities for short-term mortality in ACLF patients. These models are valuable tools for guiding timely decision-making, including the consideration of liver transplantation or withdrawal from treatment., Competing Interests: Declaration of competing interest Chien-Hung Chen, Pao-Yuan Huang, Yu Cheng, Lin, Chih-Chi Wang declare that they have no conflict of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The Yellow River Delta played a vital role in the development of the Neolithic civilization of China. However, the population history of this region from the Neolithic transitions to the present remains poorly understood due to the lack of ancient human genomes. This especially holds for key Neolithic transitions and tumultuous turnovers of dynastic history. Here, we report genome-wide data from 69 individuals dating to 5,410-1,345 years before present (BP) at 0.008 to 2.49× coverages, along with 325 present-day individuals collected from 16 cities across Shandong. During the Middle to Late Dawenkou period, we observed a significant influx of ancestry from Neolithic Yellow River farmers in central China and some southern Chinese ancestry that mixed with local hunter-gatherers in Shandong. The genetic heritage of the Shandong Longshan people was found to be most closely linked to the Dawenkou culture. During the Shang to Zhou Dynasties, there was evidence of genetic admixture of local Longshan populations with migrants from the Central Plain. After the Qin to Han Dynasties, the genetic composition of the region began to resemble that of modern Shandong populations. Our genetic findings suggest that the middle Yellow River Basin farmers played a role in shaping the genetic affinity of neighboring populations in northern China during the Middle to Late Neolithic period. Additionally, our findings indicate that the genetic diversity in the Shandong region during the Zhou Dynasty may be linked with their complex ethnicities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Skin identity is controlled by intrinsic features of the epidermis and dermis and their interactions. Modifying skin identity has clinical potential, such as the conversion of residual limb and stump (nonvolar) skin of amputees to pressure-responsive palmoplantar (volar) skin to enhance prosthesis use and minimize skin breakdown. Greater keratin 9 ( KRT9 ) expression, higher epidermal thickness, keratinocyte cytoplasmic size, collagen length, and elastin are markers of volar skin and likely contribute to volar skin resiliency. Given fibroblasts' capacity to modify keratinocyte differentiation, we hypothesized that volar fibroblasts influence these features. Bioprinted skin constructs confirmed the capacity of volar fibroblasts to induce volar keratinocyte features. A clinical trial of healthy volunteers demonstrated that injecting volar fibroblasts into nonvolar skin increased volar features that lasted up to 5 months, highlighting a potential cellular therapy.

Background: There have been concerns about the potential cardiovascular (CV) adverse effects associated with methylphenidate (MTH) use. However, only limited evidence exists on the long-term safety of MTH., Objective: To evaluate whether MTH use is associated with long-term CV risk., Methods: This was a retrospective cohort study using 2003-2017 data from the Health and Welfare Database in Taiwan. Patients newly diagnosed with attention deficit and hyperactivity disorder (ADHD) and between 3 and 18 years of age were included. Two treatment statuses were assessed: initial treatment ≥7 days and ≥180 days. Patients treated with MTH were compared with those receiving non-medication therapy. One-to-one propensity score matching was used to balance between-group differences. Study outcomes included major CV events, chronic CV disease, cardiogenic shock and all-cause mortality. Cox proportional hazard models were used to estimate HRs between the two groups., Results: We began with 307 459 patients with ADHD. After exclusion, 224 732 patients were included in the final cohort. The results showed that compared with non-ADHD medication users, patients who were treated with MTH for more than 7 days had a similar risk of major CV events (HR 0.85, 95% CI 0.72 to 0.99; p=0.040). Identical trends were found in groups who were treated for more than 180 days (HR 0.83, 95% CI 0.69 to 1.00; p=0.050). The results of the sensitivity analyses were consistent with the main analyses across all groups and individual outcomes., Conclusion: Short-term MTH use did not increase CV risk among patients with ADHD. More evidence on long-term MTH use and risk of cardiogenic shock and death is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background/aim: The mortality rate for alimentary tract hemorrhage remains high due to a variety of contributing factors. In this report, we present a case of post-severe trauma patient with life-threatening gastrointestinal bleeding caused by cytomegalovirus (CMV)-induced damage to the terminal ileum., Case Report: A 76-year-old female with a history of hypertension and gastrointestinal bleeding developed CMV ileitis post-severe trauma. Despite negative CMV IgM antibodies, PCR testing confirmed CMV infection in the biopsy tissue. Histopathological examination revealed viral inclusion bodies, with immunohistochemistry confirming CMV presence., Results: Intravenous ganciclovir effectively managed symptoms and halted bleeding. CMV ileitis, typically seen in immunocompromised states, may occur sporadically in immunocompetent individuals, including post-orthopedic surgery patients. The exact mechanism remains unclear, possibly related to surgical stress. Diagnosis relies on histopathology and immunohistochemistry., Conclusion: Early recognition and treatment are vital for optimal outcomes, emphasizing the need for awareness among orthopedic surgeons regarding CMV as a potential cause of postoperative complications., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups., Patients and Methods: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR)., Results: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]., Conclusions: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Our institution updated blunt liver and spleen injury (BLSI) protocols in 2019 in adherence to updated American Pediatric Surgery Association recommendations. This retrospective study compares resource utilization for pediatric BLSI patients treated under old and updated guidelines., Methods: Blunt liver and spleen injury patients without severe non-abdomen injuries younger than 18 years treated with prior (April 2015 to June 2019) and updated (June 2019 to December 2022) guidelines were retrospectively reviewed and compared. Each patient received an adjusted Injury Severity Score (ISS) to control for non-BLSI