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Yue-Ying Yang,1,2,* Jing Liu,2,* Yi-Tong Liu,3,4 Hsiao-Hui Ong,2 Qian-Min Chen,2,4 Ce-Belle Chen,5 Mark Thong,6 Xinni Xu,6 Sui-Zi Zhou,3,4 Qian-Hui Qiu,3,4 De-Yun Wang2 1Department of Otolaryngology-Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Otolaryngology, Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 3Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 4The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 5Centre for Ion Beam Applications, Department of Physics, National University of Singapore, Singapore; 6Department of Otolaryngology-Head and Neck Surgery, National University Hospital, National University Health System, Singapore*These authors contributed equally to this workCorrespondence: Qian-Hui Qiu, Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, No. 106 Zhongshan Road II, Guangzhou, 510080, People’s Republic of China, Tel +86 20 83827812, Email qiuqianhui@hotmail.com De-Yun Wang, Department of Otolaryngology, Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, NUHS Tower Block, 1E Kent Ridge Road, 119228, Singapore, Tel + 65 6772 5373/5370/5371, Fax +65 6775 3820, Email entwdy@nus.edu.sgPurpose: Radiotherapy (RT) is the mainstay treatment for head and neck cancers. However, chronic and recurrent upper respiratory tract infections and inflammation have been commonly reported in patients post-RT. The underlying mechanisms remain poorly understood.Method and Materials: We used a well-established model of human nasal epithelial cells (hNECs) that forms a pseudostratified layer in the air-liquid interface (ALI) and exposed it to single or repeated moderate dose γ-irradiation (1Gy). We assessed the DNA damage and evaluated the biological properties of hNECs at different time points post-RT. Further, we explored the host immunity alterations in irradiated hNECs with polyinosinic-polycytidylic acid sodium salt (poly [I:C]) and lipopolysaccharides (LPS).Results: IR induced DNA double strand breaks (DSBs) and triggered DNA damage response in hNECs. Repeated IR significantly reduced basal cell proliferation with low expression of p63/KRT5 and Ki67, induced cilia loss and inhibited mucus secretion. In addition, IR decreased ZO-1 expression and caused a significant decline in the transepithelial electrical resistance (TEER). Moreover, hyperreactive response against pathogen invasion and disrupted epithelial host defense can be observed in hNECs exposed to repeated IR.Conclusion: Our study suggests that IR induced prolonged structural and functional impairments of hNECs may contribute to patients post-RT with increased risk of developing chronic and recurrent upper respiratory tract infection and inflammation.Keywords: human nasal epithelial cells, irradiation, DNA double strand breaks, epithelial barrier, host defense

Yin-Ku Lin,1,2 Ching-Ya Wang,3,4 Yu-Huei Huang,3,4 Ya-Ching Chang,3,4 Chun-Bing Chen,3– 9 Chuang-Wei Wang,3,5– 7,&ast; Rosaline Chung-Yee Hui,3,4,&ast; Wen-Hung Chung3,5– 12,&ast; 1Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; 2School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan; 4College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; 6Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Linkou, Taiwan; 7Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, People’s Republic of China; 8Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; 9Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; 10Department of Dermatology, Beijing Tsinghua Chang Gung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 11School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 12Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan&ast;These authors contributed equally to this workCorrespondence: Wen-Hung Chung, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fusing St, Taoyuan, 333, Taiwan, Tel +886 3-3281200 #8495, Fax +886 3-3281200 #2206, Email wenhungchung@yahoo.com; chung1@cgmh.org.twPurpose: Lindioil, a medicine refined from indigo naturalis (a herb used in Chinese medicine), is effective in treating severe psoriasis; however, responses vary across individual patients. We aim to investigate genetic predispositions associated with treatment response to topical Lindioil among patients with psoriasis and correlations with plasma cytokine patterns.Patients and Methods: We enrolled 72 psoriasis patients treated with Lindioil ointment and analyzed the human leukocyte antigen class C (HLA-Cw) genotypes and plasma cytokine expression patterns. We developed regression models of treatment response, defined as Psoriasis Area and Severity Index (PASI) 75, to examine correlations among HLA-Cw alleles, cytokine levels, and treatment response to Lindioil.Results: Patients harboring HLA-Cw&ast;06:02 were significantly more likely to respond to Lindioil (P = 0.02, odds ratio [OR]: 6.88), whereas Lindoil was ineffective in those harboring HLA-Cw&ast;01:02 (P = 0.01, OR: 0.28). Patients who were HLA-Cw&ast;06:02-positive or HLA-Cw&ast;01:02-negative had better PASI scores and body surface area (BSA) improvement (73.3% vs 44.4%, P< 0.001) following an 8-week treatment period. Psoriasis patients achieving PASI 75 after 8 weeks presented with lower baseline plasma interleukin-17 (IL-17) levels than those who did not achieve PASI 75 (PASI 75: 11.28 pg/mL vs PASI < 75: 15.82 pg/mL, P = 0.05).Conclusion: Our findings suggest that the presence of the HLA-Cw&ast;06:02 or HLA-Cw&ast;01:02 alleles and plasma IL-17 levels are predictive markers of treatment response to Lindioil ointment in patients with psoriasis.Keywords: HLA-Cw&ast;06:02, HLA-Cw&ast;01:02, indigo naturalis, Lindioil, IL-17, psoriasis

Chih-Jung Chang,1,2,&ast; Hai-Qing Wang,3,&ast; Jing Zhang,3 Ying Zou,3 Yi-Hua Zhang,3 Jia-Wen Chen,3 Chun-Bing Chen,2,4– 7 Wen-Hung Chung,1,2,4– 6,8,9 Chao Ji3 1Medical Research Center and Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, Fujian, People’s Republic of China; 2Department of Dermatology and Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan; 3Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 4Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 5College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; 7Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan; 8Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, Fujian, People’s Republic of China; 9School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen-Hung ChungDepartment of Dermatology and Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, TaiwanTel +886-3-3281200 ext. 8494Email wenhungchung@yahoo.comChao JiDepartment of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of ChinaTel +86-18651619908Email jichaofy@fjmu.edu.cnBackground: Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disorder characterized by a T helper 2 (Th2) immune response phenotype. Extracellular vesicles (EVs) are a heterogeneous family of cell-derived membranous structures, which transport cellular components such as DNA and proteins, and are involved in multiple physiological and pathological processes. Increasing evidence has shown that EVs secretion took part in the pathogenesis of AD. However, the proteomic studies of plasma-derived EVs in AD patients have not been reported.Objective: In this study, we investigated the diversity of plasma EVs collected from AD patients and healthy individuals and suggested that the candidates for uniquely or differentially expressed proteins in plasma EVs could be a diagnostic marker in AD.Methods: The plasma EVs were collected from 12 patients with moderate-to-severe AD and 13 healthy subjects. Proteomic analysis was performed by using a comprehensive nanoLC‑MS/MS method.Results: Proteomic analysis revealed that a total of 1478 proteins in plasma EVs were found to be common proteins in AD, whereas a total of 1597 proteins in plasma EVs were found to be common proteins in HC. Eighty-six proteins in plasma EVs showed more than 2.5-fold up-regulation, while a total of 225 proteins in plasma EVs showed less than 1/2.5-fold down-regulation with a significant difference (p < 0.05) among AD compared with HC. The candidates for differentially expressed proteins in plasma EVs have been described as a connectivity PPI network related to several KEGG pathways, including pathways in platelet activation, complement, and so on.Conclusion: SLP-76 tyrosine phosphoprotein (SLP76) involved in platelet activation may significantly contribute to the pathogenesis of AD. We will further verify the role of SLP67 in AD via animal and cell experiments to provide a promising therapeutic or diagnostic target.Keywords: atopic dermatitis, extracellular vesicle, plasma, proteomic profiling

