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Yu-Chin An,1 Chia-Lin Tsai,2 Chih-Sung Liang,3 Yu-Kai Lin,2 Guan-Yu Lin,2 Chia-Kuang Tsai,2 Yi Liu,2 Sy-Jou Chen,1 Shih-Hung Tsai,1 Kuo-Sheng Hung,4 Fu-Chi Yang2 1Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; 2Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; 3Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; 4Center for Precision Medicine and Genomics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of ChinaCorrespondence: Fu-Chi Yang, Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China, Tel +886-2-87923311 # 88078, Fax +886-2-87927174, Email fuji-yang@yahoo.com.twPurpose: Although insomnia and migraine are often comorbid, the genetic association between insomnia and migraine remains unclear. This study aimed to identify susceptibility loci associated with insomnia and migraine comorbidity.Patients and Methods: We performed a genome-wide association study (GWAS) involving 1063 clinical outpatients at a tertiary hospital in Taiwan. Migraineurs with and without insomnia were genotyped using the Affymetrix Axiom Genome-Wide TWB 2.0. We performed association analyses for the entire cohort and stratified patients into the following subgroups: episodic migraine (EM), chronic migraine (CM), migraine with aura (MA), and migraine without aura (MoA). Potential correlations between SNPs and clinical indices in migraine patients with insomnia were examined using multivariate regression analysis.Results: The SNP rs1178326 in the gene HDAC9 was significantly associated with insomnia. In the EM, CM, MA, and MoA subgroups, we identified 30 additional susceptibility loci. Multivariate regression analysis showed that SNP rs1178326 also correlated with higher migraine frequency and the Migraine Disability Assessment (MIDAS) questionnaire score. Finally, two SNPs that had been previously reported in a major insomnia GWAS were also significant in our migraineurs, showing a concordant effect.Conclusion: In this GWAS, we identified several novel loci associated with insomnia in migraineurs in a Han Chinese population in Taiwan. These results provide insights into the possible genetic basis of insomnia and migraine comorbidity.Keywords: insomnia, migraine, GWAS, SNP, gene, comorbidity

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'IX: people and places-diverse populations and locations of care', authors address the following themes: 'LGBTQIA+health in family medicine', 'A family medicine approach to substance use disorders', 'Shameless medicine for people experiencing homelessness', '''Difficult" encounters-finding the person behind the patient', 'Attending to patients with medically unexplained symptoms', 'Making house calls and home visits', 'Family physicians in the procedure room', 'Robust rural family medicine' and 'Full-spectrum family medicine'. May readers appreciate the breadth of family medicine in these essays.

IntroductionCancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies.MethodsUsing a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies.ResultsTherapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy.DiscussionMathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.

Yue-Chen Zhao,1,2 Xin Li,3 Chao-Qun Wang,4 Yan Jiao,5 Yan-Nan Shen,2 Tie-Jun Wang,1,2,* Chao-He Zhang6,* 1Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, Jilin, People’s Republic of China; 3Department of Radiology, The Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 4Department of Gynaecology, Aviation General Hospital, Beijing, People’s Republic of China; 5Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, People’s Republic of China; 6Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tie-Jun Wang, Department of Radiation Oncology, The Second Hospital of Jilin University, NO. 218 Ziqiang Street, Changchun, 130041, People’s Republic of China, Email tjwang@jlu.edu.cn Chao-He Zhang, Department of Hematology and Oncology, The Second Hospital of Jilin University, NO. 218 Ziqiang Street, Changchun, 130041, People’s Republic of China, Email zhangchaohe@jlu.edu.cnPurpose: Abraxane (nanoparticle albumin-bound paclitaxel) is a chemotherapeutic employed commonly for the management of various cancers including breast cancer, non-small cell lung cancer, and pancreatic adenocarcinoma. Although it has clinically beneficial properties, Abraxane is accompanied by multiple adverse events (AEs) that require close observation. This study aims to evaluate the AE profile of Abraxane using recently available data from January 2004 through December 2023 in the FDA Adverse Event Reporting System (FAERS).Patients and Methods: The data for Abraxane-related AEs were obtained from the FAERS database. The dataset consisted of patient demographic characteristics as well as information on the types and outcomes of AEs reported. Reporting odds ratios (ROR) as well as proportional reporting ratio (PRR), considering the used definition of anti-cancer agent and AEs, were calculated to investigate any association with Abraxane.Results: A total of 10,310 reports associated with Abraxane AEs were identified. Blood and lymphatic system disorders were the most frequent (ROR 6.44), followed by hepatobiliary (ROR 3.16), infections (ROR 1.45), and gastrointestinal disorders (ROR 1.42). Serious outcomes included hospitalization in 36.35% and death in 29.76% of cases. The top adverse reactions matched known profiles, including peripheral sensory neuropathy (ROR: 49.48). The analysis also found new adverse reactions, such as scleroderma-like reactions (ROR: 95.4) and vascular pseudoaneurysm ruptures (ROR: 87.71).Conclusion: Our results re-emphasize the importance of a robust Post Marketing Surveillance system and suggest this FAERS database based analysis provides an updated, independent information on Abraxane related AEs to enrich its safety profile. A process of continuous vigilance and additional investigations on specific areas that may have some undesired events are imperative to increase our knowledge on how Abraxane should be handled in terms of its safety.Keywords: Abraxane, FAERS database, adverse events, signal detection, pharmacovigilance

Jheng-Ting Luo,1 Yung-Chun Hung,1,2 Gina Jinna Chen,3 Yu-Shiang Lin1 1In-Service Master Program in Artificial Intelligence in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 2School of Health Care Administration, College of Management, Taipei Medical University, Taipei, Taiwan; 3Department of Electronic and Electrical Engineering, Southern University of Science and Technology, Shenzhen, People’s Republic of ChinaCorrespondence: Yu-Shiang Lin, In-Service Master Program in Artificial Intelligence in Medicine, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi District, Taipei City, 11031, Taiwan, Email eriklin@tmu.edu.twPurpose: Facial nerve paralysis, particularly Bell’s palsy, manifests as a rapid onset of unilateral facial weakness or paralysis. Despite most patients recovering within three to six months, a significant proportion experience poor recovery. This study utilized six machine learning models to investigate the effectiveness of early treatment in Bell’s palsy.Patients and Methods: We applied data from 17 hospitals in Scotland to predict treatment outcomes. Patients were randomized into four groups: Prednisolone (corticosteroids), Acyclovir (antivirals), both, and placebo. Outcomes, defined as full resolution of symptoms, were assessed using the House-Brackmann scale at 3 and 9 months post-treatment. We employed six different machine learning models to predict recovery outcomes and evaluated model performance using AUC, precision, recall, and F1-score.Results: Among 493 patients, 72.6% recovered after three months and 89.5% after nine months. Logistic regression demonstrated the highest predictive performance for both 3-month (AUC = 0.751) and 9-month recovery (AUC = 0.720). Additionally, several models achieved Precision levels exceeding 0.9. We further employed the best-performing logistic regression for feature ranking, indicating that the patient’s age and prednisolone administration are the most significant predictors of recovery.Conclusion: The results highlight the potential of machine learning models in predicting the effectiveness of early treatment. This study conducted a comprehensive comparison of six different machine learning models, with the logistic regression showing the highest predictive performance for both 3-month and 9-month recovery. Additionally, feature ranking using logistic regression supported the importance of Prednisolone in treatment. Notably, our findings revealed the significance of age in prognosis evaluation for the first time. This suggests that future research should further develop age-specific prognostic models, enabling clinicians to tailor individualized treatment strategies more effectively. This previously unrecognized discovery provides a foundation for prognostic analysis in Bell’s palsy patients.Keywords: Bell’s palsy, machine learning, prognostic prediction, feature ranking

Yu-Juan Zheng,1 Yong-Chao Hou,2 Hua Zhao,3 Xiao-Yun Wang,4 Yu-Dan Liu,3 Li Li,5 Liang Yu,6 Ming-Mei Guo1 1Department of Cardiology, Shanxi Provincial People’s Hospital, Taiyuan, 030012, People’s Republic of China; 2Department of Emergency, Shanxi Provincial People’s Hospital, Taiyuan, 030012, People’s Republic of China; 3College of Nursing, Shanxi University of Chinese Medicine, Jinzhong, 030619, People’s Republic of China; 4Department of Endocrinology, Shanxi Provincial People’s Hospital, Taiyuan, 030012, People’s Republic of China; 5Department of Gynecology, Shanxi Provincial People’s Hospital, Taiyuan, 030012, People’s Republic of China; 6Neonatal Disease Screening Center, Shanxi Provincial Children’s Hospital, Taiyuan, 030013, People’s Republic of ChinaCorrespondence: Ming-Mei Guo, Department of Cardiology, Shanxi Provincial People’s Hospital, No. 29 Shuangtasi Street, Yingze District, Taiyuan, 030012, People’s Republic of China, Tel +86 13934533989, Email guomingmeigmm@126.comObjective: To conduct an in-depth exploration of the factors influencing unfulfilled needs in caregivers of patients with phenylketonuria.Methods: A rapid qualitative analysis approach was used to conduct semi-structured interviews with 16 caregivers of patients with phenylketonuria undergoing specialized dietary interventions, along with 5 medical professionals, within a designated phenylketonuria diagnosis and treatment center in Shanxi Province. Interview data were systematically organized, analyzed, and thematically extracted.Results: Four primary themes were extracted: self-imposed constraints (including insufficient caregiver engagement, economic limitations, and stigma); interpersonal constraints (encompassing social isolation, inadequate social support networks, and lack of doctor-patient interactions); structural limitation factors (inadequate provision of specialized professional support systems, lack of medical dietary supplements, and deficiencies in national policies); and experiential limitation factors (encompassing sensory perceptions of medical dietary supplements and insufficient continuity in psycho-emotional care).Conclusion: The unfulfilled needs of caregivers of patients with phenylketonuria primarily manifest across four dimensions. Greater emphasis on addressing these needs is warranted, necessitating increased attention to patients with phenylketonuria and their caregivers. Specifically, the focus should be directed toward addressing their emotional requirements, along with proactive development of the medical service infrastructure. Such measures are imperative for reducing unfulfilled needs among caregivers of patients and enhancing their prognosis.Keywords: caregivers, influencing factors, phenylketonuria, qualitative research, rare diseases, unmet needs