injuries. Multivariate analysis examined protocol group differences while controlling for adjusted ISS and BLSI grades. Primary outcomes were intensive care unit (ICU) length of stay (LOS), hospital LOS (analyzed using Cox regression), and patient costs (linear regression). Secondary outcomes include readmission in 2 weeks and death rates (logistic regression)., Results: A total of 176 and 170 BLSI patients were treated with old and updated protocols, respectively. Patient demographics, average BLSI grade, and adjusted ISS were similar in both groups. Patients treated with old protocols indicate decreased hazard, showing significantly more days before ICU discharge (coefficient, -0.3868; p < 0.0009) and hospital discharge (coefficient, -0.5507; p < 0.0001). Patient costs (coefficient, 0.0921; p = 0.1874) trend toward being lower in the new protocol. Readmission rates were significantly higher in the new protocol (coefficient, -1.1731; p = 0.0465), and death rates (coefficient, 0.0519; p = 0.9710) were comparable., Conclusions: Blunt liver and spleen injury patients treated under new American Pediatric Surgery Association guidelines compared with old guidelines had significant decreases in ICU and hospital LOS, a decreasing trend in costs, and comparable death rates but higher readmission rates. Future studies with larger sample sizes and detailed cost analysis would explore whether updated guidelines reduce patient costs and help elucidate the veracity or potential cause of the increased readmission rates., Level of Evidence: Therapeutic/Care Management; Level III., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The incidence of herpes zoster (HZ) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is significantly higher than that of the general public. Although routine antiviral prophylaxis is recommended, late-onset HZ has been highlighted, yet limited information is known about its clinical features and predictors. Here, we conducted a retrospective nested case-control study to identify patients with late-onset HZ, defined as a diagnosis of HZ after 1 year of transplantation, among allo-HSCT recipients between 2012 and 2017 at Peking University People's Hospital. Three controls were matched for each patient. A total of 201 patients developed late-onset HZ. Age over 20 years, absence of neutrophil engraftment by 14 days, mental disorders, immunosuppressant use at 1 year, and a peripheral CD4+/CD8+ ratio ≥0.5 at 1 year were independent risk factors, among which the CD4+/CD8+ ratio demonstrated good discriminative power for predicting late-onset HZ. For patients with a CD4+/CD8+ ratio <0.5, patient age, neutrophil engraftment time, mental disorders, and immunosuppressant use were potential risk factors. A stratification algorithm was accordingly established, classifying the transplant recipients into three risk groups. Whether the algorithm could facilitate the administration of posttransplant antiviral prophylaxis merits further validation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The chemoselective [4+2] annulation/aromatization reactions between benzofuran-derived azadienes and N-Ts cyanamides are developed, affording a convenient method for synthesizing benzofuro[3,2-d]pyrimidin-2-amines under mild conditions. Herein, N-Ts cyanamides selectively participated in reactions absolutely via carbodiimide anion intermediates and the corresponding cyanamide anion intermediates derived products were not observed. The proposed chemoselective stepwise reaction mechanism was well supported by DFT calculations., (© 2024 Wiley‐VCH GmbH.)

A durable and efficient hydrophobic/superoleophilic MIL-88A(Fe)@sponge (MS) with high throughput was fabricated via the dip-coating technique. Its adsorption capacities for pump oil, peanut oil, and CCl 4 were 32.13 g g -1 , 34.85 g g -1 , and 34.25 g g -1 , respectively. The hydrophobic surface of MS has excellent chemical resistance and physical stability in harsh environments.

Background: Taiwan habu (Protobothrops mucrosquamatus), green bamboo viper (Viridovipera stejnegeri), and Taiwan cobra (Naja atra) are the most venomous snakebites in Taiwan. Patients commonly present with limb swelling but misdiagnosis rates are high, and currently available diagnostic tools are limited. This study explores the immune responses in snakebite patients to aid in differential diagnosis., Methods: This prospective observational study investigated the changes in cytokines in snakebite patients and their potential for diagnosis., Results: Elevated pro-inflammatory cytokines IL-6 and TNF-α were observed in all snakebite patients compared to the healthy control group. While no significant disparities were observed in humoral immune response cytokines, there were significant differences in IFN-γ levels, with significantly higher IL-10 levels in patients bitten by cobras. Patients with TNF-α levels exceeding 3.02 pg/mL were more likely to have been bitten by a cobra., Conclusion: This study sheds light on the immune responses triggered by various venomous snakebites, emphasizing the potential of cytokine patterns for snakebite-type differentiation. Larger studies are needed to validate these findings for clinical use, ultimately improving snakebite diagnosis and treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Chih-Chuan Lin reports financial support was provided by the Ministry of Science and Technology of Taiwan (grant MOST 108-2314-B-182A-081). Chun-Hsiang Ou Yang reports financial support was provided by Chang Gung Medcial Foundation, Taoyuan, Taiwan. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The Ministry of Science and Technology of Taiwan and Chang Gang Medical Foundation have no role in this study proposal design, experiment performance, data collection, analysis, and manuscript preparation., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Rivaroxaban 2.5 mg plus aspirin reduced limb and cardiovascular events and increased bleeding in patients with symptomatic peripheral artery disease (PAD) after lower extremity revascularization in the VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) study. Fragile patients are at heightened risk for ischemic and bleeding events., Objectives: The purpose of this study was to investigate the safety and efficacy of rivaroxaban 2.5 mg in fragile patients from VOYAGER PAD., Methods: Patients were categorized as fragile based on prespecified criteria (age >75 years, weight ≤50 kg, or baseline estimated glomerular filtration rate <50 mL/min/1.73 m 2 ). The primary efficacy outcome was the composite of acute limb ischemia, major amputation of a vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was TIMI major bleeding., Results: Of 6,564 randomized patients, a total of 1,674 subjects were categorized as fragile at baseline. In the placebo