Li-Heng Tsai,1,2 Cheng-Yu Chien,1– 3 Chen-Bin Chen,1,2,4 Chung-Hsien Chaou,1,2 Chip-Jin Ng,1,2 Mei-Yi Lo,5 Chen-Ken Seak,6 Joanna Chen-Yeen Seak,6 Zhong Ning Leonard Goh,6 Chen-June Seak1,2,4,7 1Department of Emergency Medicine, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Emergency Medicine, Ton-Yen General Hospital, Zhubei, Taiwan; 4Department of Emergency Medicine, New Taipei Municipal Tucheng Hospital, New Taipei City, Taiwan; 5Department of Nursing, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6Sarawak General Hospital, Kuching, Sarawak, Malaysia; 7Center for Quality Management, New Taipei Municipal Tucheng Hospital, New Taipei City, TaiwanCorrespondence: Chen-June SeakDepartment of Emergency Medicine, Lin-Kou Medical Center, Chang Gung Memorial Hospital, No. 5, Fusing St., Guei-Shan Township, Taoyuan County 333, TaiwanTel +886-3-3281200 ext. 5235Fax +886-3-3287715Email julianseak@hotmail.comPurpose: Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is an emerging contagious pathogen that has caused community and nosocomial infections in many countries. This study aimed to evaluate the impact of Coronavirus disease 2019 (COVID-19) on emergency services of the largest medical center in Taiwan by comparing emergency department (ED) usage, turnover, and admission rates before the COVID-19 outbreak with those during the outbreak.Materials and Methods: A retrospective cohort study was conducted in the ED of the largest tertiary medical center in Taiwan. Trends of adult, non-trauma patients who visited the ED during February–April 2019 were compared with those during February–April 2020. The number of visits, their dispositions, crowding parameters, and turnover rates were analyzed. The primary outcome was the change in ED attendance between the two periods. The secondary outcomes were changes in hospital admission rates, crowding parameters, and turnover rates.Results: During the outbreak, there were decreased non-trauma ED visits by 33.45% (p < 0.001) and proportion of Taiwan Triage and Acuity Scale (TTAS) 3 patients (p=0.02), with increased admission rates by 4.7% (p < 0.001). Crowding parameters and turnover rate showed significant improvements.Conclusion: Comparison of periods before and during the COVID-19 outbreak showed an obvious decline in adult, non-trauma ED visits. The reduction in TTAS 3 patient visits and the increased hospital admission rates provide references for future public-health policy-making to optimise emergency medical resource allocations globally.Keywords: emergency department, Coronavirus disease 2019, Taiwan Triage and Acuity Scale, Stratification to Prevent Overcrowding Taskforce, SPOT

Chuanben Chen,1,2 Zhaodong Fei,1,2 Chaoxiong Huang,2 Jianming Ding,1,2 Lisha Chen1,2 1Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, People’s Republic of China; 2Provincial Clinical College, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China Background: The prognostic value of primary tumor volume (TV) in nasopharyngeal carcinoma (NPC) has been confirmed. However, studies of the prognosis value of tumor burden, including TV and nodal volume (NV), have been relatively infrequent. Therefore, the aim of this study was to evaluate the prognostic value of tumor burden in NPC patients treated with intensity-modulated radiotherapy.Methods: Receiver operating characteristics curves were generated to determine rational cutoff points for TV and NV. The volumes identified included 12.5, 25.0, and 50.0 mL, and 0, 12.5, and 25 mL, respectively. According to these cutoff volumes, four subgroups were established for TV as TV1–TV4, and four subgroups were established for NV as NV0–NV3. Then, the entire cohort (992 NPC patients) was divided into 16 subgroups according to these four levels of TV and NV. Based on similarities in the 5-year overall survival (OS) rates for these 16 subgroups, four patient groups were established, G1–G4.Results: The mean TV and NV values for our cohort were 39.5±30.8 mL and 16.5±17.6 mL, respectively. The 5-year distant failure-free rate, the 5-year disease-free survival rate, and the 5-year OS rate for G3 and G4 were significantly lower than those for G1 and G2. In particular, the OS curves of the four patient groups were significantly separated. A multivariate analysis identified TV >50 mL, T-stage (3–4), and N-stage (2–3) as adverse prognostic factors for OS.Conclusions: The results of this study demonstrate that tumor burden has a significant prognostic value for NPC patients treated with intensity-modulated radiotherapy. Hence, tumor burden, including TV and NV, should be incorporated into the current staging system for NPC to improve prognostic significance. Keywords: prognostic value, tumor burden, primary tumor volume , nodal volume, nasopharyngeal carcinoma

Chun-Bing Chen,1–6 Ming-Ying Wu,1–4 Chau Yee Ng,1–5 Chun-Wei Lu,1–6 Jennifer Wu,1–4,6 Pei-Han Kao,1–4,6 Chan-Keng Yang,4–7 Meng-Ting Peng,4,6–7 Chen-Yang Huang,4,6–7 Wen-Cheng Chang,4,6–7 Rosaline Chung-Yee Hui,1–4 Chih-Hsun Yang,1–4 Shun-Fa Yang,8,9 Wen-Hung Chung,1–4,6,10,11 Shih-Chi Su1–4,10 1Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan; 2Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan; 3Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan; 4College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; 7Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan; 8Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 9Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan; 10Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; 11Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China Abstract: With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5–91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management. Keywords: acute generalized exanthematous pustulosis, drug rash, eosinophilia, Stevens–Johnson syndrome, toxic epidermal necrolysis, targeted therapy, immunotherapy