Wonnam Kim,1,* Yeon-Cheol Park,2,3,* Bonhyuk Goo,2 Jung-Hyun Kim,2 Dongwoo Nam,3,4 Eunseok Kim,5,6 Hyun-Jong Lee,7 Dong-Hyun Pyun,8,9 Hae Sun Suh,8– 10 Yoonsung Lee,11 Man S Kim,11 Byung-Kwan Seo,2,3 Yong-Hyeon Baek2,3 1Division of Pharmacology, School of Korean Medicine, Pusan National University, Yangsan, Republic of Korea; 2Department of Acupuncture & Moxibustion, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea; 3Department of Acupuncture & Moxibustion, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea; 4Department of Acupuncture & Moxibustion, Kyung Hee University College of Korean Medicine, Kyung Hee University Medical Center, Seoul, Republic of Korea; 5Division of Clinical Medicine, School of Korean Medicine, Pusan National University, Yangsan, Republic of Korea; 6Department of Acupuncture and Moxibustion Medicine, Pusan National University Korean Medicine Hospital, Yangsan, Republic of Korea; 7Department of Acupuncture & Moxibustion, College of Korean Medicine, Daegu Haany University, Daegu, Republic of Korea; 8Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea; 9Institute of Regulatory Innovation Through Science (IRIS), Kyung Hee University, Seoul, Republic of Korea; 10College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; 11Clinical Research Institute, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Yong-Hyeon Baek, Department of Acupuncture & Moxibustion, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea, Tel +82 2 440 6099, Fax +82 2 440 714, Email byhacu@khu.ac.krPurpose: Knee osteoarthritis (KOA) is one of the most prevalent degenerative joint diseases worldwide. The herbal decoction, Dokhwalgisaeng-tang (DHGST), has been commonly used in East Asia to treat osteoarthritis. However, there is insufficient evidence to draw clear conclusions concerning its effectiveness and safety for patients with KOA. We aim to determine the efficacy, safety, and economic feasibility of DHGST compared with Celecoxib, an oral COX-2 inhibitor, for patients with degenerative KOA.Trial Design and Methods: This multicenter, randomized, noninferiority trial, involving 160 participants who will be randomized using block randomization with 1:1 allocation, will compare DHGST and Celecoxib. The total trial period is 24 weeks after random allocation, comprising 12 weeks of treatment and 12 weeks of follow-up. Participants with KOA will be administered 200 mg of DHGST (treatment group) or Celecoxib capsules (control group) for 12 weeks. Efficacy and safety evaluations will be conducted at weeks 0, 4, 8, and 12, and 24. The primary outcome measurement is the Korean Western Ontario McMaster score at week 12. Changes in pain intensity using a 100 mm visual analog scale, changes in quality of life using a EuroQol 5-dimension 5-level self-report survey, and patient satisfaction will also be measured to evaluate effectiveness between the two groups. A trial-based economic feasibility evaluation will be conducted to analyze treatment cost-effectiveness from societal and healthcare system perspectives. Drug safety will be assessed through adverse reactions and laboratory test findings.Discussion: This trial protocol has the following limitations. Applying a double-dummy design is not possible, as the tablet and granule forms can easily be distinguished visually, and achieving participant blinding is challenging. The trial findings are intended to inform participants, physicians, and other stakeholders in determining whether DHGST could be used as an alternative therapeutic option for KOA.Trial Registration Number: KCT0008424 (Clinical Research Information Service of the Republic of Korea), registered on 12 May 2023.Keywords: degenerative joint disease, Dokhwalgisaeng-tang, noninferiority trial, randomized controlled trial

Pranjyan Dash,1 Senthilkumar Thirumurugan,1 Nandini Nataraj,1 Yu-Chien Lin,1– 3 Xinke Liu,4,5 Udesh Dhawan,6 Ren-Jei Chung1,7 1Department of Chemical Engineering and Biotechnology, National Taipei University of Technology (Taipei Tech), Taipei, 10608, Taiwan; 2School of Materials Science and Engineering, Nanyang Technological University, Singapore, 639798, Singapore; 3ZhongSun Co., LTD, New Taipei City, 220031, Taiwan; 4College of Materials Science and Engineering, Chinese Engineering and Research Institute of Microelectronics, Shenzhen University, Shenzhen, 518060, People’s Republic of China; 5Department of Electrical and Computer Engineering, National University of Singapore, Singapore, 117583, Singapore; 6Centre for the Cellular Microenvironment, Division of Biomedical Engineering, James Watt School of Engineering, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G116EW, UK; 7High-Value Biomaterials Research and Commercialization Center, National Taipei University of Technology (Taipei Tech), Taipei, 10608, TaiwanCorrespondence: Ren-Jei Chung, Department of Chemical Engineering and Biotechnology, National Taipei University of Technology (Taipei Tech), No. 1, Sec. 3, Zhongxiao E. Road, Taipei, 10608, Taiwan, Tel +886-2-2771-2171 ext. 2547, Email rjchung@ntut.edu.twBackground: Phototherapy based on photocatalytic semiconductor nanomaterials has received considerable attention for the cancer treatment. Nonetheless, intense efficacy for in vivo treatment is restricted by inadequate photocatalytic activity and visible light response.Methods: In this study, we designed a photocatalytic heterostructure using graphitic carbon nitride (g-C3N4) and tin disulfide (SnS2) to synthesize g-C3N4/SnS2 heterostructure through hydrothermal process. Furthermore, Au nanoparticles were decorated in situ deposition on the surface of the g-C3N4/SnS2 heterostructure to form g-C3N4/SnS2@Au nanoparticles.Results: The g-C3N4/SnS2@Au nanoparticles generated intense reactive oxygen species radicals under near-infrared (NIR) laser irradiation through photodynamic therapy (PDT) pathways (Type-I and Type-II). These nanoparticles exhibited enhanced photothermal therapy (PTT) efficacy with high photothermal conversion efficiency (41%) when subjected to 808 nm laser light, owing to the presence of Au nanoparticles. The in vitro studies have indicated that these nanoparticles can induce human liver carcinoma cancer cell (HepG2) apoptosis (approximately 80% cell death) through the synergistic therapeutic effects of PDT and PTT. The in vivo results demonstrated that these nanoparticles exhibited enhanced efficient antitumor effects based on the combined effects of PDT and PTT.Conclusion: The g-C3N4/SnS2@Au nanoparticles possessed enhanced photothermal properties and PDT effect, good biocompatibility and intense antitumor efficacy. Therefore, these nanoparticles could be considered promising candidates through synergistic PDT/PTT effects upon irradiation with NIR laser for cancer treatment.Keywords: g-C3N4, SnS2, Gold nanoparticles, Photodynamic therapy, Photothermal therapy

Yu-Chi Wang,1,* Meng-Ting Cai,1,* Ming-Hong Chen,2,3 Fu-I Tung,4,5 Mei-Hsiu Chen,6,7 Tse-Ying Liu1 1Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan; 2Division of Neurosurgery, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, 220216, Taiwan; 3Department of Electrical Engineering, Yuan Ze University, Taoyuan City, 320315, Taiwan; 4Department of Orthopaedics, Yang-Ming Branch, Taipei City Hospital, Taipei, 111024, Taiwan; 5Department of Health and Welfare, College of City Management, University of Taipei, Taipei, 111036, Taiwan; 6Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, 220216, Taiwan; 7Department of Biomedical Engineering, Ming Chuang University, Taoyuan, 333, Taiwan*These authors contributed equally to this workCorrespondence: Tse-Ying Liu; Mei-Hsiu Chen, Email tyliu5@nycu.edu.tw; michelle8989@gmail.comPurpose: Osteoporosis, characterized by reduced bone mass and structural deterioration, poses a significant healthcare challenge. Traditional treatments, while effective in reducing fracture risks, are often limited by side effects. This study introduces a novel nanocomplex, europium (Eu) ions-doped superparamagnetic iron oxide (SPIO) nanocrystals encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanospheres, abbreviated as SPIO:Eu@PLGA nanospheres, as a potential therapeutic agent for osteoporosis by modulating macrophage polarization, enhancing osteoblast differentiation and inhibiting osteoclastogenesis.Methods: SPIO and SPIO:Eu nanocrystals were synthesized through pyrolysis and encapsulated in PLGA using an emulsification method. To evaluate the impact of SPIO:Eu@PLGA nanospheres on macrophage reprogramming and reactive oxygen species (ROS) production, flow cytometry analysis was conducted. Furthermore, an ovariectomized (OVX) rat model was employed to assess the therapeutic efficacy of SPIO:Eu@PLGA nanospheres in preventing the deterioration of osteoporosis.Results: In vitro, SPIO:Eu@PLGA nanospheres significantly attenuated M1 macrophage activation induced by lipopolysaccharides, promoting a shift towards the M2 phenotype. This action is linked to the modulation of ROS and the NF-κB pathway. Unlike free Eu ions, which do not achieve similar results when not incorporated into the SPIO nanocrystals. SPIO:Eu@PLGA nanospheres enhanced osteoblast differentiation and matrix mineralization while inhibiting RANKL-induced osteoclastogenesis. In vivo studies demonstrated that SPIO:Eu@PLGA nanospheres effectively targeted trabecular bone surfaces in OVX rats under magnetic guidance, preserving their structure and repairing trabecular bone loss by modulating macrophage polarization, thus restoring bone remodeling homeostasis. The study underscores the critical role of Eu doping in boosting the anti-osteoporotic effects of SPIO:Eu@PLGA nanospheres, evident at both cellular and tissue levels in vitro and in vivo.Conclusion: The inclusion of Eu into SPIO matrix suggests a novel approach for developing more effective osteoporosis treatments, particularly for conditions induced by OVX. This research provides essential insights into SPIO:Eu@PLGA nanospheres as an innovative osteoporosis treatment, addressing the limitations of conventional therapies through targeted delivery and macrophage polarization modulation.Keywords: osteoporosis, macrophage polarization, osteoblast, osteoclast, nanocrystals, poly(lactic-co-glycolic acid)

Qi Huang,1– 3,* Xu-Yun Huang,1,2,* Yu-Ting Xue,1,2,* Xiao-Hui Wu,1,2,* Yu-Peng Wu,1,2,* Zhi-Bin Ke,1,2 Zhen Kang,1,2 Yi-Cheng Xu,1,2 Dong-Ning Chen,1,2 Yong Wei,1,2 Xue-Yi Xue,1,2 Zhi-Yang Huang,3 Ning Xu1,2,4 1Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, People’s Republic of China; 3Department of Urology, Quanzhou First Hospital, Fujian Medical University, Quanzhou, 362000, People’s Republic of China; 4Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning Xu, Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, People’s Republic of China, Tel +86-059187981687, Email drxun@fjmu.edu.cn Zhi-Yang Huang, Department of Urology, Quanzhou First Hospital, Fujian Medical University, No. 250, East Street, Licheng District, Quanzhou, Fujian, 362000, People’s Republic of China, Email hzy8902@126.comIntroduction: This study aims to explore the role of cuproptosis-related genes in ACC, utilizing data from TCGA and GEO repositories, and to develop a predictive model for patient stratification.Methods: A cohort of 123 ACC patients with survival data was analyzed. RNA-seq data of 17 CRGs were examined, and univariate Cox regression identified prognostic CRGs. A cuproptosis-related network was constructed to show interactions between CRGs. Consensus clustering classified ACC into three subtypes, with transcriptional and survival differences assessed by PCA and survival analysis. Gene set variation analysis (GSVA) and ssGSEA evaluated functional and immune infiltration characteristics across subtypes. Differentially expressed genes (DEGs) were identified, and gene clusters were established. A risk score (CRG_score) was generated using LASSO and multivariate Cox regression, validated across datasets. Tumor microenvironment, stem cell index, mutation status, drug sensitivity, and hormone synthesis were examined in relation to the CRG_score. Protein expression of key genes was validated, and functional studies on ASF1B and NDRG4 were performed.Results: Three ACC subtypes were identified with distinct survival outcomes. Subtype B showed the worst prognosis, while subtype C had the best. We identified 214 DEGs linked to cell proliferation and classified patients into three gene clusters, confirming their prognostic value. The CRG_score predicted patient outcomes, with high-risk patients demonstrating worse survival and possible resistance to immunotherapy. Drug sensitivity analysis suggested higher responsiveness to doxorubicin and etoposide in high-risk patients.Conclusion: This study suggests the potential prognostic value of CRGs in ACC. The CRG_score model provides a robust tool for risk stratification, with implications for treatment strategies.Keywords: cuproptosis, overall survival, immune microenvironment, molecular signature