arm, fragile patients were at higher risk of the primary outcome (HR: 1.34; 95% CI: 1.12-1.61) and TIMI major bleeding (HR: 1.57; 95% CI: 0.83-2.96), compared with nonfragile patients. The effect of rivaroxaban on the primary endpoint was not modified by frailty status (fragile HR: 0.93; 95% CI: 0.75-1.15; nonfragile HR: 0.83; 95% CI: 0.72-0.97; P interaction = 0.37). Rivaroxaban increased TIMI major bleeding in fragile (HR: 1.54; 95% CI: 0.82-2.91) and nonfragile patients (HR: 1.37; 95% CI: 0.84-2.23; P interaction = 0.65)., Conclusions: Patients with PAD after lower extremity revascularization meeting fragile criteria are at higher risk of ischemic complications and bleeding. Rivaroxaban reduces ischemic risk and increases bleeding regardless of frailty status. These data may assist in personalization of antithrombotic therapy in fragile population., Competing Interests: Funding Support and Author Disclosures VOYAGER PAD was funded by Bayer and Janssen Pharmaceuticals. The Colorado Prevention Center Clinical Research held the database and performed all analyses, and the decision to submit this manuscript for publication was made by the VOYAGER PAD Publications Committee. Drs Canonico, Low Wang, Hsia, Nehler, Capell, Berkowitz, and Bonaca receive salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between July 2021 and July 2023 from the following organizations: Abbott Laboratories, Agios Pharmaceuticals, Inc, Alexion Pharma Godo Kaisha, Amgen Inc, Anthos Therapeutics, Inc, ARCA biopharma, Inc, AstraZeneca Pharma India, AstraZeneca Pharmaceuticals LP, AstraZeneca UK Ltd, AstraZeneca Produtos Farmaceuticos, Lda, Atentiv, LLC, Bayer, Bayer (Proprietary) Limited, Bayer Aktiengesellschaft, Bayer Pharma AG, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, LLC, Bristol Myers Squibb, CellResearch Corporation Pte Ltd, Cleerly, Inc, Colorado Department of Public Health and Environment, Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics, Inc, EPG Communication Holdings Ltd, Esperion Therapeutics, Inc, Faraday Pharmaceuticals, Inc, HeartFlow Inc, Insmed, Ionis Pharmaceuticals, IQVIA Inc, Janssen Pharmaceuticals, Inc, Janssen Research and Development, LLC, Janssen Scientific Affairs LLC, Lexicon Pharmaceuticals, Inc, LSG Corporation, MedImmune Limited, Medpace, Inc, Medscape, Merck Sharp and Dohme Corp, Nectero Medical Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk, Osiris Therapeutics, Inc, Pfizer, PPD Development, LP, Prothena Biosciences Limited, Regeneron, Regents of the University of Colorado (aka UCD), Sanifit Therapeutics SA, Sanofi, Silence Therapeutics PLC, Stanford University, Stealth BioTherapeutics Inc, The Brigham and Women's Hospital, Inc, Thrombosis Research Institute, University of Colorado Denver, University of Pittsburgh, VarmX, and WraSer, LLC. Dr Hsia owns stock in AstraZeneca. Dr Debus has received grant support from Cook and Terumo Aortic. Dr Patel has received grant support, advisory board fees, and consulting fees from AstraZeneca, Bayer, and Janssen; has received grant support from Medtronic and Philips Healthcare; and has received grant support and advisory board fees from Heartflow. Dr Anand has received lecture fees from Bayer and Janssen. Dr Muehlhofer was employed by Bayer. Dr Haskell was employed by Janssen Pharmaceuticals; and has owned stock in Johnson and Johnson. Dr Berkowitz was employed by Bayer during the operationalization of the VOYAGER PAD study. Dr Bauersachs has received consulting fees and lecture fees from Bayer, Bristol Myers Squibb, and Pfizer. Dr Bonaca has received support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project); and has stock in Medtronic and Pfizer. Dr Ycas has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is a leading cause of disability and death. Thus, timely and effective secondary brain injury intervention is crucial, with potential to improve the prognosis of TBI. Oxidative stress contributes to post-traumatic secondary cognitive impairment, and the reduction of post-traumatic oxidative stress effectively enhances cognitive function. Phosphoglycerate-mutating enzyme 5 (PGAM5), a member of the phosphoglycerate transporter enzyme family, is upregulated in TBI and induces mitochondrial autophagy. This further exacerbates damage following TBI. The present study focused on the small molecule drug, LFHP-1c, which is a novel inhibitor of PGAM5. The present study used an in vivo mouse model incorporating a controlled cortical impact-induced TBI, to examine the impact of LFHP-1c on oxidative stress and cognitive function. The present study aimed to determine the impact of LFHP-1c on the PGAM5-Kelch-like ECH-associated protein 1 (KEAP1)- nuclear factor erythroid 2-related factor 2 (NRF2) ternary complex within the TBI context. Results of the present study indicated that LFHP-1c suppresses PGAM5 expression and inhibits the development of the PGAM5-KEAP1-NRF2 ternary complex, thereby promoting the release of NRF2 and KEAP1. This in turn promotes the entry of NRF2 into the nucleus following TBI, leading to increased expression of anti-oxidative stress downstream factors, such as heme oxygenase-1, glutathione peroxidase 1 and superoxide dismutase 1. In addition, LFHP-1c also released KEAP1, leading to mitochondrial Rho GTPase 2 degradation and reducing perinuclear aggregation of mitochondria in the cell, which reduced oxidative stress and ultimately improved cognitive function after TBI., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors. Published by Elsevier Ltd.)

Background/purpose: The National Medicines Policy (NMP) is crucial as it sets the framework for ensuring access to affordable, high-quality medicines and promoting their rational use, which is essential for public health and the efficiency of the healthcare system. This study aims to evaluate the current state of Taiwan's NMP, identify pressing issues for improvement, and establish actionable suggestions through expert consensus to ensure the sustainable provision and use of medications., Methods: A modified two-round Delphi technique was employed. The first-round survey identified key issues and suggestions for policy improvement, while the second-round survey evaluated the feasibility and effectiveness of these suggestions. The expert panel, consisting of 50 specialists from pharmacy, medicine, public health, and the pharmaceutical industry, evaluated key issues related to the NMP's efficacy using a 4-point Likert scale., Results: The first-round survey identified 13 key issues in Taiwan's NMP, primarily focusing on the rational use and accessibility of medications. The second-round survey proposed 54 policy improvement suggestions for these issues, of which 20 were considered strong suggestions and 23 were moderate suggestions. The policy recommendations cover medication