Background: As a drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) is potentially fatal. Most patients with DRESS recover within a few weeks; however, some patients may suffer from a prolonged disease course and develop autoimmune sequelae., Objective: We investigated the immune mechanism and therapeutic targets of patients with recalcitrant DRESS with a prolonged disease course., Methods: A total of 32 patients with recalcitrant DRESS with a prolonged treatment course ≥8 weeks, 28 patients with short-duration DRESS with a treatment course <2 weeks, and 26 healthy individuals were enrolled in the study for analysis., Results: Bulk transcriptome results demonstrated that mRNA expression levels of CCR8 and CXCR3 were significantly increased in the blood samples from patients in the acute stage of prolonged DRESS (adjusted p-values: CCR8=1.50×10-9 and CXCR3=2.60×10-4, respectively, for comparison of patients with prolonged DRESS to the healthy donor group). Serum and skin lesional concentrations of CCL1 and CXCL10, as the ligands of CCR8 and CXCR3, respectively, were significantly elevated in patients with prolonged DRESS as compared to those patients with short-duration DRESS. The results from high-parameter flow cytometry and autoantibody screening also identified significant escalations of CD8+ GNLY+CXCR3+effector memory T cells, CD8+central memory T cells, CD4+CCR8+Th2 cells, and IgG-anti-HES6 autoantibodies in patients with prolonged DRESS. Furthermore, in vitro blocking assays revealed that JAK inhibitors (mainly tofacitinib and upadacitinib) significantly decreased the release of CCL1 and CXCL10, and some patients with prolonged DRESS were successfully treated with JAK inhibitors., Conclusions: JAK inhibitors (tofacitinib and upadacitinib) were associated with decreased concentrations of CCL1 and CXCL10, suggesting that they may attenuate CCR8/CCL1- and CXCR3/CXCL10-axis-mediated memory T cell activation, which contribute to disease pathogenesis for patients with recalcitrant DRESS and a long-term treatment course., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: The rate of survival after out-of-hospital cardiac arrest varies depending on the timeliness and effectiveness of prehospital interventions. This study was conducted to compare out-of-hospital cardiac arrest outcomes between intravenous and intraosseous routes and between upper and lower extremity routes for drug administration., Methods and Results: We retrospectively analyzed data (collected using the Utstein template) from 1220 patients who had experienced out-of-hospital cardiac arrest in Taiwan's Taoyuan City between January 2021 and August 2023. The patients were stratified into intravenous and intraosseous groups by treatment approach and upper and lower extremity access groups by access site. The study outcomes were survival to discharge, favorable neurologic outcomes (Cerebral Performance Category score 1 or 2), and survival for >2 hours. The study groups were statistically compared before and after propensity score matching. Significant pre-propensity score matching differences were observed between intravenous and intraosseous groups, and the aforementioned study outcomes were better in the intravenous group than in the intraosseous group. However, the between-group differences became nonsignificant after propensity score matching. Furthermore, lower extremity access and delayed epinephrine administration were associated with worse outcomes. Survival rates fell below 12.6% when time to treatment exceeded 15 minutes, particularly in the cases of intraosseous access and lower extremity access., Conclusions: This study highlights the benefits of early intervention and upper extremity access for drug administration in patients with out-of-hospital cardiac arrest. Intraosseous access may serve as a viable alternative to intravenous access. Timely administration of essential drugs during resuscitation can improve clinical outcomes and thus has implications for emergency medical service training.

Background: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), shows superior lung cancer treatment efficacy. However, osimertinib-induced severe hypersensitivity, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), is frequently observed in Asian populations and hinders cancer treatment., Objective: We investigated the genetic HLA predisposition and immune pathomechanism of osimertinib-induced hypersensitivity., Methods: We enrolled 17 patients with osimertinib-induced delayed hypersensitivity (7 with severe SJS/TEN and 10 with mild maculopapular exanthema [MPE]), 98 osimertinib-tolerant subjects, and 2123 general population controls. HLA genotyping, drug-induced lymphocyte activation test (LAT), and surface plasmon resonance (SPR) assay were performed., Results: HLA-B*51:02 was present in 83.3% of osimertinib-induced SJS/TEN patients but only in 3.3% of the general population controls (P = 2.8×10 -7 , Pc=6.9×10 -6 , odds ratio [OR]=146), and 0% of osimertinib-tolerant controls (P = 6.5×10 -8 , Pc=1.6×10 -6 , OR=707). The association of HLA-B*51:01 and HLA-A*24:02 with osimertinib-induced MPE patients, rather than with osimertinib-tolerant subjects (P = 0.002, OR=15.7 for HLA-B*51:01; P = 0.003, OR=9.5 for HLA-A*24:02), was identified as a phenotype-specific association. Granulysin-the SJS/TEN-specific cytotoxic protein-was significantly higher in SJS/TEN patients' plasma (39.8±4.5 ng/ml, P<0.001) and in in vitro LAT (sensitivity=83.3%, P<0.01) compared to the tolerant controls. Patients with osimertinib-induced hypersensitivity appeared to tolerate alternative EGFR-TKIs. SPR results also confirmed that HLA-B*51:02 protein has a higher binding affinity for osimertinib and lower or no affinity for other EGFR-TKIs., Conclusions: HLA-B*51:02 frequently occurs in Asian populations and is strongly associated with osimertinib-induced SJS/TEN. Our findings suggest HLA-B*51:02 screening as a preemptive test to reduce osimertinib-induced severe hypersensitivity., (Copyright © 2024. Published by Elsevier Inc.)

Background: Survival following an out-of-hospital cardiac arrest depends on prompt defibrillation. Despite the efforts made to install automated external defibrillators (AEDs) in crowded areas, their usage rate remains suboptimal. This study evaluated the efficiency of installing AEDs at key landmarks in Taoyuan City to enhance accessibility and usage., Methods and Results: This retrospective cohort study analyzed nontraumatic public out-of-hospital cardiac arrest cases in Taoyuan City from 2017 to 2021, using data from the Taoyuan Fire Department and a regional registry. AED data were collected for 1163 devices. A geographic information system mapped target locations within the city, and real-world walking routes were examined to assess coverage. The primary outcome was actual coverage and the coverage efficiency ratio, calculated as the actual coverage divided by the number of facilities at a location. The coverage efficiency ratio compared the coverage efficiency of target locations with existing public access defibrillators (PADs). Top locations for superior coverage in both downtown and outside downtown areas were bus stops and convenience stores (7-Eleven and FamilyMart), which outperformed existing PADs. Convenience stores had a higher coverage efficiency ratio than the public service sector. Bus stops showed high AED usage rates before ambulance arrival., Conclusions: The current PAD locations in Taoyuan City offer limited coverage, which highlights the need for strategically installed AEDs, particularly in convenience stores. Policymakers should consider using the cultural relevance and accessibility of convenience stores, particularly 7-Eleven branches, to enhance AED usage rates.