Fu-Xing-Zi Li,1 Feng Xu,1 Chang-Chun Li,1 Li-Min Lei,1 Su-Kang Shan,1 Ming-Hui Zheng,1 Xiao Lin,2 Bei Guo,1 Ke-Xin Tang,1 Jia-Yue Duan,1 Yun-Yun Wu,1 Ye-Chi Cao,1 Jun-Jie Liu,3 Ling-Qing Yuan1 1Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Department of Periodontal Division, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of ChinaCorrespondence: Ling-Qing Yuan, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China, Email allenylq@csu.edu.cnPurpose: Anecdotal reports have praised the benefits of cold exposure, exemplified by activities like winter swimming and cold water immersion. Cold exposure has garnered acclaim for its potential to confer benefits and potentially alleviate diabetes. We posited that systemic cold temperature (CT, 4– 8°C) likely influences the organism’s blood components through ambient temperature, prompting our investigation into the effects of chronic cold exposure on type 2 diabetic (T2DM) mice and our initial exploration of how cold exposure mitigates the incidence of T2DM.Methods: The effects of CT (4– 8°C) or room temperature (RT, 22– 25°C) on T2DM mice were investigated. Mice blood and organ specimens were collected for fully automated biochemical testing, ELISA, HE staining, immunohistochemistry, and immunofluorescence. Glucose uptake was assessed using flow cytometry with 2-NBDG. Changes in potential signaling pathways such as protein kinase B (AKT), phosphorylated AKT (p-AKT), insulin receptor substrates 1 (IRS1), and phosphorylated IRS1 (p-IRS1) were evaluated by Western blot.Results: CT or CT mice plasma-derived extracellular vesicles (CT-EVs) remarkably reduced blood glucose levels and improved insulin sensitivity in T2DM mice. This treatment enhanced glucose metabolism, systemic insulin sensitivity, and insulin secretion function while promoting glycogen accumulation in the liver and muscle. Additionally, CT-EVs treatment protected against the streptozocin (STZ)-induced destruction of islets in T2DM mice by inhibiting β-cell apoptosis. CT-EVs also shielded islets from destruction and increased the expression of p-IRS1 and p-AKT in adipocytes and hepatocytes. In vitro experiments further confirmed its pro-insulin sensitivity effect.Conclusion: Our data indicate that cold exposure may have a potentially beneficial effect on the development of T2DM, mainly through the anti-diabetic effect of plasma-derived EVs released during cold stimulation. This phenomenon could significantly contribute to understanding the lower prevalence of diabetes in colder regions.Keywords: cold exposure, plasma-derived extracellular vesicles, type 2 diabetes, insulin sensitivity, β‑cell destruction

Chi-Han Lin,1,2,&ast; Yung-Chia Kuo,1– 3,&ast; Hsuan-Chih Kuo,1– 3,&ast; Ching-Ting Wang,4 Shi-Ming Lin,1,5 Alan Chao-Wei Lee,1,6 Ming-Chin Yu,1,6,7 Wei-Chen Lee,1,6 Cherry Chiao-Erh Chen,2,3 Jason Chia-Hsun Hsieh1– 3 1College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 2Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 3Division of Hematology-Oncology, Department of Internal Medicine, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan; 4Registered Nurse, Case Manager of Nursing Department, Chang Gung Memorial Hospital, Linkou, Taoyuan, 333, Taiwan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 6Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 7Department of Surgery, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan&ast;These authors contributed equally to this workCorrespondence: Jason Chia-Hsun Hsieh, Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, No. 5, Fu-Hsin Street, Gueishan District, Taoyuan City, 333, Taiwan, Tel +886-3-3281200 Ext 8825, Email wisdom5000@gmail.comBackground: Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear.Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns.Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses.Conclusion: Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.Keywords: hepatitis, immune checkpoint inhibitor, advanced hepatocellular carcinoma, liver enzymes, overall survival

Purpose: Non-obstructive azoospermia (NOA) represents the persistent absence of sperm in ejaculate without obstruction, stemming from diverse disease processes. This survey explores global practices in NOA diagnosis, comparing them with guidelines and offering expert recommendations. Materials and Methods:Materials and Methods: A 56-item questionnaire survey on NOA diagnosis and management was conducted globally from July to September 2022. This paper focuses on part 1, evaluating NOA diagnosis. Data from 367 participants across 49 coun-tries were analyzed descriptively, with a Delphi process used for expert recommendations. Results:Results: Of 336 eligible responses, most participants were experienced attending physicians (70.93%). To diagnose azoosper-mia definitively, 81.7% requested two semen samples. Commonly ordered hormone tests included serum follicle-stimulating hormone (FSH) (97.0%), total testosterone (92.9%), and luteinizing hormone (86.9%). Genetic testing was requested by 66.6%, with karyotype analysis (86.2%) and Y chromosome microdeletions (88.3%) prevalent. Diagnostic testicular biopsy, distinguishing obstructive azoospermia (OA) from NOA, was not performed by 45.1%, while 34.6% did it selectively. Differ-entiation relied on physical examination (76.1%), serum hormone profiles (69.6%), and semen tests (68.1%). Expectations of finding sperm surgically were higher in men with normal FSH, larger testes, and a history of sperm in ejaculate. Conclusions:Conclusions: This expert survey, encompassing 367 participants from 49 countries, unveils congruence with recommended guidelines in NOA diagnosis. However, noteworthy disparities in practices suggest a need for evidence-based, international consensus guidelines to standardize NOA evaluation, addressing existing gaps in professional recommendations.

Rui Wang,1,2 Meng Li,2 Yao Wang,1 Chao Zhi Tang,3 Yuan Chen Wang4 1Department of Neurology, Henan Rongjun Hospital, Xinxiang City, Henan Province, People’s Republic of China; 2Department of Neurology, The Fifth Clinical College of Xinxiang Medical College, Xinxiang City, People’s Republic of China; 3College of Life Science, Henan Normal University, Xinxiang City, Henan Province, People’s Republic of China; 4School of Clinical Medicine, Zhengzhou University, Zhengzhou City, Henan Province, People’s Republic of ChinaCorrespondence: Rui Wang, Email 2360062620@qq.comObjective: To explore the effect of infection on hyperglycemic hemichorea.Methods: The clinical data of 11 patients with hyperglycemic hemichorea admitted to the Affiliated People’ s Hospital of Xinxiang Medical College and the Second People’s Hospital of Xinxiang were retrospectively analyzed, including gender, age, clinical symptoms, imaging features, blood glucose, glycated hemoglobin, infection indicators, and treatment conditions.Results: Eleven patients had acute or sub-acute onset, including 9 females and 2 males, with an average age of 74.55 years. Nine patients presented with unilateral limb involuntary movement and 2 patients presented with bilateral limb involuntary movement. Imaging findings of 9 patients showed abnormalities in the basal ganglia region. Random blood glucose levels were all elevated at admission, with an average blood glucose value of 26.20 mmol/l. Urine ketone bodies were positive in 2 patients, inflammatory indexes were elevated in 7 patients, symptoms of hypoglycemic treatment and anti-infection treatment in 10 patients disappeared, and symptoms of 1 patient disappeared after improved microcirculation treatment.Conclusion: The disease tends to occur in middle-aged and elderly women, and the blood glucose may fluctuate significantly during the onset. Infection may lead to the occurrence and development of the disease. Active control of blood sugar, inflammation and improvement of brain metabolism can effectively control symptoms and prevent recurrence.Keywords: hyperglycemia, infection, hemichorea, clinical analysis

Cheng-Jie Mao,1,&ast; Hao Peng,2,&ast; Sheng Zhuang,1,&ast; Ying-Chun Zhang,3 Wei-Ye Xie,1 Jia-Hui Yan,1 Hui-Hui Liu,1 Jing Chen,1 Jun-Yi Liu,4 Jianan Zhang,5 Hai Jiang,5 Yonghong Zhang,2 Mingzhi Zhang,2 Chun-Feng Liu1,6 1Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Epidemiology, School of Public Health, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China; 3Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 4Department of Neurology, The Fourth Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 5Department of Chronic Disease, Taicang Center of Disease Prevention and Control, Suzhou, People’s Republic of China; 6Institute of Neuroscience, Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chun-Feng Liu, Department of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, People’s Republic of China, Email liuchunfeng@suda.edu.cn Mingzhi Zhang, Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park, Suzhou, 215123, People’s Republic of China, Email zhangmingzhi@suda.edu.cnBackground: Sleep is critical in health problems including Parkinson’s disease (PD). This study examined the association between sleep characteristics and the likelihood of prodromal PD.Methods: At baseline examination of the Heart and Brain Investigation in Taicang (HABIT) study, potential PD biomarkers were obtained for 8777 participants aged over 50 years, and the probability of prodromal PD was assessed based on the Chinese expert consensus and Movement Disorder Society (MDS) criteria. General and component sleep characteristics were evaluated by the Pittsburgh Sleep Quality Index (PSQI). Median regression was applied to examine the association between sleep and the probability of prodromal PD, adjusting for age, sex, education level, physical activity, obesity, fast plasma glucose, lipids, and hypertension.Results: Based on China criteria, a higher level of PSQI score was significantly associated with a higher probability of prodromal PD (β = 0.02, 95% CI: 0.01– 0.03) and a higher risk of having an increased probability of prodromal PD (OR = 1.04, 95% CI: 1.02– 1.05). Compared to participants with good quality sleep, those with poor quality sleep had a 0.07% increased probability of prodromal PD (95% CI: 0.01– 0.13) and a 19% increased risk of having a high prodromal PD probability (95% CI: 1.04– 1.20). Similar associations between sleep quality and the probability of prodromal PD were also observed using the MDS criteria. Subjective sleep quality, sleep latency, habitual sleep efficiency, daytime dysfunction, and use of sleep medications were also associated with the probability of prodromal PD.Conclusion: Poor sleep quality was associated with a high probability of prodromal PD. Sleep may be helpful for understanding and intervention of prodromal PD.Keywords: prodromal Parkinson’s disease, sleep, Parkinson’s disease