reimbursement, pharmacy professional services, administration, legislation, and education., Conclusion: The study highlights the urgent need for reforms in Taiwan's NMP, providing specific policy improvement suggestions to ensure high-quality medications and pharmaceutical services while supporting the sustainable operation of Taiwan's NHI system. The study underscores the significance of proactive measures to fortify healthcare sustainability in the face of evolving healthcare landscapes., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Purpose: Multiple studies have reported models for predicting early recurrence of hepatocellular carcinoma (HCC) after liver resection (LR). However, these models are too complex to use in daily practice. We aimed to develop a simple model., Method: We enrolled 1133 patients with newly diagnosed HCC undergoing LR. The Kaplan - Meier method and log-rank test were used for survival analysis and Cox proportional hazards analysis to identify prognostic factors associated with early recurrence (i.e., recurrence within two years after LR)., Results: Early recurrence was identified in 403 (35.1%) patients. In multivariate analysis, alpha-fetoprotein (AFP) 20-399 vs. < 20 ng/ml (HR = 1.282 [95% confidence interval = 1.002-1.639]; p = 0.048); AFP ≥ 400 vs. < 20 ng/ml (HR = 1.755 [1.382-2.229]; p < 0.001); 7th edition American Joint Committee on Cancer (AJCC) stage 2 vs. 1 (HR = 1.958 [1.505-2.547]; p < 0.001); AJCC stage 3 vs. 1 (HR = 4.099 [3.043-5.520]; p < 0.001); and pathology-defined cirrhosis (HR = 1.46 [1.200-1.775]; p < 0.001) were associated with early recurrence. We constructed a predictive model with these variables, which provided three risk strata for recurrence-free survival (RFS): low risk, intermediate risk, and high risk, with two-year RFS of 79%, 57%, and 35%, respectively (p < 0.001)., Conclusion: We developed a simple model to predict early recurrence risk for patients undergoing LR for HCC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Parkinson's disease (PD) is a common neurodegenerative disease that has received widespread attention; however, current clinical treatments can only relieve its symptoms, and do not effectively protect dopaminergic neurons. The purpose of the present study was to investigate the therapeutic effects of human umbilical cord mesenchymal stem cell-derived exosomes loaded with brain-derived neurotrophic factor (BDNF-EXO) on PD models and to explore the underlying mechanisms of these effects., Main Methods: 6-Hydroxydopamine was used to establish in vivo and in vitro PD models. Western blotting, flow cytometry, and immunofluorescence were used to detect the effects of BDNF-EXO on apoptosis and ferroptosis in SH-SY5Y cells. The in vivo biological distribution of BDNF-EXO was detected using a small animal imaging system, and dopaminergic neuron improvements in brain tissue were detected using western blotting, immunofluorescence, immunohistochemistry, and Nissl and Prussian blue staining., Key Findings: BDNF-EXO effectively suppressed 6-hydroxydopamine-induced apoptosis and ferroptosis in SH-SY5Y cells. Following intravenous administration, BDNF-EXO crossed the blood-brain barrier to reach afflicted brain regions in mice, leading to a notable enhancement in neuronal survival. Furthermore, BDNF-EXO modulated microtubule-associated protein 2 and phosphorylated tau expression, thereby promoting neuronal cytoskeletal stability. Additionally, BDNF-EXO bolstered cellular antioxidant defense mechanisms through the activation of the nuclear factor erythroid 2-related factor 2 signaling pathway, thereby conferring neuroprotection against damage., Significance: The novel drug delivery system, BDNF-EXO, had substantial therapeutic effects in both in vivo and in vitro PD models, and may represent a new treatment strategy for PD., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Catalytic peroxymonosulfate (PMS) activation processes don't solely rely on electron transfer from dominant metal centers due to the complicated composition and interface environment of catalysts. Herein the synthesis of a cobalt based metal-organic framework containing polyvanadate [V 4 O 12 ] 4- cluster, Co 2 (V 4 O 12 )(bpy) 2 (bpy = 4,4'-bipyridine), is presented. The catalyst demonstrates superior degradation activity toward various micropollutants, with higher highest occupied molecular orbital (HOMO), via nonradical attack. The X-ray absorption spectroscopy and density functional theory (DFT) calculations demonstrate that Co sites act as both PMS trapper and electron donor. In situ spectral characterizations and DFT calculations reveal that the terminal oxygen atoms in the [V 4 O 12 ] 4- electron sponge could interact with the terminal hydrogen atoms in PMS to form hydrogen bonds, promoting the generation of SO 5 * intermediate via both dynamic pull and direct electron transfer process. Further, Co 2 (V 4 O 12 )(bpy) 2 exhibits long-term water purification ability, up to 40 h, towards actual wastewater discharged from an ofloxacin production factory. This work not only presents an efficient catalyst with an electron sponge for water environmental remediation via nonradical pathway, but also provides fundamental insights into the Fenton-like reaction mechanism., (© 2024. The Author(s).)

Introduction: Following acute enterovirus (EV) infection, outcomes vary based on factors like the immune response, viral cell entry receptor expression levels, tissue tropism, and genetic factors of both the host and virus. While most individuals exhibit mild, self-limited symptoms, others may suffer severe complications or prolonged infections that can lead to autoimmune disorders., Methods: To elucidate host responses to EV infection, we performed whole exome sequencing on blood samples from both infected and uninfected individuals. Our initial focus was on genes encoding EV entry receptors-PSGL-1, SCARB2, and ANAXA2 for EV-A71, and CD155 for poliovirus-and on host genes ACBD3 and PI4KΒ , crucial for EV replication., Results: Although no specific genetic variants directly associated with EV infection were identified, we discovered 118 variants across 116 genes enriched in East Asian populations through multi-layered variant filtering. These variants were further analyzed for their potential impacts on organs, biological processes, and molecular pathways. Phenome-wide association studies were conducted to refine our understanding of their contributions to EV infection susceptibility., Discussion: Our findings aim to develop a predictive panel based on these 118 variants, which could help susceptible individuals during EV outbreaks, guiding targeted clinical interventions and preventative strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sung, Luxton, Hung, Wu, Wang, Hsu and Hu.)