Objective: This study aims to use the maximum standardised uptake value (SUV max ) of 18F-fluorodeoxyglucose positron emission tomography to improve the cost effectiveness of nimotuzumab (NTZ) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC)., Methods: Two hundred and forty-eigh patients with LA-NPC, who met the inclusion criteria, were recruited from January 2012 to June 2019. The survival differences and independent factors were assessed using the Kaplan-Meier method and by Cox proportional hazards regression analysis. A cost effectiveness analysis was performed., Results: The optimal cut-off value for SUV max was 12.92. Multivariable analysis indicated a prognostic significance of overall survival (OS) for the NTZ treatment (p = 0.023) and SUV max (p = 0.014). The exploratory subgroup survival analysis revealed that LA-NPC patients with SUV max > 12.92 treated with concurrent chemoradiotherapy (CCRT) and NTZ had a significantly improved 3-year OS compared to patients treated with CCRT alone (96.2 vs 73.2%, p = 0.047). Furthermore, the treatment cost for NTZ was $6,317.61. This incurred an additional cost of $274.68 for every 1% increase in OS., Conclusions: For patients with LA-NPC with SUV max > 12.92, the addition of NTZ to CCRT can improve OS and is cost effective., (Copyright © 2024 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

Background: Early detection of nasopharyngeal carcinoma (NPC) poses a significant challenge. The absence of highly sensitive and specific diagnostic biomarkers for nasopharyngeal carcinoma contributes to the unfavourable prognosis of NPC patients. Here, we aimed to establish a non-invasive approach for detecting NPC using circulating cell-free DNA (cfDNA)., Methods: We investigated the potential of next-generation sequencing (NGS) of peripheral blood cells as a diagnostic tool for NPC. We collected data on genome-wide nucleosome footprint (NF), 5'-end motifs, fragmentation patterns, CNV information, and EBV content from 553 Chinese subjects, including 234 NPC patients and 319 healthy individuals. Through case-control analysis, we developed a diagnostic model for NPC, and validated its detection capability., Findings: Our findings revealed that the frequencies of NF, fragmentation, and motifs were significantly higher in NPC patients compared to healthy controls. We developed an NPC score based on these parameters that accurately distinguished NPC from non-NPC cases according to the American Joint Committee on Cancer staging system from non-NPC (validation set: area under curve (AUC) = 99.9% (95% CI: 99.8%-100%), se: 98.15%, sp: 100%). This model showed superior performance over plasma EBV DNA. Additionally, the NPC score effectively differentiated between NPC patients and healthy controls, even after clinical treatment. Furthermore, the NPC score was found to be independent of potential confounders such as age, sex, or TNM stage., Interpretation: We have developed and verified a non-invasive approach with substantial potential for clinical application in detecting NPC., Funding: A full list of funding bodies that contributed to this study can be found in Funding section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The newly released Asian Working Group for Cachexia (AWGC) criteria share similar diagnostic items with the Global Leadership Initiative on Malnutrition (GLIM) criteria. This study aims to compare the AWGC cachexia and GLIM malnutrition in patients with gastric cancer and investigate whether one diagnosis continues to be a prognostic factor in individuals diagnosed with the other condition., Methods: Data of patients who underwent radical gastrectomy for gastric adenocarcinoma were prospectively collected from 2013 to 2019. The AWGC and GLIM criteria were applied to diagnosis cachexia and malnutrition, respectively. Univariate and multivariate logistic and Cox regression were used to verify the effect of relevant factors on postoperative complications and overall survival., Results: A total of 1420 patients were included, among whom 174 (12.3 %) were diagnosed with AWGC-cachexia alone, 85 (6.0 %) were diagnosed with GLIM-malnutrition alone, and 324 (22.8 %) had both AWGC-cachexia and GLIM-malnutrition. Both AWGC-cachexia and GLIM-malnutrition were independent risk factors for complications and overall survival. When they coexisted, the odds ratios (OR) and hazard ratios (HR) tended to be higher. In the AWGC-cachexia subset, GLIM-malnutrition remained an independent risk factor (HR = 1.544, 95 % CI = 1.098-2.171, P = 0.012) for overall survival after the adjustment of confounding factors. Similarly, in the GLIM-malnutrition subset, AWGC-cachexia remained an independent risk factor for overall survival (HR = 1.697, 95 % CI = 1.087-2.650, P = 0.020). Patients with both cachexia and malnutrition had the worst overall survival., Conclusion: AWGC-cachexia and GLIM-malnutrition criteria were two non-redundancy tools in reflecting mortality risk in preoperative nutritional assessment., 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 Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Rationale: Very-low-density lipoprotein receptor (VLDLR) involves in ocular neovascularization, a major cause of severe vision loss. However, the underlying molecular mechanisms were not completely clarified. Here, we aimed to investigate roles of circular RNAs (circRNAs) in VLDLR-associated ocular neovascularization., Methods: Vldlr knockout (Vldlr-/-, ko), Robo4 knockout (Robo4-/-, ko) and wild-type (WT) mice were used. Mouse model of oxygen induced retinopathy (OIR) and high-throughput sequence were performed to profile the differential expression of circRNA and transcripts. RNase R treatment, Sanger PCR sequencing and quantitative polymerase chain reaction (qPCR) were used to validate candidate circRNAs and their expression patterns. Choroidal sprouting assay ex vivo and laser induction choroid neovascularization were used to determine the expression and functions of QKI/CircSlc17a5 on choroidal neovascularization., Results: In macrophage and ocular tissues derived from Vldlr (Vldlr-/-,Vldlr ko) or Robo4 (Robo4-/-,Robo4 ko) deficiency as well as wild-type (WT) mice, Quaking (Qki) expression was significantly down-regulated in Vldlr deficiency compared to WT and Robo4 deficiency groups. Ectopic VLDLR expression or Reelin stimulation increased expression of QKI in bEnd.3 cells. Circular RNA sequencing uncovered that VLDLR regulated the biogenesis of certain circular RNAs, including the circSlc17a5. The number of Circular RNAs increased in mice treated with OIR. QKI mediated the biogenesis of circSlc17a5, which was an important regulator of choroidal angiogenesis., Conclusion: CircSlc17a5 regulated by VLDLR/QKI plays important roles in the choroidal angiogenesis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Dorsal approach is the potentially effective strategy for minimally invasive liver resection. This study aimed to compare the outcomes between robot-assisted and laparoscopic hemihepatectomy through dorsal approach., Methods: We compared the patients who underwent robot-assisted hemihepatectomy (Rob-HH) and who had laparoscopic hemihepatectomy (Lap-HH) through dorsal approach between January 2020 and December 2022. A 1:1 propensity score-matching (PSM) analysis was performed to minimize bias and confounding factors., Results: Ninety-six patients were included, 41 with Rob-HH and 55 with Lap-HH. Among them, 58 underwent left hemihepatectomy (LHH) and 38 underwent right hemihepatectomy (RHH). Compared with Lap-HH group, patients with Rob-HH had less estimated blood loss (median: 100.0 vs. 300.0 mL, P = 0.016), lower blood transfusion rates (4.9% vs. 29.1%, P= 0.003) and postoperative complication rates (26.8% vs. 54.5%, P = 0.016). These significant differences consistently existed after PSM and in the LHH subgroups. Furthermore, robot-assisted LHH was associated with decreased Pringle duration (45 vs. 60 min, P = 0.047). RHH subgroup analysis showed that compared with Lap-RHH, Rob-RHH was associated with less estimated blood loss (200 vs. 400 mL, P = 0.013). No significant differences were found in other perioperative outcomes among pre- and post-PSM cohorts, such as Pringle duration, operative time, and hospital stay., Conclusions: The dorsal approach was a safe and feasible strategy for hemi-hepatectomy with favorable outcomes under robot-assisted system in reducing intraoperative blood loss, transfusion, and postoperative complications., (Copyright © 2024 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Purpose: Investigate the oxylipin profiles in the aqueous humor of primary open-angle glaucoma (POAG) patients., Methods: Aqueous humor samples were collected from 17 POAG patients and 15 cataract subjects and subjected to a liquid chromatography/mass spectrometry (LC-MS) analysis to detect the oxylipins. The prediction potential of the differential abundant oxylipins was assessed by the receiver operating characteristic (ROC) curves. Pathway and correlation analyses on the oxylipins and clinical and biochemical parameters were also conducted., Results: The LC-MS analysis detected a total of 76 oxylipins, of which 29 oxylipins reached the detection limit. The multivariate analysis identified five differential abundant oxylipins, 15-keto-prostaglandin F2 alpha (15-kPGF2α), Leukotriene B4 (LTB4), 12,13-Epoxyoctadecenoic acid (12,13-Epome), 15-Hydroxyeicosatetraenoic acid (15-HETE) and 11-Hydroxyeicosatetraenoic acid (11-HETE). The five oxylipins are enriched in the arachidonic acid metabolism and linoleic acid metabolism pathways. Pearson correlation analysis showed that 11-HETE was positively correlated with intraocular pressure and central corneal thickness and negatively with cup/disk area ratio in the POAG patients. In addition, 15-kPGF2α was moderately and positively correlated with the mean deviation (MD) of visual field defect, and LTB4 was moderately and negatively correlated with macular thickness., Conclusions: This study revealed the oxylipin profile in the aqueous humor of POAG patients. Oxylipins involved in the arachidonic acid metabolism pathway could play a role in POAG, and anti-inflammatory therapies could be potential treatment strategies for POAG.