Lizhen Huang,1,&ast; Yanjun Jin,2,&ast; Ching-Wen Chien,3 Qinyi Xu,3 Yen-Ching Chuang,4– 6 Tao-Hsin Tung6,7 1School of Economics and Management, Fuzhou University, Fuzhou, Fujian, 350108, People’s Republic of China; 2Department of Urology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, 317000 People’s Republic of China; 3Institute for Hospital Management, Tsing Hua University, Shenzhen Campus, Shenzhen, People’s Republic of China; 4Business College, Taizhou University, Taizhou, Zhejiang, 318000, People’s Republic of China; 5Institute of Public Health & Emergency Management, Taizhou University, Taizhou, Zhejiang, 318000, People’s Republic of China; 6Key Laboratory of Evidence-Based Radiology of Taizhou, Linhai, Zhejiang, 317000, People’s Republic of China; 7Evidence-based Medicine Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, 317000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yen-Ching Chuang; Tao-Hsin Tung, Email yenching.chuang@gmail.com; ch2876@gmail.comBackground: Improving overall and individual health literacy is a major focus of national initiatives in China and similar initiatives globally. However, few studies have examined the identification and improvement of individual health literacy levels, especially among patients.Purpose: To develop an interpretable method with decision rules to assess the health literacy levels of male patients and identify key factors influencing health literacy levels.Methods: Using a convenience sampling method, we conducted on-site surveys with 212 male patients of a hospital in China from July 2020 to September 2020. The questionnaire was developed by the Ministry of Health of the People’s Republic of China. A total of 206 of the completed surveys were ultimately included for analyses in this study. The rough set theory was used to identify conditional attributes (ie, key factors) and decision attributes (ie, levels of health literacy) and to establish decision rules between them. These rules specifically describe how different combinations of conditional attributes can affect health literacy levels among men.Results: Basic knowledge, concepts, and health skills are important in identifying whether male patients have health literacy. Health skills, scientific health concepts, healthy lifestyles and behaviors, infectious disease prevention and control literacy, basic medical literacy, and health information literacy can be identified as cognitive behaviors with varying degrees of health literacy among patients.Conclusion: This model can effectively identify the key factors and decision rules for male patients’ health literacy. Simultaneously, it can be applied to clinical nursing practice, making it easier for hospitals to guide male patients to improve their health literacy.Keywords: health literacy, male patients, key factors, decision rules, rough set theory, RST

Ying-Chao Ma,1 Ya-Qing Sun,2 Xia Wu,1 Yong-Jing Wang,1 Xiu-Ling Yang,1 Jian-Jun Gu3 1Department of Pharmacy, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050000, People’s Republic of China; 2College of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei Province, 050000, People’s Republic of China; 3Department of Cardiac Surgery, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050000, People’s Republic of ChinaCorrespondence: Jian-Jun Gu, Department of Cardiac Surgery, Second Hospital of Hebei Medical University, No. 215 of Heping West Road, Xinhua District, Shijiazhuang, 050000, Hebei Province, People’s Republic of China, Tel +8631166002991, Email jianjungu62@126.com Xiu-Ling Yang, Department of Pharmacy, Second Hospital of Hebei Medical University, No. 215 of Heping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, People’s Republic of China, Tel +8631166002712, Email yangxuilingyxl0d@126.comObjective: To assess the efficacy and safety of colistin sulfate in treating infections caused by carbapenem-resistant organisms (CRO) and to analyze potential factors impacting its effectiveness.Methods: In this retrospective study, medical records of CRO-infected patients from June 2020 to June 2023 were analyzed, divided into effective and ineffective treatment groups, and compared for clinical outcomes and adverse reactions. Multifactorial logistic regression and ROC curve analysis were used to identify influencing factors.Results: The study included 226 patients, with 124 in the effective treatment group and 102 in the ineffective group. A total of 293 CRO strains were cultured. The clinical efficacy rate of colistin sulfate was 54.87%, the microbiological efficacy rate 46.46%, and the hospital mortality rate 20.80%, with nephrotoxicity observed in 11.50% of patients. Multifactorial analysis identified APACHE II scores and vasoactive drug use as independent predictors of ineffective treatment, while treatment duration and albumin levels predicted effective treatment. ROC analysis indicated that albumin levels > 34 g/L, APACHE II scores < 13, and treatment duration > 10 days correlated with better clinical efficacy.Conclusion: Colistin sulfate is both safe and effective in clinical settings. Factors such as treatment duration, albumin levels, APACHE II scores, and vasoactive drug use independently affect its clinical efficacy, providing valuable guidance for its informed clinical application.Keywords: colistin sulphate, carbapenem-resistant organism, clinical efficacy, influencing factors, safety evaluation

Yi-Chun Liu,1 Shuh-Kuan Liau,1 Cheng-Chieh Hung,1 Chao-Yu Chen,1 Yueh-An Lu,1 Yu-Jr Lin,2 Ya-Chung Tian,1 Yung-Chang Chen,1 Fan-Gang Tseng,3,4 Hsiang-Hao Hsu1 1Department of Nephrology, Kidney Research Center, Chang Gung Memorial Hospital, Linkou Branch, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 2Research Services Center for Health Information, from Chang Gung University, Taoyuan, Taiwan; 3Department of Engineering and System Science, Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan; 4Institute of Nano Engineering and Microsystems, National Tsing Hua University, Hsinchu, TaiwanCorrespondence: Hsiang-Hao Hsu, Department of Nephrology, Kidney Research Center, Chang Gung Memorial Hospital, Linkou Branch, College of Medicine, Chang Gung University, No. 5 Fu-Shin Street, Guishan, Taoyuan, 333, Taiwan, Tel +886-3-328-1200 ext. 8181, Fax +886-3-3282173, Email hsianghao@gmail.comBackground: Listeriosis is caused by the facultative anaerobic bacterium Listeria monocytogenes. Infection from Listeria-contaminated food or water is the main etiology. If Listeria travels outside the intestines, it can cause invasive listeriosis, such as sepsis, meningitis, and meningoencephalitis. Invasive illness is especially dangerous for pregnant women and their newborns, elderly people, and people with compromised immune systems or medical conditions such as end-stage kidney disease (ESKD) patients receiving long-term dialysis.Purpose: Describe the manifestations and hospital outcomes of invasive listeriosis and identify the risk factors for in-hospital and one-year mortality in ESKD patients receiving long-term dialysis.Patients and Methods: This retrospective observational study examined hospitalized patient records at a Taiwanese tertiary medical center from August 1, 2000, to August 31, 2021. ESKD patients on chronic dialysis were identified with invasive listeriosis by blood culture and discharge diagnosis. Over 21 years, we accurately recorded 26 cases.Results: ESKD patients on chronic dialysis with invasive listeriosis have a poor prognosis. Only 53.8% of chronic dialysis patients with invasive listeriosis survived their first hospital episode. 42.3% of hospitalized ESKD patients with invasive listeriosis survived one year later. In univariate analysis, shock, tachypnea (RR ≥ 22), respiratory failure, qSOFA score ≥ 2, and lower initial platelet count were linked to greater in-hospital mortality rates.Conclusion: ESKD patients with invasive listeriosis have a grave prognosis. Our research reveals that an early blood sample for a bacterial culture may identify invasive listeriosis in chronic dialysis patients with fever, nausea or vomiting, confusion, and respiratory distress. This study is the first to identify a lower platelet count and qSOFA score ≥ 2 as markers of high-risk invasive listeriosis in ESKD patients.Keywords: chronic dialysis, ESKD, invasive listeriosis, qSOFA, outcome

Correction to: Molecular Psychiatry, published online 2 May 2023 In this article Honami Arai, Irene Bollettini, Rosa Calvo Escalona, Ana Coelho, Federica Colombo, Leila Darwich, Martine Fontaine, Toshikazu Ikuta, Jonathan C. Ipser, Asier Juaneda-Seguí, Hitomi Kitagawa, Gerd Kvale, Mafalda Machado-Sousa, Astrid Morer, Takashi Nakamae, Jin Narumoto, Joseph O’Neill, Sho Okawa, Eva Real, Veit Roessner, Joao R. Sato, Cinto Segalàs, Roseli G. Shavitt, Dick J. Veltman, Kei Yamada were missing from the author list indexed under the ENIGMA-OCD Working Group. Additionally, there was an error regarding Tokiko Yoshida’s name, where the first name and last name were written in the wrong order. The original article has been corrected.

Ning Luo,1,&ast; Yi-Chen Zeng,1,&ast; Bai-Tian Fu,1 Je Wie Low,2 Jian-Qiao Fang1 1The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Institute of International Education of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian-Qiao Fang, The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China, Email fangjianqiao7532@163.comIntroduction: Diabetic peripheral neuropathy (DPN) affects patients’ quality of life significantly. To date, selecting the appropriate treatment remains challenging. While electroacupuncture (EA) has shown promise as an effective adjunct therapy for DPN, and infrared thermography (IRT) has been considered as a potential predictor of treatment efficacy, the evidence for both remains inconclusive. As such, the objectives of this trial are twofold: to ascertain the efficacy of EA for DPN, and to explore the feasibility of IRT as an adjunctive objective tool for efficacy assessment.Methods: The study was designed as a randomized, parallel, controlled trial. It spanned over 6 weeks of treatment and an additional 4 weeks of follow-up. 104 eligible participants will be stratified for severity of disease: mild with Toronto clinical scoring system(TCSS) score 6– 8, moderate (TCSS score 9– 11), and severe (TCSS score 12– 19), and each level will be randomised in a 1:1 ratio into a EA group and waiting-list group. The waiting-list group received only the current conventional medication, while the EA group received an additional 12 EA sessions on top of the conventional medication. The primary outcome indicators is nerve conduction velocity (NCV), which will be tested at the baseline and week 6. Total clinical efficiency, TCSS, Clinical symptoms score of Traditional Chinese Medicine (TCM), Patient global impression of change(PGIC), Temperature of regions of interest (ROIs), and Physico chemical examination will be used as secondary outcome indicators. In addition, safety assessment will be determined based on adverse events during the trial.Conclusion: The expected results of this study will determine whether EA improves efficacy in the treatment of DPN with an acceptable safety profile, and investigating variations in the efficacy of EA across different levels of DPN severity. Furthermore, it will explore the viability of IRT as an objective measure for evaluating treatment effectiveness for DPN.Clinical Trial Registration: ClinicalTrials.gov identifier, NCT06054087.Keywords: electroacupuncture, waiting-list, diabetic peripheral neuropathy, clinical trial, infrared thermography