Background/aims: Hepatitis C virus (HCV) eradication using antiviral agents augments the metabolic profile. Changes in glycated hemoglobin (HbA1c) levels in chronic hepatitis C patients who receive glecaprevir/pibrentasvir (GLE/PIB) remain elusive., Methods: Data from 2417 patients treated with GLE/PIB from the Taiwan HCV Registry were analyzed, and pretreatment HbA1c levels were compared with 3-months after the-end-of treatment levels. A sustained virological response (SVR) was defined as undetectable HCV RNA at 12 weeks after the end of treatment. A significant change in HbA1c level was defined as the 75th percentile of the change in the HbA1c level before and after treatment (decrement >0.2%)., Results: Serum HbA1c levels decreased significantly (6.0 vs 5.9%, P < 0.001). Post-treatment HbA1c levels decreased in all subgroups, except in non-SVR patients (5.7 vs 5.7%, P = 0.79). Compared to patients without significant HbA1c improvement (decrement >0.2%), those with HbA1c improvement were older (60.2 vs 58.6 years, P < 0.001), had higher serum creatinine levels (1.9 vs 1.6 mg/dL, P < 0.001), triglycerides (129.8 vs 106.2 mg/dL, P < 0.001), fasting glucose (135.8 vs 104.0 mg/dL, P < 0.001), and pretreatment HbA1c (7.1 vs 5.7%, P < 0.001) and had a higher proportion of male sex (57.9% vs 50.9%, P = 0.003), diabetes (84.3 vs 16.8%, P < 0.001), more advanced stages of chronic kidney disease (CKD) (15.7 vs 11.1 %, P < 0.001), anti-diabetic medication use (47.3 vs 16.4%, P < 0.001) and fatty liver (49.6 vs 38.3 %, P < 0.001). Multivariate analysis revealed that the factors associated with significant HbA1c improvement were age (odds ratio [OR]/95% confidence intervals [CI]: 1.01/1.00-1.02, P = 0.01), HbA1c level (OR/CI: 2.83/2.48-3.24, P < 0.001) and advanced CKD stages (OR/CI: 1.16/1.05-1.28, P = 0.004). If the HbA1c variable was not considered, the factors associated with significant HbA1c improvement included alanine aminotransferase level (OR/CI, 1.002/1.000-1.004, P = 0.01), fasting glucose level (OR/CI: 1.010/1.006-1.013, P < 0.001), and diabetes (OR/CI: 3.35/2.52-4.45, P < 0.001)., Conclusions: The HbA1c levels improved shortly after HCV eradication using GLE/PIB. The improvement in glycemic control can be generalized to all subpopulations, particularly in patients with a higher baseline HbA1c level or diabetes., Competing Interests: Declaration of competing interest Ming-Lung Yu. Research support from Abbvie, Abbott, BMS, Gilead, Merck and Roche. Consultant for Abbvie, Abbott, Ascletis, BMS, Gilead, J&J, Merck, Novartis, Pharmaessential and Roche. Speaker for Abbvie, Abbott, Ascletis, BMS, Gilead, Merck, Pharmaessential and Roche. Chung-Feng Huang. Speaker for Abbvie, BMS, Gilead, Merck, and Roche., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The susceptibility of the immune system to immunotoxic chemicals is evident, particularly in the thymus, a vital primary immune organ prone to atrophy due to exposure to toxicants. Fipronil (FPN), a widely used insecticide, is of concern due to its potential neurotoxicity, hepatotoxicity, and immunotoxicity. Our previous study showed that FPN disturbed the antigen-specific T-cell functionality in vivo . As T-cell lineage commitment and thymopoiesis are closely interconnected with the normal function of the T-cell-mediated immune responses, this study aims to further examine the toxic effects of FPN on thymocyte development. In this study, 4-week-old BALB/c mice received seven doses of FPN (1, 5, 10 mg/kg) by gavage. Thymus size, medulla/cortex ratio, total thymocyte counts, double-positive thymocyte population, and IL-7-positive cells decreased dose-dependently. IL-7 aids the differentiation of early T-cell precursors into mature T cells, and several essential genes contribute to the maturation of T cells in the thymus. Foxn 1 ensures that the thymic microenvironment is suitable for the maturation of T-cell precursors. Lyl 1 is involved in specifying lymphoid cells and maintaining T-cell development in the thymus. The c-Kit/SCF collaboration fosters a supportive thymic milieu to promote the formation of functional T cells. The expression of IL- 7, IL- 7 R , c-Kit , SCF , Foxn 1, and Lyl 1 genes in the thymus was significantly diminished in FPN-treated groups with the concordance with the reduction of IL-7 signaling proteins (IL-7, IL-7R, c-KIT, SCF, LYL1, FOXO3A, and GABPA), suggesting that the dysregulation of T-cell lineage-related genes may contribute to the thymic atrophy induced by FPN. In addition, FPN disturbed the functionality of thymocytes with an increase of IL-4 and IFN-γ production and a decrease of IL-2 secretion after T-cell mitogen stimulation ex vivo . Collectively, FPN significantly deregulated genes related to T-cell progenitor differentiation, survival, and expansion, potentially leading to impaired thymopoiesis.

Tellurium is a rare element, and ammonium trichloro (dioxoethylene-o,o') tellurate (AS101) is the most bioactive molecule among several synthetic tellurium compounds. AS101 was found to be immunomodulatory and can modulate types of cytokines. However, the effect of AS101 on tumor metastasis remains unclear. Heparanase, an endo-glucuronidase, cleaves heparin sulfate side chains of proteoglycans on the cell surface, further leading to the degradation of the extracellular matrix. Heparanase also releases angiogenic factors in the extracellular matrix, is overexpressed in tumor cells, and promotes tumor metastasis and angiogenesis. In this study, we investigated the effect of AS101 in 4T1 and CT26 cells, especially heparanase. Heparanase expression was downregulated in 4T1 and CT26 cells after treatment with AS101 in vitro . The protein level involved in the protein kinase-B/mammalian target of rapamycin (AKT/mTOR) signaling pathway also declined. Cell migration assays revealed the inhibitory effect of AS101 on migration. The results of this study indicate that AS101 inhibits tumor migration by downregulating heparanase through the AKT/mTOR signaling pathway and has positive effects in vivo ., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been an established life-saving procedure for adult trauma patients, but the evidence for its use in pediatric patients is still under question. The purpose of this study was to examine the outcome of REBOA in pediatric patients., Methods: We retrospectively analyzed observational cohort data from the American College of Surgeons-Trauma Quality Improvement Program from 2017 to 2019. We analyzed 183 506 trauma patients aged 7-18, and 111 patients were matched by propensity score analysis. Basic demographics, injury severity, trauma type, and clinical outcomes of the patients receiving REBOA and those not receiving REBOA were compared. In the REBOA patients, a subgroup analysis was performed to evaluate the potential influence of age and body weight on the outcomes of REBOA., Results: After the pretreatment factors were balanced for the REBOA and no-REBOA groups, the patients in the REBOA group had more