The growing demand for biological therapeutics has increased interest in large-volume perfusion bioreactors, but the operation and scalability of perfusion membranes remain a challenge. This study evaluates perfusion cell culture performance and monoclonal antibody (mAb) productivity at various membrane fluxes (1.5-5 LMH), utilizing polyvinylidene difluoride (PVDF), polyethersulfone (PES), or polysulfone (PS) membranes in tangential flow filtration mode. At low flux, culture with PVDF membrane maintained higher cell culture growth, permeate titer (1.06-1.34 g/L) and sieving coefficients (≥83%) but showed lower permeate volumetric throughput and higher transmembrane pressure (TMP) (>1.50 psi) in the later part of the run compared to cultures with PES and PS membrane. However, as permeate flux increased, the total mass of product decreased by around 30% for cultures with PVDF membrane, while it remained consistent with PES and PS membrane, and at the highest flux studied, PES membrane generated 12% more product than PVDF membrane. This highlights that membrane selection for large-volume perfusion bioreactors depends on the productivity and permeate flux required. Since operating large-volume perfusion bioreactors at low flux would require several cell retention devices and a complex setup, PVDF membranes are suitable for low-volume operations at low fluxes whereas PES membranes can be a desirable alternative for large-volume higher demand products at higher fluxes., (© 2024 Wiley Periodicals LLC.)

Background: Statin therapy is associated with an increased risk of hyperglycaemia and new-onset diabetes mellitus. The absolute increase in glycosylated haemoglobin (HgbA1c, a measure of average glucose level over the past three months) is typically small; dramatic and clinically relevant increases are rare., Case Summary: A 52-year-old man of South Indian descent with a history of hyperlipidaemia was started on rosuvastatin 40 mg daily for primary prevention of atherosclerotic cardiovascular disease. He did not have a history of diabetes mellitus. He developed polyuria and weight loss within weeks of starting statin therapy. Laboratory assessment was notable for HgA1c of 12.4% and LDL cholesterol of 84 mg/dL. Rosuvastatin was discontinued. He was not started on antidiabetic therapy as there was suspicion that statin therapy was the culprit for his HgbA1c rise. He soon had symptom resolution, and follow-up HgA1c 3 months later was 5.5%. Two years later, patient presented to the hospital with an acute coronary syndrome. He was discharged on rosuvastatin 40 mg daily and developed polyuria 1 week later. Rosuvastatin was discontinued, and atorvastatin 40 mg daily was initiated. Antidiabetic therapy was not started. He had resolution of his symptoms; follow-up HgA1c was below the diabetes threshold., Discussion: Statins are associated with a small increased risk of developing diabetes mellitus. The beneficial effects of statins on cardiovascular events typically outweigh any increased risk conferred by hyperglycaemia. While high-intensity statin therapy is routinely used as initial therapy for secondary prevention, we have no documentation explaining the choice of high-intensity statin for primary prevention in this case., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The outbreak of COVID-19 pandemic has raised urgent vaccine development to prevent viral transmission. Cutaneous adverse events such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been observed following COVID-19 vaccination. In this systematic review, we aimed to investigate the clinical features and outcomes of EM/SJS/TEN following COVID-19 vaccination. A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and Cochrane databases up to July 3, 2022. We included studies reporting patients who developed EM, SJS, or TEN following COVID-19 vaccination. A total of 47 studies involving 90 patients with EM and 16 patients with SJS/TEN were reviewed and outlined. EM predominantly occurred after the messenger ribonucleic acid vaccines (70.4%), mostly after the first (47.5%) and second doses (42.4%), with delayed onsets ranging from 1 day to 30 days. SJS/TEN were observed following either the first (55.6%)- or second-dose (33.3%) vaccination, with onset times ranging from 6 hours to 14 weeks. Three EM cases and 1 SJS case showed recurrence upon reexposure to the same vaccines. No mortality was reported. Most patients exhibited improvement or resolution after treatment, with resolution times ranging from 6 days to 8 weeks. In conclusion, EM and epidermal necrolysis, including SJS and TEN, have emerged as potential cutaneous adverse events following COVID-19 vaccine administration. Further research is warranted to elucidate the pathogenesis and casual relationship between COVID-19 vaccines and EM/SJS/TEN.