Yu-Chieh Ho,1,&ast; Chia-Ti Wang,1,&ast; Tzu-Chieh Weng,2 Chung-Han Ho,3,4 Kang-Ting Tsai,5,6 Chien-Chin Hsu,1,7 Hung-Jung Lin,1,7,8 Hsiu-Chin Chen,5,9 Chien-Cheng Huang1,7,10 1Department of Emergency Medicine, Chi Mei Medical Center, Tainan, Taiwan; 2Division of Hospital Medicine, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; 3Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan; 4Department of Information Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan; 5Department of Senior Welfare and Services, Southern Taiwan University of Science and Technology, Tainan, Taiwan; 6Division of Geriatrics and Gerontology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; 7School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan; 8Department of Emergency Medicine, Taipei Medical University, Taipei, Taiwan; 9Department of Nursing, Chi Mei Medical Center, Tainan, Taiwan; 10Department of Emergency Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Chien-Cheng Huang, Department of Emergency Medicine, Chi Mei Medical Center, 901 Zhonghua Road, Yongkang District, Tainan City, 710, Taiwan, Tel +886-6-281-2811, Fax +886-6-281-6161, Email jasonhuang0803@gmail.com Hsiu-Chin Chen, Department of Nursing, Chi Mei Medical Center, Tainan, Taiwan, 901 Zhonghua Road, Yongkang District, Tainan City, 710, Taiwan, Tel +886-6-281-2811, Fax +886-6-281-6161, Email 300006@mail.chimei.org.twPurpose: The home-based medical integrated program (HMIP) is a novel model for home healthcare (HHC) in Taiwan, initiated in 2016 to enhance care quality. However, the outcomes of this program on health outcomes and medical resource utilization in HHC patients remain unclear. Thus, we conducted this study to clarify it.Patients and Methods: The authors utilized the Taiwan National Health Insurance Research Database to identify HHC patients who received HMIP and those who did not between January 2015 and December 2017. A retrospective cohort study design was used. Convenience sampling was employed to select patients who met the inclusion criteria: being part of the HHC program and having complete data for analysis.Results: A total of 4982 HHC patients in the HMIP group and 10,447 patients in the non-HMIP group were identified for this study. The mean age in the HMIP group and non-HMIP group was 77.6 years and 76.1 years, respectively. Compared with the non-HMIP group, the HMIP group had lower total medical costs for HHC, fewer outpatient department visits and lower medical costs, lower medical costs for emergency department visits, fewer hospitalizations, and a lower mortality rate (34.6% vs 41.2%, p< 0.001).Conclusion: The HMIP is a promising model for improving care quality and reducing medical resource utilization in HHC patients. While this suggests that the non-HMIP model should be replaced, it’s important to note that both non-HMIP and HMIP models currently coexist. The HMIP may serve as an important reference for other nations seeking to improve care quality and reduce medical resource utilization in their own HHC systems.Keywords: home-based medical integrated plan, health outcomes, medical resource utilization, Taiwan

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

Chin-Yi Yang,1,2,&ast; Ya-Ching Chang,2,&ast; Hao-Chih Tai,3 Yi-Hua Liao,4 Yu-Huei Huang,2 Rosaline Chung-Yee Hui,2 Yuan-Sung Kuo,3 Shyue-Yih Horng,3 Yi-Shuan Sheen,4 Tim-Mo Chen,5 Yuan-Sheng Tzeng,5 Chih-Hsin Wang,5 Shou-Cheng Teng,5 Chun-Kai Oscar Chang,5 Chang-Yi Chou5 1Department of Dermatology, New Taipei Municipal TuCheng Hospital, New Taipei City, 236, Taiwan; 2Department of Dermatology, Linkou Chang-Gung Memorial Hospital, Taoyuan, 333, Taiwan; 3Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan; 4Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan; 5Division of Plastic Surgery, Tri-Service General Hospital, Taipei, 100, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hao-Chih Tai, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Zhongshan S. Road, Zhongzheng Dist, Taipei, 100225, Taiwan, Tel +886 2 2312-3456&num;65062 65520, Email taihc1@gmail.com; taihc@ntu.edu.tw Yi-Hua Liao, Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Zhongshan S. Road, Zhongzheng Dist, Taipei, 100225, Taiwan, Tel +886 2 2312-3456&num; 265317, Email yihualiao@ntu.edu.twPurpose: Porcine-based dermal injectable collagen is effective for nasolabial fold correction. In the present study, a new dermal injectable collagen, incorporating a novel cross-linking technology and premixed with lidocaine, was introduced. The study aimed to determine the efficacy of the new dermal injectable collagen in improving bilateral nasolabial fold wrinkles, and reducing pain during injection.Patients and Methods: This prospective, double-blind, multicenter, parallel-group, randomized trial enrolled participants with moderate-to-severe bilateral nasolabial fold wrinkles from February 2019 to March 2021. Participants were randomly assigned to the test group (new dermal injectable collagen with lidocaine featuring a novel cross-linking technology) or control group (traditionally cross-linked dermal injectable collagen with lidocaine). Participants were monitored for adverse events (AEs), and for pain using the Thermometer Pain Scale (TPS) and a visual analog scale (VAS). Efficacy was measured using the Wrinkle Severity Rating Scale (WSRS) and the Global Aesthetic Improvement Scale (GAIS).Results: On the poor or better sides, the 2 groups exhibited a significant decrease in WSRS scores at 4, 12, 24, and 36 weeks after treatment, compared to baseline WSRS scores (all, p < 0.05). Compared to the control group, the test group had a greater decrease in WSRS score (poor or better sides) at 12, 24, 36, and 52 weeks after treatment (all, p < 0.05). A similar observation was also found in the WSRS response rate and GAIS score of the 2 groups. VAS and TPS scores were not significantly different between the 2 groups (p > 0.05), indicating that pain reduction was similar in the 2 groups. All AEs were anticipated AEs associated with facial aesthetic injections, and most recovered within 0 to 30 days without sequelae. There were no differences in AEs between the 2 groups (all, p > 0.05).Conclusion: The new dermal injectable collagen with lidocaine exhibited better efficacy for correcting nasolabial fold wrinkles compared to the control group. Both relieved pain and produced only transient and tolerable AEs.Keywords: adverse event, bilateral nasolabial folds, dermal filler, pain, porcine collagen, wrinkles

Chih-Yen Hsiao,1 Yi-Chien Lee,2,3 Douglas JH Shyu,4 Che-Ping Su,5 Man-Yi Lin,5 Nai-Yu Guo,6 Cheng-Lun Chiang,1 Yih-Yuan Chen5 1Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan; 2Department of Internal Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, Taiwan; 3School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Biological Science and Technology, National Pingtung University of Science and Technology, Neipu, Pingtung, Taiwan; 5Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan; 6Department of Respiratory Care, Chang-Gung University of Science and Technology, Chiayi, TaiwanCorrespondence: Yih-Yuan Chen, Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan, Tel +886-5-271-7795, Email yychen@mail.ncyu.edu.twObjective: The most common extraintestinal pathogen and infection site is uropathogenic Escherichia coli (UPEC), which causes urinary tract infections (UTIs). UPEC is also a common pathogen in bloodstream infections; in severe cases, it can lead to death. Although host and bacterial virulence factors have been demonstrated to be associated with UTI pathogenesis, the role of the related contributing factors in UTI and urinary source bacteremia is not yet fully understood. This study aimed to compare and analyze the factors contributing to urinary bacteremia in patients with UTI.Methods: A total of 171 E. coli strains collected from patients with UTI and urinary source bacteremia at Chiayi Christian Hospital were used. Phylogenetic groups and virulence factors were determined using PCR. Drug resistance patterns were determined using the disk diffusion assay.Results: Previous studies have demonstrated that fimbriae and papGII may be associated with first-step infections and severe UTIs, respectively. As expected, highly virulent E. coli strains (belonging to the phylogenetic B2 and D groups) were dominant in the bacteremic UTI (90%) and UTI (86.27%) groups. However, our results showed that the UTI group had a significantly higher prevalence of sfa/focDE (belonging to the S and FIC fimbriae) than the bacteremic UTI group (29.4% vs 12.5%; p=0.008). In the bacteremic group, we found that sfa/focDE was only detected in highly virulent strains. The bacteremic UTI group had a significantly higher prevalence of papGII (belonging to P fimbriae) than the UTI group (55.8% vs 37.3%; p=0.026). In addition, the P fimbriae gene cluster, including papC, papEF, and papGII, was predominant in highly virulent strains. Notably, our results show that multidrug-resistant (MDR) strains were significantly less virulent than non MDR strains.Conclusion: Taken together, our results provide insights into the contributing factors in patients with UTI and urinary bacteremia.Keywords: Escherichia coli, urinary tract infection, urinary source bacteremia, virulence factors, multidrug resistance

Yu Chen Xu,1,&ast; Qiu Qin Wang,1,&ast; Meng Yuan Chen,1 Yu Jie Gao,1 Jia Yi Wang,1 Hao Tian Ge,1 Heng Weng,1 Ju Ping Chen,2 Gui Hua Xu1 1School of Nursing, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 2Department of Neurology, Changshu Hospital of Traditional Chinese Medicine, Suzhou, 215500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gui Hua Xu, School of Nursing, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China, Email 7115@njucm.edu.cn Ju Ping Chen, Department of Neurology, Changshu Hospital of Traditional Chinese Medicine, Suzhou, 215500, People’s Republic of China, Email 1523515573@qq.comPurpose: Pain is a common yet undertreated symptom of Parkinson’s disease (PD). This study investigated the effect of Gua Sha therapy on pain in patients with PD.Patients and Methods: A total of 56 PD patients with pain were randomized into either the experimental group (n=28), receiving 12 sessions of Gua Sha therapy, or the control group (n=28) without additional treatment. Participants underwent assessment at baseline, after the twelfth invention, and at the 2-month follow-up timepoints. The primary outcome was KPPS and VAS. Secondary outcomes included UPDRS I–III, PDSS-2, HADS, PDQ-39, and blood biomarkers (5-HT, IL-8, IL-10).Results: The experimental group reported a significant improvement in pain severity, motor functions, affective disorder, and sleep quality (P < 0.05). Furthermore, increasing trends in both 5-HT and IL-10, as well as decreasing trends in IL-8 were observed. No serious adverse events occurred.Conclusion: The preliminary findings suggest that Gua Sha therapy may be effective and safe for alleviating pain and improving other disease-related symptoms in PD patients.Keywords: Parkinson’s disease, pain, Gua Sha therapy, randomized controlled trial

Abstract Background The glycolytic enzyme alpha-enolase is a known biomarker of many cancers and involved in tumorigenic functions unrelated to its key role in glycolysis. Here, we show that expression of alpha-enolase correlates with subcellular localisation and tumorigenic status in the MCF10 triple negative breast cancer isogenic tumour progression model, where non-tumour cells show diffuse nucleocytoplasmic localisation of alpha-enolase, whereas tumorigenic cells show a predominantly cytoplasmic localisation. Alpha-enolase nucleocytoplasmic localisation may be regulated by tumour cell-specific phosphorylation at S419, previously reported in pancreatic cancer. Results Here we show ENO1 phosphorylation can also be observed in triple negative breast cancer patient samples and MCF10 tumour progression cell models. Furthermore, prevention of alpha-enolase-S419 phosphorylation by point mutation or a casein kinase-1 specific inhibitor D4476, induced tumour-specific nuclear accumulation of alpha-enolase, implicating S419 phosphorylation and casein kinase-1 in regulating subcellular localisation in tumour cell-specific fashion. Strikingly, alpha-enolase nuclear accumulation was induced in tumour cells by treatment with the specific exportin-1-mediated nuclear export inhibitor Leptomycin B. This suggests that S419 phosphorylation in tumour cells regulates alpha-enolase subcellular localisation by inducing its exportin-1-mediated nuclear export. Finally, as a first step to analyse the functional consequences of increased cytoplasmic alpha-enolase in tumour cells, we determined the alpha-enolase interactome in the absence/presence of D4476 treatment, with results suggesting clear differences with respect to interaction with cytoskeleton regulating proteins. Conclusions The results suggest for the first time that tumour-specific S419 phosphorylation may contribute integrally to alpha-enolase cytoplasmic localisation, to facilitate alpha-enolase’s role in modulating cytoskeletal organisation in triple negative breast cancer. This new information may be used for development of triple negative breast cancer specific therapeutics that target alpha-enolase.