transfused packed red blood cells within the first 4 hours (3250 mL vs. 600 mL, p<0.001), and the mortality rate was higher in the REBOA group, but it did not reach statistical significance (56.8% vs. 36.5%, p=0.067). No significant difference was detected regarding in-hospital complications. In the subgroup analysis of the patients who received REBOA, we discovered no significant difference in mortality and complications between the subgroups when compared by age (>15 years old/≤15 years old) or weight (>58 kg or ≤58 kg)., Conclusions: Pediatric trauma patients who received REBOA were not significantly associated with an increased risk of mortality when compared with no-REBOA patients with matched basic demographics and pretreatment factors. Younger age and lighter body weight did not seem to influence the outcomes of REBOA regarding survival and complications., Level of Evidence: Level III., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Since April 2022, the SARS-CoV-2 Omicron variant has caused a notable increase in pediatric COVID-19 cases in Taiwan. During the acute phase of infection, some children required admissions to pediatric intensive care units (PICU). This study aimed to analyze their clinical presentations and outcomes while exploring associated factors., Methods: Medical records were retrospectively collected from patients with COVID-19 (aged <18 years) admitted to our PICU from April 2022-March 2023. Early stage is defined as the period without adequate vaccination and treatment guidelines for children from April-June 2022, and the remaining months are referred to as late stage. Clinical characteristics and outcomes were compared between patients in early and late stages., Results: We enrolled 78 children with COVID-19, with a median length of stay (LOS) in PICU of 3 days and a 5% mortality rate. Patients admitted during the early stage had lower vaccination rates (7% vs. 50%), higher pediatric logistic organ dysfunction scores (2 vs. 0.1), and longer LOS in the PICU (6 vs. 2 days) than those admitted during the late stage. Multivariate analysis identified admission during the early stage as a risk factor for prolonged LOS (>7 days) in the PICU (odds ratio: 3.65, p = 0.047)., Conclusion: Without available vaccinations and suitable treatment guidelines, children with COVID-19 tended to have more severe illness and prolonged LOS in the PICU. These observations highlight the importance of vaccinations and familiarity of medical providers with adequate management of this newly-emerging infectious disease., Competing Interests: Declaration of competing interest The authors declare no conflict of interest related to the subject matter or materials discussed in this article., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Objective: To discuss the efficacy and safety of the dual immunotherapy of nivolumab plus ipilimumab in patients with advanced non-small cell lung cancer (NSCLC) who are double negative for driver gene and programmed death-ligand 1 (PD-L1) expression. Methods: We conducted a retrospective collection of clinical data for 61 patients with advanced NSCLC who were negative for both driver genes and PD-L1 and received dual immunotherapy with nivolumab plus ipilimumab at the First Affiliated Hospital of Guangzhou Medical University from January 2019 to June 2023. Based on treatment conditions, patients were divided into first-line and non-first-line dual immunotherapy groups. Patients were followed up monthly, with the follow-up period ending on October 1, 2023. The efficacy was evaluated using Solid Tumor Response Evaluation Criteria, and adverse reactions were assessed according to the Common Terminology Criteria for Adverse Events developed by the National Cancer Institute in the United States. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the differences in progression-free survival (PFS) and overall survival (OS) between first-line and non-first-line dual immunotherapy patients. The influence factors of PFS were analyzed using a multivariate Cox proportional hazards regression model. Results: Among the 61 NSCLC patients, 49 were male (80.3%), with an age range of 23-88 years [(65.3±7.4) years]. There were 14 cases (23.0%) classified as stage ⅢC and 47 cases (77.0%) classified as stage Ⅳ according to TNM staging. Forty cases (65.6%) received non-first-line treatment. The objective response rate (ORR) was 24.6% (15/61), and the disease control rate (DCR) was 52.5% (32/61). All 61 patients were followed up, with a median follow-up time of 17.8 months. The median PFS was 6.0 months (95% CI : 5.5-6.4 months), and the median OS was 17.0 months (95% CI : 14.8-19.2 months). For patients receiving first-line dual immunotherapy, the median PFS was longer than for those receiving non-first-line dual immunotherapy [7.0 months (95% CI : 6.0-7.9 months) vs 4.0 months (95% CI : 3.3-4.6 months), P <0.001]; similarly, the median OS for patients receiving first-line dual immunotherapy was longer than for those receiving non-first-line dual immunotherapy [19.0 months (95% CI : 18.1-19.9 months) vs 13.0 months (95% CI : 10.8-15.1 months), P <0.001]. Multivariate Cox risk regression model analysis showed that distant tumor metastasis ( HR =1.414, 95% CI : 1.253-1.725), non-first-line dual immunotherapy ( HR =1.412, 95% CI : 1.184-1.652), and tumor mutation burden<10 mut/Mb ( HR =1.328, 95% CI : 1.151-1.546) were risk factors for PFS, while non-squamous carcinoma ( HR =0.917, 95% CI: 0.823-0.984) was a protective factor for PFS. Immune-related adverse reactions occurred in 41 cases (67.2%), including 21 cases (32.8%) of grade 3-4 adverse reactions. Eight cases (13.1%) discontinued treatment, and there were no deaths. Conclusions: Dual immunotherapy with nivolumab plus ipilimumab can be a treatment option for driver gene and PD-L1 double-negative advanced NSCLC. Distant tumor metastasis, non-first-line dual immunotherapy, and tumor mutation burden<10 mut/Mb are risk factors affecting patients' PFS, while non-squamous cell carcinoma is a protective factor affecting patients' PFS.

Metal-organic frameworks (MOFs) have become a hot spot in the area of functional materials and have undergone rapid development in a wide range of fields in the 21st century. However, the scalable application of MOFs is still constrained by high production cost at the front end. Additionally, systematic discussion of the reuse of spent MOFs is lacking. Encouragingly, an increasing number of studies have been focusing on the low-cost production and recycling of MOF-based materials, providing feasible solutions for resource recovery and reduction. To stimulate future enthusiasm and interest in realizing the blue economy of MOFs, ranging from front-end production to terminal disposal, we have presented and summarized the state-of-the-art progress in the sustainable synthesis, separation, and reuse of MOFs. Based on the existing challenges, we also propose fit-for-purpose future directions in the MOF field to move toward blue economy.