The 2023 consensus from the Taiwanese Dermatological Association (TDA) and Taiwan Lung Cancer Society (TLCS) addresses the management of tyrosine kinase inhibitor (TKI)-induced skin toxicities in non-small cell lung cancer (NSCLC). Providing a comprehensive overview, the consensus reflects recent advances in understanding causes and developmental processes of TKI-related skin toxicities. Aimed at guiding clinicians in Taiwan, the consensus integrates new treatment perspectives while incorporating experiences from local dermatology experts. Recommendations underwent a voting process, achieving consensus when 75% or more of experts agreed, leading to their inclusion. Approved by over 90% of participants, the recommended treatment algorithms for major skin toxicities offer valuable insights for clinicians managing TKI-associated effects in NSCLC patients., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a severe spectrum of rare mucocutaneous reactions, primarily drug-induced and characterized by significant morbidity and mortality. These conditions manifest through extensive skin detachment, distinguishing them from other generalized skin eruptions. The rarity and severity of SJS/TEN underscore the importance of accurate diagnostic criteria and effective treatments, which are currently lacking consensus. This review proposes new diagnostic criteria to improve specificity and global applicability. Recent advancements in understanding the immunopathogenesis of SJS/TEN are explored, emphasizing the role of drug-specific T cell responses and HLA polymorphisms in disease onset. The review also addresses current therapeutic approaches, including controversies surrounding the use of immunosuppressive agents and the emerging role of TNF-α inhibitors. Novel therapeutic strategies targeting specific pathogenic mechanisms, such as necroptosis and specific immune cell pathways, are discussed. Furthermore, the development of new drugs based on these insights, including targeted monoclonal antibodies and inhibitors, are examined. The review concludes by advocating for more robust and coordinated efforts across multidisciplinary medical fields to develop effective treatments and diagnostic tools for SJS/TEN, with the aim of improving patient outcomes and understanding of the disease and its mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Dysphagia is a common gastrointestinal complaint in the pediatric population and should raise concern for oropharyngeal as well as esophageal disorders. We describe a 7-year old patient who was admitted to the hospital for sudden onset dysphagia, abdominal pain, and decreased oral intake. Extensive evaluations including endoscopy eventually revealed herpes simplex esophagitis as well as eosinophilic esophagitis. Herpes simplex esophagitis is a rare condition in the immunocompetent population and is typically self-resolving. Eosinophilic esophagitis is a chronic, inflammatory condition characterized by esophageal eosinophilia and signs of esophageal dysfunction. The concurrent presentation of both conditions in the pediatric population has rarely been described., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Iron supplementation is frequently used in the treatment of iron deficiency anemia in the pediatric population. We describe a case of an 11-year old male who developed adverse side effects following treatment with oral ferrous sulfate tablets for 2 months. The diagnosis was made following findings of iron deposition on histology obtained during endoscopy. The iron supplementation was changed from tablet to liquid form, and repeat endoscopy 4 months following initial diagnosis showed resolution of the histologic findings of iron pill-induced gastritis., Competing Interests: Disclosures. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. CBC, SC, and DR had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org.)

Introduction: Generalized pustular psoriasis (GPP) is a rare and severe psoriasis subtype characterized by the rapid onset of coalescing sterile pustules over broad body areas and systemic inflammation. Data on its clinical course and outcomes in Taiwan are limited. We evaluated the clinical profile and outcomes of patients with GPP flares in Taiwan., Methods: This retrospective analysis included adult patients with moderate-to-severe GPP flares occurring in January 2008-December 2021. Data were extracted from medical charts and electronic health records in the Chang Gung Research Database. Statistical analyses were performed using SAS for Windows (version 9.4). Multivariate Poisson regression models were built to investigate different predictors of GPP flare rate., Results: Thirty-four patients with 81 moderate-to-severe GPP flares were identified. Of the 14 patients undergoing genetic analysis, 10 (71.4%) had an IL36RN mutation. Patients' mean age at the index GPP flare was 47.1 ± 16.5 years; 58.0% of the flares were severe, while 42.0% were moderate. Overall, 96.3% of GPP flares were treated with at least one systemic therapy, acitretin being the most prescribed (85.2%), followed by cyclosporine (45.7%) and methotrexate (18.5%). After treatment, the proportion of flares responding positively increased from 0% on day 2 to 6.2% by week 12. Patients were newly diagnosed with psoriasis (23.5%), hypertension (20.6%), diabetes mellitus (14.7%), psoriatic arthritis (2.9%), malignant tumor (8.8%), and depression/anxiety (2.9%) after enrollment. Complications occurring within 12 weeks of GPP flares included arthritis (25.9% of the flares), skin infection (8.6%), and other infections (2.5%). No fatalities were reported. In the multivariate model, former smokers, patients with hepatic disease, and patients with psoriatic arthritis had an increased GPP rate ratio (RR) of 13.33 (95% confidence interval, CI, 2.87-61.78), 14.08 (95% CI 3.04-65.29), and 34.84 (95% CI 4.77- 254.42), respectively. Contrarily, obese and rheumatoid arthritis patients had a lower GPP rate ratio of 0.21 (95% CI 0.08-0.54) and 0.07 (95% CI 0.006-0.78), respectively., Conclusions: Our findings highlight the complexity of GPP flare presentations and the need for individualized, patient-centered management approaches and continued research to improve affected individuals' care and outcomes., (© 2024. The Author(s).)

Introduction: The mainstay of successful treatment for parathyroid carcinoma remains complete surgical excision. Although intraoperative parathyroid hormone (ioPTH) monitoring is a useful adjunct during parathyroidectomy for benign primary hyperparathyroidism, its utility for parathyroid carcinoma remains unclear., Methods: A retrospective review of 796 patients who underwent parathyroidectomy with ioPTH monitoring for primary hyperparathyroidism revealed 13 patients with parathyroid carcinoma on final pathology from two academic institutions. A systematic review yielded 5 additional parathyroid carcinoma patients. Complete excision of malignancy, or operative success (eucalcemia ≥6 mo. after parathyroidectomy); operative failure (persistent hypercalcemia <6 mo. after parathyroidectomy); and perioperative complications were evaluated. Comparison of the >50% ioPTH decrease alone to >50% ioPTH decrease into normal reference range was analyzed using Chi-squared, Kolmogorov-Smirnov, Kruskal-Wallis tests., Results: All 18 parathyroid carcinoma patients achieved a >50% ioPTH decrease, and 14 patients also had a final ioPTH level decrease into normal reference range. 93% of patients who met normal parathyroid hormone reference range had operative success, whereas only two of the four (50%) patients with parathyroid carcinoma with a >50% ioPTH decrease alone demonstrated operative success., Conclusions: Parathyroidectomy guided by a >50% ioPTH decrease into normal reference range may better predict complete excision of malignant tissue in patients with parathyroid carcinoma compared to >50% ioPTH decrease alone. IoPTH monitoring should be used in conjunction with clinical judgment and complete en bloc resection for optimal treatment and success., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Recognizing emotions from electroencephalography (EEG) signals is a challenging task due to the complex, nonlinear, and nonstationary characteristics of brain activity. Traditional methods often fail to capture these subtle dynamics, while deep learning approaches lack explainability. In this research, we introduce a novel three-phase methodology integrating manifold embedding, multilevel heterogeneous recurrence analysis (MHRA), and ensemble learning to address these limitations in EEG-based emotion recognition., Approach: The proposed methodology was evaluated using the SJTU-SEED IV database. We first applied uniform manifold approximation and projection (UMAP) for manifold embedding of the 62-lead EEG signals into a lower-dimensional space. We then developed MHRA to characterize the complex recurrence dynamics of brain activity across multiple transition levels. Finally, we employed tree-based ensemble learning methods to classify four emotions (neutral, sad, fear, happy) based on the extracted MHRA features., Main Results: Our approach achieved high performance, with an accuracy of 0.7885 and an AUC of 0.7552, outperforming existing methods on the same dataset. Additionally, our methodology provided the most consistent recognition performance across different emotions. Sensitivity analysis revealed specific MHRA metrics that were strongly associated with each emotion, offering valuable insights into the underlying neural dynamics., Significance: This study presents a novel framework for EEG-based emotion recognition that effectively captures the complex nonlinear and nonstationary dynamics of brain activity while maintaining explainability. The proposed methodology offers significant potential for advancing our understanding of emotional processing and developing more reliable emotion recognition systems with broad applications in healthcare and beyond., 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 Wang, Chen, Imamura, Tapia, Somers, Zee and Lim.)