Bang-Bin Chen,1,2 Po-Chin Liang,1– 3 Tiffany Ting-Fang Shih,1,2 Tsung-Hao Liu,4– 6 Ying-Chun Shen,4– 6 Li-Chun Lu,4– 6 Zhong-Zhe Lin,4,6 Chiun Hsu,4– 6 Chih-Hung Hsu,4– 6 Ann-Lii Cheng,4– 7 Yu-Yun Shao4– 6 1Department of Medical Imaging, National Taiwan University Hospital, Taipei City, Taiwan; 2Department of Radiology, College of Medicine, National Taiwan University, Taipei City, Taiwan; 3Department of Medical Imaging, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu City, 300, Taiwan; 4Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan; 5Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan; 6Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; 7Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanCorrespondence: Yu-Yun Shao, Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei City, 100, Taiwan, Tel +886-2 23123456 ext. 66008, Fax +886-2 23711174, Email yuyunshao@gmail.comPurpose: We investigated whether spleen volume (SV) changes were associated with treatment outcomes in advanced hepatocellular carcinoma (HCC) patients who received immunotherapy or first-line sorafenib.Patients and Methods: Patients with advanced HCC who underwent immunotherapy or first-line sorafenib at our institute were retrospectively analyzed. CT was used to measure SV before and within 3 months of treatment initiation. Tumor assessment followed Response Evaluation Criteria in Solid Tumors version 1.1. The association between SV change and tumor response or progression-free survival (PFS) was analyzed. The inverse probability of treatment weighting (IPTW) was used to adjust for differences in baseline characteristics.Results: The immunotherapy group comprised 143 patients (124 men, mean age, 59.8 years ± 11.2 [standard deviation]), while the sorafenib group had 57 (47 men, mean age, 59.6 years ± 9.9). SV increased in 108 (75.5%) immunotherapy and 21 (36.8%) sorafenib patients. In the immunotherapy group, patients with increased SV were more likely than those with decreased SV to have a higher disease control rate (76.9% vs 57.1%, p = 0.024) and durable clinical benefit (52.8% vs 25.7%, p = 0.005). It was also associated with extended PFS in the immunotherapy group in both the univariate (p = 0.028) and multivariate (p = 0.014) analysis. By contrast, in the sorafenib group, an increased in SV was not associated with treatment response but was presumably associated with reduced PFS (p = 0.072) in the multivariate analysis. After IPTW adjustment, the increase in SV remained a significant predictor for DCB and PFS in the immunotherapy group.Conclusion: Most patients exhibited an increase in SV after the initiation of immunotherapy, which may be used to predict response and prognosis. However, this association was not observed in patients who received sorafenib.Plain Language Summary: The study provides significant evidence that an increase in spleen volume is associated with better treatment outcomes in advanced hepatocellular carcinoma patients undergoing immunotherapy. These findings offer oncologists a new potential biomarker for optimizing treatment strategies. Specifically, increased spleen volume could be used to predict higher rates of disease control and durable clinical benefits, allowing for more personalized care. Keywords: hepatocellular carcinoma, immunotherapy, sorafenib, response, survival

BackgroundEvaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA).MethodsUsing previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus.ResultsThe ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated.ConclusionThis review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

Electrochemical conversion of CO2 requires selective catalysts and high solubility of CO2 in the electrolyte to reduce the energy requirement and increase the current efficiency. In this study, the CO2 reduction reaction (CO2RR) over Ag electrodes in acetonitrile-based electrolytes containing 0.1 M [EMIM][2-CNpyr] (1-ethyl-3-methylimidazolium 2-cyanopyrolide), a reactive ionic liquid (IL), is shown to selectively (>94%) convert CO2 to CO with a stable current density (6 mA·cm-2) for at least 12 h. The linear sweep voltammetry experiments show the onset potential of CO2 reduction in acetonitrile shifts positively by 240 mV when [EMIM][2-CNpyr] is added. This is attributed to the pre-activation of CO2 through the carboxylate formation via the carbene intermediate of the [EMIM]+ cation and the carbamate formation via binding to the nucleophilic [2-CNpyr]- anion. The analysis of the electrode-electrolyte interface by surface-enhanced Raman spectroscopy (SERS) confirms the catalytic role of the functionalized IL where the accumulation of the IL-CO2 adduct between -1.7 and -2.3 V vs Ag/Ag+ and the simultaneous CO formation are captured. This study reveals the electrode surface species and the role of the functionalized ions in lowering the energy requirement of CO2RR for the design of multifunctional electrolytes for the integrated capture and conversion.

Introdução: O padrão de apresentação do clone HPN avaliado por citometria de fluxo multiparamétrica (CFM) durante o tratamento da hemoglobinúria paroxística noturna (HPN) pode variar conforme o tipo de anemia hemolítica associada. Relato de caso: Paciente feminina, 17 anos, com astenia e hipermenorreia e pancitopenia (Hb 2,5 g/dL 1900 leucócitos 146 neutrófilos 5000 plaquetas reticulócitos 1% LDH 255 - VR 220). Mielograma e exame anatomopatológico confirmaram hipocelularidade intensa da medula óssea (< 5%). A CFM de sangue periférico detectou clone HPN em granulócitos 1,0% e monócitos 1,5%, mas não em hemácias. Sem doador de medula óssea, iniciou tratamento imunossupressor com ciclosporina, metilprednisolona e timoglobulina de coelho, com resposta parcial. A avaliação sequencial do clone HPN mostrou 5,3% em neutrófilos e 1,5% em hemácias. Após dois anos estável laboratorialmente e sem transfusões, houve piora súbita da anemia - Hb 5,6 g/dL, astenia e dores abdominais intensas, além de icterícia e hemoglobinúria. A paciente retomou alta demanda transfusional, com aumento da desidrogenase lática (LDH 1088), reticulocitose (> 100.000/uL) e medula óssea hipocelular (40%) com ninhos de eritroblastos. O percentual de clone HPN discrepante entre neutrófilos (87,3%) e hemácias (26,4%) era compatível com o grau de hemólise naquele momento, confirmando evolução clonal da aplasia para HPN Clássica e Hemolítica. Foi indicado uso de inibidor de complemento C5 (Eculizumab), iniciado em regime de urgência devido ao quadro de insuficiência renal dialítica e grande risco de trombose e morte. Houve melhora dos níveis de creatinina, diminuição do LDH e melhora da anemia. O clone HPN logo após a inibição do complemento aumentou tanto em neutrófilos (98%) quanto em hemácias (75%), sugerindo diminuição da massa eritrocitária hemolisada. Após estabilização, entretanto, a paciente voltou a apresentar necessidade transfusional, reticulócitos e bilirrubina aumentados, porém mantendo níveis baixos de LDH, clone HPN discrepante (neutrófilos > 80% e hemácias < 60%), sugerindo hemólise extra-vascular (HEV). Optou-se por incluir a paciente em protocolo com inibidor do complemento proximal C3 (Danicopan). Após duas semanas de uso houve resolução completa da anemia (Hb 13,0 g/dL), diminuição dos reticulócitos e bilirrubinas, e clone HPN semelhante entre neutrófilos e hemácias (85% e 83%). Infelizmente, a medicação teve que ser suspensa devido a evento adverso grave (coledocolitíase provavelmente secundária a hemólise de escape). Após suspensão a paciente voltou a apresentar HEV (reticulócitos altos, LDH baixo, clone HPN em hemácias < neutrófilos). Recentemente foi possível iniciar a medicação inibidora de C3 proximal Pegcetacoplana. A paciente se adaptou muito bem ao uso subcutâneo duas vezes por semana, e seus níveis de hemoglobina subiram (14 g/dL), com diminuição rápida dos reticulócitos e da icterícia, e melhora significativa da astenia. A avaliação do clone HPN em neutrófilos - 98% e hemácias - 95% confirma a ausência de hemólise intra ou extravascular. Conclusão: Este caso demonstra que a citometria de fluxo juntamente com parâmetros laboratoriais básicos como reticulócitos, LDH e bilirrubinas pode auxiliar na interpretação do tipo de hemólise e da resposta aos inibidores de complemento. Tanto Eculizumab quanto Danicopan mostraram benefícios clínicos significativos nos contextos utilizados, embora a paciente tenha apresentado complicações e eventos adversos. O uso subsequente de Pegcetacoplana resultou em melhora clínica evidente desta paciente, impactando inclusive na qualidade de vida. Este relato reforça a importância do monitoramento contínuo e personalizado do tratamento da Hemoglobinúria Paroxística Noturna na atualidade.

Introduction: The presence of BCR::ABL1 gene rearrangements (Philadelphia Chromosome) in acute lymphoblastic leukemia (Ph+ ALL) at diagnosis is critical for prognostic stratification and treatment decisions. Distinguishing between Ph+ ALL and lymphoid blast crisis of chronic myeloid leukemia (CML-BC) is challenging. While most Ph+ ALL cases present with a p190 (e1a2) fusion, a subset displays p210 (e13a2 or e14a2) or p230 fusions. It remains unclear whether these cases are true de novo Ph+ ALL or undiagnosed chronic phase CML progressing to blastic crisis. Methods: Retrospective analysis of patients diagnosed with ALL (characterized by > 20% lymphoblasts) referred for hematopoietic cell transplantation (HCT) between 2019 and 2024, who exhibited t(9;22)(q34;q11) or BCR::ABL1 rearrangements identified through cytogenetic analysis or RT-PCR. The relationship between transcript subtypes identified through molecular biology and clinical, morphological, and phenotypic characteristics, and minimal residual disease (MRD) via RQ-PCR (molMRD) and flow cytometry (flowMRD) were analysed in relation to survival outcomes. Results: 30 ALL patients assessed between 2016 and 2024 had Ph+ (24% of 125 ALL), 18M/12F, 22 adults median age 36.6 years (range 19-75.6) and 8 children (4.77 y, range 3.8-14). Twenty patients with p190 (e1a2) transcript were classified as Ph+ ALL (17 B-cell Ph+ ALL and 3 early T-cell Ph+ ALL) and 10 patients with p210 transcript were classified as having CML blastic crisis. In the CML group, transcript subtypes included e13a2 (b2a2) in 2 patients, e14a2 (b3a2) in 1, and multiple associated transcripts (b2a2 and/or b3a2 with e1a2) in 7 patients. Of these 10 patients, only 2 had a prior CML history with previous ITK use; 4 presented with extramedullary disease (2 CNS, 1 breast, 1 liver), and 4 had leukocytosis with neutrophilia in the initial CBC, suggesting myeloid involvement. The Ph+ ALL group had a lower median age at diagnosis (23.9 vs. 41.8 years) compared to the CML-BC group, lower median leukocyte (5,565 vs. 57,850/uL) and platelet counts (32,000 vs. 134,000/uL) at diagnosis. There were no differences in precursor left shift or blast predominance between groups. All patients received polychemotherapy including tyrosine kinase inhibitors (TKIs). Early death due to refractory disease occurred in five older adult patients (16.6%). Three children and two AYA patients maintained a complete response to TKI therapy. Twenty patients (7 BC-CML and 12 Ph+ ALL) underwent HCT; five of these relapsed, with three undergoing a second HCT and two dying due to relapsed disease. No differences was found in overall survival (63.6% vs. 50.0%, p = 0.25), median survival time (14.5 years vs. 2.5 years), or relapse rates between groups. MRD was evaluated using RQ-PCR and MFC at 1-, 2-, and 3 months post-transplantation. MRD analysis showed a strong correlation between MFC and RQ-PCR results (r = 0.643, 95% CI 0.50-0.74, p < 0.001). Of the 54 samples classified as MRD-negative by RQ-PCR, 53 (98.1%) were also MRD-negative by MFC. Among the 48 samples deemed MRD-positive by PCR, 39 (81.3%) were confirmed positive by MFC. When restricted to samples with > 0.01% MRD by PCR, the proportion of those containing ALL cells according to MFC remained high (28 of 30, 93.3%). Conclusion: In conclusion, this retrospective study underscores the complexity in distinguishing Ph+ ALL from CML-BC and highlight the importance of comprehensive molecular and phenotypic analyses in guiding treatment strategies and prognostication. Future research should focus on refining methodologies for MRD assessment of Ph+ ALL patients and exploring their synergistic potential to better distinguish between Ph+ ALL and CML-BC.