Objectives: Airway anomalies increase risk of morbidity and mortality in postoperative pediatric patients with congenital heart disease (CHD). We aimed to identify airway anomalies and the association with intermediate outcomes in patients undergoing surgery for CHD., Design: Single-center, hospital-based retrospective study in Taiwan, 2017-2020., Setting: A tertiary referral hospital in Taiwan., Patients: All pediatric patients who underwent surgery for CHD and were admitted to the PICU and had data about airway evaluation by cardiopulmonary CT scan or bronchoscopy., Interventions: None., Measurements and Main Results: Among 820 CHD patients identified as having undergone airway evaluation in the PICU, 185 (22.6%) were diagnosed with airway anomalies, including structural lesions in 146 of 185 (78.9%), and dynamic problems were seen in 87 of 185 (47.0%). In this population, the explanatory factors associated with greater odds (odds ratio [OR]) of airway anomaly were premature birth (OR, 1.90; p = 0.002), genetic syndromes (OR, 2.60; p < 0.001), and in those with preoperative ventilator use (OR, 4.28; p < 0.001). In comparison to those without airway anomalies, the presence of airway anomalies was associated with higher hospital mortality (11.4% vs. 2.7%; p < 0.001), prolonged intubation days (8 d [1-27 d] vs. 1 d [1-5 d]; p < 0.001), longer PICU length of stay (23 d [8-81 d] vs. 7 d [4-18 d]; p < 0.001), and greater hazard of intermediate mortality (adjusted hazard ratio, 2.60; p = 0.001)., Conclusions: In our single-center retrospective study, 2017-2020, between one-in-five and one-in-four of our postoperative CHD patients undergoing an airway evaluation had airway anomalies. Factors associated with greater odds of airway anomaly included, those with premature birth, or genetic syndromes, and preoperative ventilator use. Overall, in patients undergoing airway evaluation, the finding of an airway anomalies was associated with longer postoperative intubation duration and greater hazard of intermediate mortality., Competing Interests: Dr. S.-C. Huang’s institution received funding from the Ministry of Science and Technology of Taiwan (MOST-110-2314-B-002-090-MY3 and MOST- 112-2314-B-002-180-); he received support for article research from the Ministry of Science and Technology of Taiwan. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Despite the efficacy of onabotulinumtoxinA, its safety profile remains a concern. This meta-analysis reviewed the major adverse events (AEs) associated with intravesical onabotulinumtoxinA treatment in patients with neurogenic detrusor overactivity (NDO) and idiopathic overactive bladder (iOAB). Randomized controlled trials (RCTs) conducted between January 2000 and December 2022 were searched for adult patients administered different onabotulinumtoxinA dosages or onabotulinumtoxinA vs. placebo. Quality assessment was performed using the Cochrane Collaboration tool, and statistical analysis was performed using Review Manager version 5.3. A total of 26 RCTs were included in the analysis, including 8 on NDO and 18 on iOAB. OnabotulinumtoxinA vs. placebo significantly increased the urinary tract infection (UTI) incidence in patients with NDO (relative risk, or RR, 1.54) and iOAB (RR, 2.53). No difference in the RR with different onabotulinumtoxinA dosages was noted. Urinary retention was frequent with onabotulinumtoxinA use in the NDO (RR, 6.56) and iOAB (RR, 7.32) groups. Similar observations were made regarding the risks of de novo clean intermittent catheterization (CIC). The risk of voiding difficulty increased with onabotulinumtoxinA use in patients with iOAB. Systemic AEs of onabotulinumtoxinA, including muscle weakness (RR, 2.79) and nausea (RR, 3.15), were noted in patients with NDO; most systemic AEs had a low incidence and were sporadic.

In this study, biotin esterified debranched starch (Bio-DBS) nanoparticles with different molecular weights were prepared to improve the stability and antioxidant activity of resveratrol. The molecular weights of branched starch (DBS 3 , DBS 9 and DBS p ) determined by high-performance size-exclusion chromatography (HPSEC) were 3306, 3696, and 4688, respectively. Biotin was covalently coupled to DBS through the esterification reaction as a new material to prepare nanoparticles. The morphology, particle size, and loading capacity of Bio-DBS nanoparticles were all related to the molecular weights of DBS. The 1 H NMR results indicated that there was a hydrogen bonding interaction between Bio-DBS and resveratrol, which contributed to the photochemical and antioxidant activity of resveratrol in the nanoparticles. The highest encapsulation efficiency (78.9 %) and loading capacity (15.78 %) of resveratrol were observed in Bio-DBS 3 nanoparticles. Additionally, the cell viability was over 80 % when the concentration of Bio-DBS 3 reached to 200 μg/mL. The Bio-DBS nanoparticles significantly improved the thermal stability, photostability, and antioxidant properties of resveratrol. Therefore, the Bio-DBS nanoparticles prepared in this study can be used as a promising carrier to improve the stability and antioxidant activity of resveratrol and may have potential applications in oral delivery., Competing Interests: Declaration of competing interest The authors have no conflict of interests related to this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Data scarcity is one of the most critical issues impeding the development of prediction models for chemical effects. Multitask learning algorithms leveraging knowledge from relevant tasks showed potential for dealing with tasks with limited data. However, current multitask methods mainly focus on learning from datasets whose task labels are available for most of the training samples. Since datasets were generated for different purposes with distinct chemical spaces, the conventional multitask learning methods may not be suitable. This study presents a novel multitask learning method MTForestNet that can deal with data scarcity problems and learn from tasks with distinct chemical space. The MTForestNet consists of nodes of random forest classifiers organized in the form of a progressive network, where each node represents a random forest model learned from a specific task. To demonstrate the effectiveness of the MTForestNet, 48 zebrafish toxicity datasets were collected and utilized as an example. Among them, two tasks are very different from other tasks with only 1.3% common chemicals shared with other tasks. In an independent test, MTForestNet with a high area under the receiver operating characteristic curve (AUC) value of 0.911 provided superior performance over compared single-task and multitask methods. The overall toxicity derived from the developed models of zebrafish toxicity is well correlated with the experimentally determined overall toxicity. In addition, the outputs from the developed models of zebrafish toxicity can be utilized as features to boost the prediction of developmental toxicity. The developed models are effective for predicting zebrafish toxicity and the proposed MTForestNet is expected to be useful for tasks with distinct chemical space that can be applied in other tasks.Scieific contributionA novel multitask learning algorithm MTForestNet was proposed to address the challenges of developing models using datasets with distinct chemical space that is a common issue of cheminformatics tasks. As an example, zebrafish toxicity prediction models were developed using the proposed MTForestNet which provide superior performance over conventional single-task and multitask learning methods. In addition, the developed zebrafish toxicity prediction models can reduce animal testing., (© 2024. The Author(s).)