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf) 3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C 3 -alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel-Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1 H NMR, 13 C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups.

Background: Glioblastoma is an aggressive brain cancer, usually of unknown etiology, and with a very poor prognosis. Survival from diagnosis averages only 3 months if left untreated and this only increases to 12-15 months upon treatment. Treatment options are currently limited and typically comprise radiotherapy plus a course of the DNA-alkylating chemotherapeutic temozolomide. Unfortunately, the disease invariably relapses after several months of treatment with temozolomide, due to the development of resistance to the drug. Increased local tryptophan metabolism is a feature of many solid malignant tumours through increased expression of tryptophan metabolising enzymes. Glioblastomas are notable for featuring increased expression of the tryptophan catabolizing enzymes indole-2,3-dioxygenase-1 (IDO1), and especially tryptophan-2,3-dioxygenase-2 (TDO2). Increased IDO1 and TDO2 activity is known to suppress the cytotoxic T cell response to tumour cells, and this has led to the proposal that the IDO1 and TDO2 enzymes represent promising immuno-oncology targets. In addition to immune modulation, however, recent studies have also identified the activity of these enzymes is important in the development of resistance to chemotherapeutic agents., Methods: In the current study, the efficacy of a novel dual inhibitor of IDO1 and TDO2, AT-0174, was assessed in an orthotopic mouse model of glioblastoma. C57BL/6J mice were stereotaxically implanted with GL261(luc2) cells into the striatum and then administered either vehicle control, temozolomide (8 mg/kg IP; five 8-day cycles of treatment every 2 days), AT-0174 (120 mg/kg/day PO) or both temozolomide + AT-0174, all given from day 7 after implantation., Results: Temozolomide decreased tumour growth and improved median survival but increased the infiltration of CD4 + Tregs. AT-0174 had no significant effect on tumour growth or survival when given alone, but provided clear synergy in combination with temozolomide, further decreasing tumour growth and significantly improving survival, as well as elevating CD8 + T cell expression and decreasing CD4 + Treg infiltration., Conclusion: AT-0174 exhibited an ideal profile for adjunct treatment of glioblastomas with the first-line chemotherapeutic drug temozolomide to prevent development of CD4 + Treg-mediated chemoresistance., (© 2024. The Author(s).)

Objective: To examine the precise function of influenza A virus target genes (IATGs) in malignancy., Methods: Using multi-omics data from the TCGA and TCPA datasets, 33 tumor types were evaluated for IATGs. IATG expression in cancer cells was analyzed using transcriptome analysis. Copy number variation (CNV) was assessed using GISTICS 2.0. Spearman's analysis was used to correlate mRNA expression with methylation levels. GSEA was used for the enrichment analysis. Pearson's correlation analysis was used to examine the association between IATG mRNA expression and IC50. The ImmuCellAI algorithm was used to calculate the infiltration scores of 24 immune cell types., Results: In 13 solid tumors, IATG mRNA levels were atypically expressed. Except for UCS, UVM, KICH, PCPG, THCA, CHOL, LAMI, and MESO, most cancers contained somatic IATG mutations. The main types of CNVs in IATGs are heterozygous amplifications and deletions. In most tumors, IATG mRNA expression is adversely associated with methylation. RT-PCR demonstrated that EGFR , ANXA5 , CACNA1C , CD209 , UVRAG were upregulated and CLEC4M was downregulated in KIRC cell lines, consistent with the TCGA and GTEx data., Conclusion: Genomic changes and clinical characteristics of IATGs were identified, which may offer fresh perspectives linking the influenza A virus to cancer., (Copyright © 2024 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Background and Objectives : In patients with urolithiasis-related obstructive pyelonephritis (UROP), sepsis represents a critical and concerning complication that can substantially increase the mortality rate. This study aimed to identify the risk factors for sepsis in UROP patients and to develop a predictive nomogram model. Materials and Methods : We analyzed data from 148 patients who met the UROP criteria and were admitted to Chang Gung Memorial Hospital between 1 January 2016 and 31 December 2021. The primary outcome evaluated was the incidence of sepsis, as defined by the most recent Sepsis-3 guidelines. To identify potential risk factors for sepsis, we employed the Least Absolute Shrinkage and Selection Operator (LASSO) regression technique. Subsequently, we utilized multivariable logistic regression to construct the predictive model. Results : There was a total of 102 non-sepsis cases and 46 sepsis cases. Risk factors for sepsis in multivariable analysis were a history of diabetes mellitus (DM) (OR = 4.24, p = 0.007), shock index (SI) (×10 -1 ) (OR = 1.55, p < 0.001), C-reactive protein (CRP) (mg/dL) (OR = 1.08, p = 0.005), and neutrophil to lymphocyte ratio (NLR) (×10) (OR = 1.58, p = 0.007). The nomogram exhibited an area under the receiver operating characteristic curve of 0.890 (95% CI 0.830-0.949). Conclusions : Our study demonstrated that patients with UROP who have DM, higher SI, higher NLR, and elevated CRP levels are significantly more likely to develop sepsis. These insights may aid in risk stratification, and it is imperative that clinicians promptly initiate treatment for those identified as high risk.

Soil salinization and sodification, the primary causes of land degradation and desertification in arid and semi-arid regions, demand effective monitoring for sustainable land management. This study explores the utility of partial least square (PLS) latent variables (LVs) derived from visible and near-infrared (Vis-NIR) spectroscopy, combined with remote sensing (RS) and auxiliary variables, to predict electrical conductivity (EC) and sodium absorption ratio (SAR) in northern Xinjiang, China. Using 90 soil samples from the Karamay district, machine learning models (Random Forest, Support Vector Regression, Cubist) were tested in four scenarios. Modeling results showed that RS and Land use alone were unreliable predictors, but the addition of topographic attributes significantly improved the prediction accuracy for both EC and SAR. The incorporation of PLS LVs derived from Vis-NIR spectroscopy led to the highest performance by the Random Forest model for EC (CCC = 0.83, R 2  = 0.80, nRMSE = 0.48, RPD = 2.12) and SAR (CCC = 0.78, R 2  = 0.74, nRMSE = 0.58, RPD = 2.25). The variable importance analysis identified PLS LVs, certain topographic attributes (e.g., valley depth, elevation, channel network base level, diffuse insolation), and specific RS data (i.e., polarization index of VV + VH) as the most influential predictors in the study area. This study affirms the efficiency of Vis-NIR data for digital soil mapping, offering a cost-effective solution. In conclusion, the integration of proximal soil sensing techniques and highly relevant topographic attributes with the RF model has the potential to yield a reliable spatial model for mapping soil EC and SAR. This integrated approach allows for the delineation of hazardous zones, which in turn enables the consideration of best management practices and contributes to the reduction of the risk of degradation in salt-affected and sodicity-affected soils., 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 Ltd. All rights reserved.)