Introduction: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disease with an average prevalence of 1 in 5000-8000 inhabitants. It is caused by an alteration in angiogenesis that leads to vascular alterations. It is present from birth, and is clinically diagnosed using the Curacao criteria, which are present in 80% of patients between 20 and 30 years of age. Genetic diagnosis is also possible. Clinical case: 77 years old, female, personal history of epistaxis since childhood, chronic iron deficiency anemia requiring iron treatment and repeated digestive hemorrhages, multiple blood transfusions and gastrointestinal resection surgery due to incoherent bleeding. Admission due to functional anemic syndrome due to dyspnea in the context of upper digestive hemorrhage. Microcytic hypochromic anemia hemoglobin 4.9 g/dl requiring transfusion of 2 units of deplasmatized blood, compatible extended phenotype. On admission, fibrogastroscopy reported multiple ectasias and 2 ulcerated gastroduodenal lesions. Physical examination revealed pale skin and mucosa and telangiectasias in the hands, fingertips, face and lips that she had had since childhood. Based on the Curacao diagnostic criteria in force since 2000, a clinical diagnosis of HHT was made in our patient due to recurrent spontaneous epistaxis, mucocutaneous telangiectasias in characteristic sites, and gastrointestinal arteriovenous malformations (AVMs), which is why she presents 3 of the 4 Curacao criteria. Treatment with ferrous sulphate was started for her anaemia, and she was followed up in a transfusion medicine outpatient clinic upon discharge and given family counselling. Conclusions: It is important for the medical team to be aware of this HHT pathology to recognize its existence as early as possible, to carry out a correct study, treatment and follow-up in order to avoid its complications and improve the quality of life of these patients.

Renal cell carcinoma (RCC) is the most common solid tumour of the kidney and accounts for 3% of all cancers. While immune checkpoint inhibitor (ICI)-based combination therapies have emerged as the first-line treatment for metastatic renal cell carcinoma (mRCC), the role of surgery has become more controversial. This review summarizes the evidence, current role and future directions for surgery in mRCC management. The survival benefits of cytoreductive nephrectomy (CN) shown in the interferon era have encountered increasing disputes in the tyrosine-kinase inhibitor (TKI) and ICI eras. Undoubtedly, several systematic reviews based on retrospective data have supported the survival benefits of CN. Nevertheless, 2 prospective trials, CARMENA and SURTIME, proved that sunitinib as the upfront therapy resulted in noninferior survival outcomes compared with immediate CN. The safety of CN does have solid ground in the current literature. Several studies suggested that preoperative systemic therapy did not seem to aggravate perioperative complications or mortality rates, in experienced centres. Meticulous patient selection is the rule of thumb in the modern management of mRCC patients. The limitations of the existing prognostication models, however, must be acknowledged. Clinicians should adopt a multidisciplinary and holistic approach and contemplate all patient, disease, surgeon and socio-economical factors, before deciding who should go for surgery. The advent of metastasis-directed therapy (MDT) and survival benefits of adjuvant pembrolizumab shown in the oligometastatic subgroup, where complete metastasectomy could be achieved (M1 NED), calls for more comparative studies against upfront ICI combinations. In summary, CN brings survival benefits to well-selected good-to-intermediate-risk mRCC patients. Individualized and multidisciplinary care is pivotal.

In the hopes of observing the highest-energy neutrinos (E>1 EeV) populating the Universe, both past (RICE, AURA, ANITA) and current (RNO-G, ARIANNA, ARA and TAROGE-M) polar-sited experiments exploit the impulsive radio emission produced by neutrino interactions. In such experiments, rare single event candidates must be unambiguously identified above backgrounds. Background rejection strategies to date primarily target thermal noise fluctuations and also impulsive radio-frequency signals of anthropogenic origin. In this paper, we consider the possibility that ‘fake’ neutrino signals may also be generated naturally via the ‘triboelectric effect.’ This broadly describes any process in which force applied at a boundary layer results in displacement of surface charge, leading to the production of an electrostatic potential difference ΔV. Wind blowing over granular surfaces such as snow can induce such a potential difference, with subsequent coronal discharge. Discharges over timescales as short as nanoseconds can then lead to radio-frequency emissions at characteristic MHz–GHz frequencies. Using data from various past (RICE, AURA, SATRA, ANITA) and current (RNO-G, ARIANNA and ARA) neutrino experiments, we find evidence for such backgrounds, which are generally characterized by: (a) a threshold wind velocity which likely depends on the experimental trigger criteria and layout; for the experiments considered herein, this value is typically O(10 m/s), (b) frequency spectra generally shifted to the low-end of the frequency regime to which current radio experiments are typically sensitive (100–200 MHz), (c) for the strongest background signals, an apparent preference for discharges from above-surface structures, although the presence of more isotropic, lower amplitude triboelectric discharges cannot be excluded.

En-Yi Lin,1,2 Shao-Xi Hsu,1 Bing-Hua Wu,1 Yu-Chen Deng,1,3 Wei Wuli,1 Yuan-Sheng Li,3 Jui-Hao Lee,3 Shinn-Zong Lin,2,4 Horng-Jyh Harn,2,5 Tzyy-Wen Chiou1 1Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan; 2Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; 3Everfront Biotech Inc, Taipei, Taiwan; 4Department of Neurosurgery, Hualien Tzu Chi Hospital, Hualien, Taiwan; 5Department of Pathology, Hualien Tzu Chi Hospital, Hualien, TaiwanCorrespondence: Tzyy-Wen Chiou, Department of Life Science, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Road, Shou-Feng, Hualien, Taiwan, Tel +886-3-890-3638, Email twchiou@gms.ndhu.edu.tw Horng-Jyh Harn, Department of Pathology, Hualien Tzu Chi Hospital, Hualien, Taiwan, Tel +886-3-856-1825, Email arthewduke@gmail.comPurpose: Exosomes are membrane vesicles secreted by various cells and play a crucial role in intercellular communication. They can be excellent delivery vehicles for oligonucleotide drugs, such as microRNAs, due to their high biocompatibility. MicroRNAs have been shown to be more stable when incorporated into exosomes; however, the lack of targeting and immune evasion is still the obstacle to the use of these microRNA-containing nanocarriers in clinical settings. Our goal was to produce functional exosomes loaded with target ligands, immune evasion ligand, and oligonucleotide drug through genetic engineering in order to achieve more precise medical effects.Methods: To address the problem, we designed engineered exosomes with exogenous cholecystokinin (CCK) or somatostatin (SST) as the targeting ligand to direct the exosomes to the brain, as well as transduced CD47 proteins to reduce the elimination or phagocytosis of the targeted exosomes. MicroRNA-29b-2 was the tested oligonucleotide drug for delivery because our previous research showed that this type of microRNA was capable of reducing presenilin 1 (PSEN1) gene expression and decreasing the β-amyloid accumulation for Alzheimer’s disease (AD) in vitro and in vivo.Results: The engineered exosomes, containing miR29b-2 and expressing SST and CD47, were produced by gene-modified dendritic cells and used in the subsequent experiments. In comparison with CD47-CCK exosomes, CD47-SST exosomes showed a more significant increase in delivery efficiency. In addition, CD47-SST exosomes led to a higher delivery level of exosomes to the brains of nude mice when administered intravenously. Moreover, it was found that the miR29b-2-loaded CD47-SST exosomes could effectively reduce PSEN1 in translational levels, which resulted in an inhibition of beta-amyloid oligomers production both in the cell model and in the 3xTg-AD animal model.Conclusion: Our results demonstrated the feasibility of the designed engineered exosomes. The application of this exosomal nanocarrier platform can be extended to the delivery of other oligonucleotide drugs to specific tissues for the treatment of diseases while evading the immune system.Keywords: oligonucleotide drug, functional nanocarriers, hippocampus, SH-SY5Y, 3xTG-AD

Chih-Yuan Wang,1 Shyang-Rong Shih,1 Kuen-Yuan Chen,2 Yi-Chieh Chung,1 Pei-Jie Huang1 1Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; 2Department of Internal Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, TaiwanCorrespondence: Chih-Yuan Wang, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, 7, Chung-Shan South Road, Taipei, Taiwan, Email cyw1965@gmail.com; cyw1965@ntu.edu.twBackground: The recurrence rate of thyroid cancer can be as high as 30%. The purpose of this study was to examine changes of urine exosomal peptide levels after thyroidectomy in patients with thyroid cancer to determine if levels can predict the risk of recurrence.Methods: Patients > 20 years old as newly diagnosed with papillary thyroid cancer who had received a thyroidectomy were recruited. Urine samples were collected at 12 months after enrollment to the study, and 1 year later. Urine exosomes containing different peptides were identified and compared.Results: A total of 70 patients were enrolled in the study, and were classified by the interval between surgery and enrollment: 42 patients with < 5 years between surgery and enrollment, 14 patients between 5– 10 years, and 14 patients longer than 10 years. No recurrence was observed in any patient during the 2 years after enrollment. No significant differences were found in the levels of serum proteins or urine exosomal peptides between groups, or between intervals. Known risk factors for high-risk thyroid cancer had only a mild correlation with serum protein levels and urine exosomal peptides.Conclusion: Our study revealed the long-term basal fluctuation ranges of serum proteins and urine exosomal peptides in patients with thyroid cancer who underwent thyroidectomy. For high-risk patients after thyroidectomy, concentrations of serum proteins or urine exosomal peptides within the ranges may indicate there is a lower risk of thyroid cancer recurrence during long-term follow-up.Trial Registration: ClinicalTrials.gov: NCT03488134.Keywords: thyroid cancer, urine exosome, peptide, thyroglobulin, recurrence