Background: Hepatitis B virus (HBV)-specific T cell response is a major host immune response to control the virus. However, it is still unclear how it affects long-term outcomes of chronic hepatitis B patients, especially those who stop nucleos(t)ide analogue (NA) therapy. We aimed to explore whether the HBV-specific T cell response at the end of treatment (EOT) was associated with clinical outcomes., Methods: In a prospective cohort study, 51 HBeAg-negative patients who discontinued NA therapy were enrolled., Results: In a mean follow-up of 25.3 months, 25 patients developed clinical relapse. We found that a stronger hepatitis B core (HBc)-specific T cell response at EOT was associated with a lower risk of clinical relapse. Compared to the low-response group, the high-response group had a lower risk of clinical relapse with hazard ratio of 0.21 (95% CI: 0.05-0.88). The high HBc-specific T cell response was associated with reduced surge of HBV DNA and HBcrAg during the first year of follow-up. The T cell response at EOT was comparable between different NA treatments. Notably, the overall HBV-specific T cell response could be partially restored along with clinical relapse; however, such reinvigorated T cell response was not associated with HBsAg seroclearance., Conclusions: A higher HBc-specific T cell response at EOT was associated with lower risk of clinical relapse and reduced surge of HBV DNA and HBcrAg levels off NA therapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Objective: The prevalence and the cluster characteristics of risk factors of stroke were assessed in a Chinese diabetic population., Methods: Clinical data of 30 693 inpatients who were diagnosed with type 2 diabetes mellitus (T2DM) and admitted between 2013 and 2018 were retrospectively analyzed. The age-standardized prevalence of stroke was estimated using the 2010 Chinese population census data, and risk factors were analyzed by multiple imputation and regression., Results: The crude and standardized prevalence rates of stroke in patients with T2DM were 34.4% and 21.5%, respectively, and 85.2% of the stroke patients had ischemic stroke. Nearly half of the patients who experienced stroke had clusters of more than 4 risk factors. Compared with no-risk-factor clustering, the risk of stroke significantly increased 3-4 times in the presence of more than 4 risk-factor clusters (P<0.001). Hypertension was the most common major risk factor for ischemic stroke [odds ratio (OR), 2.34; 95% confidence interval (CI), 2.18-2.50] and hemorrhagic stroke (OR, 3.68; 95% CI 2.95-4.59; P<0.001). Moreover, a 1-standard-deviation increase in fasting blood glucose (FBG) was significantly negatively correlated with ischemic stroke risk, and the same change in FBG was significantly associated with an 8% increased risk of hemorrhagic stroke., Conclusion: The prevalence of stroke in patients with T2DM is rather high, and the clustering of risk factors is associated with the development of stroke in T2DM patients. Risk factors differ in different stroke subtypes. Identifying risk factors for a specific high-risk group is necessary., (© 2024. Huazhong University of Science and Technology.)

Background: Domestic and foreign studies on lung cancer have been oriented to the medical efficacy of low-dose computed tomography (LDCT), but there is a lack of studies on the costs, value and cost-effectiveness of the treatment. There is a scarcity of conclusive evidence regarding the cost-effectiveness of LDCT within the specific context of Taiwan. This study is designed to address this gap by conducting a comprehensive analysis of the cost-effectiveness of LDCT and chest X-ray (CXR) as screening methods for lung cancer., Methods: Markov decision model simulation was used to estimate the cost-effectiveness of biennial screening with LDCT and CXR based on a health provider perspective. Inputs are based on probabilities, health status utility (quality-adjusted life years (QALYs)), costs of lung cancer screening, diagnosis, and treatment from the literatures, and expert opinion. A total of 1,000 simulations and five cycles of Markov bootstrapping simulations were performed to compare the incremental cost-utility ratio (ICUR) of these two screening strategies. Probability and one-way sensitivity analyses were also performed., Results: The ICUR of early lung cancer screening compared LDCT to CXR is $-24,757.65/QALYs, and 100% of the probability agree to adopt it under a willingness-to-pay (WTP) threshold of the Taiwan gross domestic product (GDP) per capita ($35,513). The one-way sensitivity analysis also showed that ICUR depends heavily on recall rate. Based on the prevalence rate of 39.7 lung cancer cases per 100,000 people in 2020, it could be estimated that LDCT screening for high-risk populations could save $17,154,115., Conclusion: LDCT can detect more early lung cancers, reduce mortality and is cost-saving than CXR in a long-term simulation of Taiwan's healthcare system. This study provides valuable insights for healthcare decision-makers and suggests analyzing cost-effectiveness for additional variables in future research., Competing Interests: The authors report no conflict with any product mentioned or concept discussed in this article., (Copyright 2024, Sheu et al.)

Humans are extensively exposed to organophosphate flame retardants (OPFRs), an emerging group of organic contaminants with potential nephrotoxicity. Nevertheless, the estimated daily intake (EDI) and prognostic impacts of OPFRs have not been assessed in individuals with chronic kidney disease (CKD). In this 2-year longitudinal study of 169 patients with CKD, we calculated the EDIs of five OPFR triesters from urinary biomonitoring data of their degradation products and analyzed the effects of OPFR exposure on adverse renal outcomes and renal function deterioration. Our analysis demonstrated universal OPFR exposure in the CKD population, with a median EDI ΣOPFR of 360.45 ng/kg body weight/day (interquartile range, 198.35-775.94). Additionally, our study revealed that high tris(2-chloroethyl) phosphate (TCEP) exposure independently correlated with composite adverse events and composite renal events (hazard ratio [95 % confidence interval; CI]: 4.616 [1.060-20.096], p = 0.042; 3.053 [1.075-8.674], p = 0.036) and served as an independent predictor for renal function deterioration throughout the study period, with a decline in estimated glomerular filtration rate of 4.127 mL/min/1.73 m 2 (95 % CI, -8.127--0.126; p = 0.043) per log ng/kg body weight/day of EDI TCEP . Furthermore, the EDI TCEP and EDI ΣOPFR were positively associated with elevations in urinary 8-hydroxy-2'-deoxyguanosine and kidney injury molecule-1 during the study period, indicating the roles of oxidative damage and renal tubular injury in the nephrotoxicity of OPFR exposure. To conclude, our findings highlight the widespread OPFR exposure and its possible nephrotoxicity in the CKD population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)