Introduction: In the realm of computational pathology, the scarcity and restricted diversity of genitourinary (GU) tissue datasets pose significant challenges for training robust diagnostic models. This study explores the potential of Generative Adversarial Networks (GANs) to mitigate these limitations by generating high-quality synthetic images of rare or underrepresented GU tissues. We hypothesized that augmenting the training data of computational pathology models with these GAN-generated images, validated through pathologist evaluation and quantitative similarity measures, would significantly enhance model performance in tasks such as tissue classification, segmentation, and disease detection., Methods: To test this hypothesis, we employed a GAN model to produce synthetic images of eight different GU tissues. The quality of these images was rigorously assessed using a Relative Inception Score (RIS) of 1.27 ± 0.15 and a Fréchet Inception Distance (FID) that stabilized at 120, metrics that reflect the visual and statistical fidelity of the generated images to real histopathological images. Additionally, the synthetic images received an 80% approval rating from board-certified pathologists, further validating their realism and diagnostic utility. We used an alternative Spatial Heterogeneous Recurrence Quantification Analysis (SHRQA) to assess the quality of prostate tissue. This allowed us to make a comparison between original and synthetic data in the context of features, which were further validated by the pathologist's evaluation. Future work will focus on implementing a deep learning model to evaluate the performance of the augmented datasets in tasks such as tissue classification, segmentation, and disease detection. This will provide a more comprehensive understanding of the utility of GAN-generated synthetic images in enhancing computational pathology workflows., Results: This study not only confirms the feasibility of using GANs for data augmentation in medical image analysis but also highlights the critical role of synthetic data in addressing the challenges of dataset scarcity and imbalance., Conclusions: Future work will focus on refining the generative models to produce even more diverse and complex tissue representations, potentially transforming the landscape of medical diagnostics with AI-driven solutions.

Understanding tumor-host immune interactions and the mechanisms of lung cancer response to immunotherapy is crucial. Current preclinical models used to study this often fall short of capturing the complexities of human lung cancer and lead to inconclusive results. To bridge the gap, we introduce two new murine monoclonal lung cancer cell lines for use in immunocompetent orthotopic models. We demonstrate how our cell lines exhibit immunohistochemical protein expression (TTF-1, NapA, PD-L1) and common driver mutations (KRAS, p53, and p110α) seen in human lung adenocarcinoma patients, and how our orthotopic models respond to combination immunotherapy in vivo in a way that closely mirrors current clinical outcomes. These new lung adenocarcinoma cell lines provide an invaluable, clinically relevant platform for investigating the intricate dynamics between tumor and the immune system, and thus potentially contributes to a deeper understanding of immunotherapeutic approaches to lung cancer treatment.

Steamed ginseng water (SGW) is a by-product of the repeated thermal processing of red ginseng, which is characterized by a high bioactive content, better skin care activity, and a large output. However, its value has been ignored, resulting in environmental pollution and resource waste. In this study, UHPLC-Q-Exactive-MS/MS liquid chromatography-mass spectrometry and multivariate statistical analysis were conducted to characterize the compositional features of the repeated thermal-treated SGW. The antioxidant activity (DPPH, ABTS, FRAP, and OH) and chemical composition (total sugars, total saponins, and reducing and non-reducing sugars) were comprehensively evaluated based on the entropy weighting method. Four comparison groups (groups 1 and 3, groups 1 and 5, groups 1 and 7, and groups 1 and 9) were screened for 37 important common difference markers using OPLS-DA analysis. The entropy weight method was used to analyze the weights of the indicators; the seventh SGW sample was reported to have a significant weight. The results of this study suggest that heat treatment time and frequency can be an important indicator value for the quality control of SGW cycling operations, which have great potential in antioxidant products., Competing Interests: The authors declare no conflicts of interest.

Change of direction, stops, and pivots are among the most common non-contact movements associated with anterior cruciate ligament (ACL) injuries in soccer. By observing these dynamic movements, clinicians recognize abnormal kinematic patterns that contribute to ACL tears such as increased knee valgus or reduced knee flexion. Different motions and physical demands are observed across playing positions, which may result in varied lower limb kinematic patterns. In the present study, 28 college and sub-elite soccer players performed four dynamic motions (change of direction with and without ball, header, and instep kick) with the goal of examining the effect of on-field positioning, leg dominance, and gender in lower body kinematics. Motion capture software monitored joint angles in the knee, hip, and ankle. A three-way ANOVA showed significant differences in each category. Remarkably, centrally positioned players displayed significantly greater knee adduction (5° difference, p = 0.013), hip flexion (9° difference, p = 0.034), hip adduction (7° difference, p = 0.016), and dorsiflexion (12° difference, p = 0.022) when performing the instep kick in comparison to their laterally positioned counterparts. These findings suggest that central players tend to exhibit a greater range of motion when performing an instep kicking task compared to laterally positioned players. At a competitive level, this discrepancy could potentially lead to differences in lower limb muscle development among on-field positions. Accordingly, it is suggested to implement position-specific prevention programs to address these asymmetries in lower limb kinematics, which can help mitigate dangerous kinematic patterns and consequently reduce the risk of ACL injury in soccer players., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Beron-Vera et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

As the number of vaccinated individuals has increased, there have been increasing reports of cutaneous hypersensitivity reactions. The main COVID-19 vaccines administered include messenger ribonucleic acid vaccines, non-replicating viral vector vaccines, inactivated whole-virus vaccines, and protein-based vaccines. These vaccines contain active components such as polyethylene glycol, polysorbate 80, aluminum, tromethamine, and disodium edetate dihydrate. Recent advances in understanding the coordination of inflammatory responses by specific subsets of lymphocytes have led to a new classification based on immune response patterns. We categorize these responses into four patterns: T helper (Th)1-, Th2-, Th17/22-, and Treg-polarized cutaneous inflammation after stimulation of COVID-19 vaccines. Although the association between COVID-19 vaccination and these cutaneous adverse reactions remains controversial, the occurrence of rare dermatoses and their short intervals suggest a possible relationship. Despite the potential adverse reactions, the administration of COVID-19 vaccines is crucial in the ongoing battle against severe acute respiratory syndrome coronavirus 2., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)