Qing-Ren Liu,1 Yu-Chen Dai,2 Mu-Huo Ji,3 Pan-Miao Liu,4 Yong-Yan Dong,4 Jian-Jun Yang4 1Department of Anesthesiology, Xishan People’s Hospital of Wuxi City, Wuxi, 214105, People’s Republic of China; 2Department of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, People’s Republic of China; 3Department of Anesthesiology, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, People’s Republic of China; 4Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, People’s Republic of ChinaCorrespondence: Jian-Jun Yang, Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, NO. 1 East Jianshe Road, Zhengzhou, 450052, People’s Republic of China, Email yjyangjj@126.comAbstract: Acute postsurgical pain (APSP) has received growing attention as a surgical outcome. When poorly controlled, APSP can affect short- and long-term outcomes in patients. Despite the steady increase in awareness about postoperative pain and standardization of pain prevention and treatment strategies, moderate-to-severe APSP is frequently reported in clinical practice. This is possibly because pain varies widely among individuals and is influenced by distinct factors, such as demographic, perioperative, psychological, and genetic factors. This review investigates the risk factors for APSP, including gender, age, obesity, smoking history, preoperative pain history, pain sensitivity, preoperative anxiety, depression, pain catastrophizing, expected postoperative pain, surgical fear, and genetic polymorphisms. By identifying patients having an increased risk of moderate-to-severe APSP at an early stage, clinicians can more effectively manage individualized analgesic treatment protocols with a combination of pharmacological and non-pharmacological interventions. This would alleviate the transition from APSP to chronic pain and reduce the severity of APSP-induced chronic physical disability and social psychological distress.Keywords: acute postoperative pain, acute postsurgical pain, risk factors, predictors

Yi-Hsien Shiao,1,2 Chung-Chieh Yu,3 Yuan-Chieh Yeh1,4 1Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung Medical Center, Keelung, Taiwan; 2Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Chest, Critical Care, and Sleep Medicine, Chang Gung Memorial Hospital, Keelung Medical Center, Keelung, Taiwan; 4Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, TaiwanCorrespondence: Yuan-Chieh Yeh, Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung Medical Center, No. 222, Maijin Road, Anle Dist, Keelung, 204, Taiwan, Tel +886 02-24313131 ext 2777, Fax +886 02-24313161, Email b9005030@gmail.comPurpose: Obstructive sleep apnea (OSA) is a common breathing disorder during sleep that is associated with symptoms such as snoring, excessive daytime sleepiness, and breathing interruptions. Polysomnography (PSG) is the most reliable diagnostic test for OSA; however, its high cost and lengthy testing duration make it difficult to access for many patients. With the availability of free snore applications for home-monitoring, this study aimed to validate the top three ranked snore applications, namely SnoreLab (SL), Anti Snore Solution (ASS), and Sleep Cycle Alarm (SCA), using PSG.Patients and Methods: Sixty participants underwent an overnight PSG while simultaneously using three identical smartphones with the tested apps to gather sleep and snoring data.Results: The study discovered that all three applications were significantly correlated with the total recording time and snore counts of PSG, with ASS showing good agreement with snore counts. Furthermore, the Snore Score, Time Snoring of SL, and Sleep Quality of SCA had a significant correlation with the natural logarithm of apnea hypopnea index (lnAHI) of PSG. The Snore Score of SL and the Sleep Quality of SCA were shown to be useful for evaluating snore severity and for pre-diagnosing or predicting OSA above moderate levels.Conclusion: These findings suggest that some parameters of free snore applications can be employed to monitor OSA progress, and future research could involve adjusted algorithms and larger-scale studies to further authenticate these downloadable snore and sleep applications.Keywords: polysomnography, snoring, smartphone applications, apps, obstructive sleep apnea, apnea hypopnea index

Yi-Chia Su,1 Chip-Jin Ng,1– 3 Liang-Tien Chien,4,5 Li-Heng Tsai,1,2 Cheng-Yu Chien,1,2,6,7 Shou-Chien Hsu1,2,8 1Department of Emergency Medicine, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan, Taiwan; 2Department of Emergency Medicine, Chang Gung Memorial Hospital Taipei Branch, Taipei, Taiwan; 3Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan; 4Graduate Institute of Management, College of Management, Chang Gung University, Taoyuan, Taiwan; 5Taoyuan Fire Department, Taoyuan, Taiwan; 6Department of Emergency Medicine, Ton-Yen General Hospital, Zhubei, Taiwan; 7Department of Senior Service Industry Management, Minghsin University of Science and Technology, Hsinchu, Taiwan; 8Department of Occupational Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, TaiwanCorrespondence: Shou-Chien Hsu, Department of Emergency Medicine, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, No. 5 Fushing Street, Gueishan District, Taoyuan City, 333, Taiwan, Tel +886-3-3281200 &num; 2505, Fax +886-3-3287715, Email otsuka32@gmail.comPurpose: Various factors, such as event location and response time, influence the outcomes of out-of-hospital cardiac arrest (OHCA). Very few studies have explored the delivery of basic life support (BLS) to patients having OHCA at health clinics or nursing homes—settings with professional BLS providers. Thus, in this study, we compared prognostic and survival outcomes between health clinics, nursing homes, and other public places (eg, workplaces and sports facilities/recreational areas) to offer insights for optimizing OHCA outcomes.Patients: This study included adults who had nontraumatic OHCA in Taoyuan City between January 2017 and December 2022.Methods: We collected data on patient characteristics, emergency medical service parameters, onsite patient management, automated external defibrillator (AED) locations, OHCA prognosis, and survival outcomes. Multivariate analyses were performed to predict survival to discharge (primary outcome) and neurological outcomes at discharge (secondary outcome).Results: During the study period, the numbers of OHCA events at health clinics, nursing homes, and other public places were 158, 208, and 1986, respectively. The mean age of OHCA in health medical clinics, nursing home and other public places were 63.4, 81.5 and 64.7, respectively (P value< 0.001). The proportion of witnessed events, rate of bystander resuscitation, and frequency of AED utilization were the highest for health clinics (53.2% (84/158), 83.4% (132/158), and 13.3% (21/158), respectively, P value< 0.001). The average AED–scene distances and response times were the lowest for health clinics (388.8 m and 5.4 min, respectively). In initial shockable rhythm group, the probabilities of survival to discharge at discharge were the highest for health clinics (aOR=1.41, 95% CI=1.04– 1.81, P value=0.041)) and lowest for nursing homes (aOR=0.84, 95% CI=0.76– 0.93, P value=0.024).Conclusion: Our research shows that OHCA patients at medical health clinics have higher rates of witnessing and bystander CPR and AED usage than other public places. However, while survival rates for patients with shockable rhythms are slightly better at health clinics, the neurological outcomes are not significantly different. The AED–scene distances are too far to be used effectively.Keywords: public access defibrillators, geographic information system, out-of-hospital cardiac arrest, automated external defibrillators, emergency medical services

Shi-Hua Yan,1,2 Yong Chen,3 Zhi-Qian Huang,1 Wen-Xi Zhong,1 Xiao-Tian Wang,1 Yang-Can Tang,1 Xu-Yi Zhao,1 Yu-Shan Wu,1 Chun Zhou,4 Wei Zhu,5 Wei Xiao,1,6 Xuan Li,2 Dong-Shu Zhang1,2 1School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 2Department of Traditional Chinese Medicine, The Tenth affiliated Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, Guangdong, 523058, People’s Republic of China; 3Department of Rheumatology and Immunology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, People’s Republic of China; 4School of Pharmaceutical Sciences; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 5Guangzhou Center for Disease Control and Prevention, Guangzhou, 510440, People’s Republic of China; 6Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, People’s Republic of ChinaCorrespondence: Dong-Shu Zhang, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Email nyzds@sina.com Wei Xiao, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, People’s Republic of China, Email xw7688@smu.edu.cnPurpose: Acupoint autohemotherapy (A-AHT) has been proposed as an alternative and complementary treatment for atopic dermatitis (AD), yet the exact role of its blood component in terms of therapeutic efficacy and mechanism of action is still largely unknown.Methods: This study aimed to evaluate the therapeutic efficacies and action mechanisms of intramuscular injections of autologous whole blood (AWB) and mouse immunoglobulin G (IgG) (autologous or heterologous) at acupoints on 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse models. Serum levels of total immunoglobulin E (IgE), IgG, interleukin-10 (IL-10), and interferon-gamma (IFN-γ) were measured, as well as mRNA expression levels of Forkhead box P3 (FoxP3), IL-10 and IFN-γ in dorsal skin lesions, and IL-10+, IFN-γ+ and FoxP3+CD4+T cells in murine spleen.Results: It showed that repeated acupoint injection of AWB, autologous total IgG (purified from autologous blood in AD mice) or heterologous total IgG (purified from healthy blood in normal mice) effectively reduced the severity of AD symptoms and decreased epidermal and dermal thickness as well as mast cells in skin lesions. Additionally, AWB acupoint injection was found to upregulate FoxP3+, IL-10+ and IFN-γ+ CD4+T cells in murine spleen, suppressing the production of IgE antibodies and increasing that of IgG antibodies in the serum. Furthermore, both AWB and autologous total IgG administrations significantly elevated FoxP3 expression, mRNA levels of IL-10 and IFN-γ in dorsal skin lesions. However, acupoint injection of heterologous total IgG had no effect on regulatory T (Treg) and Th1 cells modulation.Conclusion: These findings suggest that the therapeutic effects of A-AHT on AD are mediated by IgG-induced activation of Treg cells.Keywords: autologous whole blood, acupoint injection, atopic dermatitis, anti-idiotypic immunomodulation, Tregs

Kai-Ming Jhang,1,&ast; Guan-Chun Liao,2,&ast; Wen-Fu Wang,1,&ast; Yu-Chun Tung,3,&ast; Shao-Wei Yen,4 Hsin-Hung Wu2,5 1Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan; 2Department of Business Administration, National Changhua University of Education, Changhua, Taiwan; 3Department of Pharmacy, Taichung Veterans General Hospital, Taichung, Taiwan; 4Department of Information Management, National Changhua University of Education, Changhua, Taiwan; 5Faculty of Education, State University of Malang, Malang, East Java, Indonesia&ast;These authors contributed equally to this workCorrespondence: Hsin-Hung Wu, Email hhwu@cc.ncue.edu.twPurpose: This study aimed to find the caregiving burden level for patients with dementia who had multiple chronic diseases by simultaneously considering both patient and caregiver factors.Participants and Methods: A cross-sectional study with 284 patients with dementia having multiple chronic diseases managed by the dementia collaborative care team at Changhua Christian Hospital in Taiwan was conducted. The input variables were from patients, such as age, gender, mood symptoms, and behavioral and psychological symptoms, and caregivers, including age, relation to the patient, caregiver’s mood, and caregiving burden. The Apriori algorithm was employed to determine the association between patient and caregiver factors and different caregiving burden levels by setting up the minimum support of 1% and confidence of 90% along with lift > 1.Results: When caring for patients with dementia, twenty scenarios were found for caregivers with a severe burden. In addition, 1936 scenarios were related to caregivers with a moderate-to-severe burden. Specifically, there were eight scenarios for patients with three chronic diseases which could be further categorized into five general rules. Two hundred and fifty scenarios belonging to patients with two chronic diseases could be classified into 16 different combinations from eight chronic diseases of the database.Conclusion: Caregiver’s mood, patients with mild dementia, and patients aged 75– 84 years were associated with a severe caregiving burden. College and above education of the caregiver, the patient aged 85 years or more, and at least one of caregiver’s moods were the variables to result in a moderate-to-severe burden for caregivers caring for patients with three multiple chronic diseases. Moreover, college and above education of the caregiver, mood symptom, age of the caregiver, and age of the patient were important variables for caregivers who had a moderate-to-severe burden taking care of patients with two chronic diseases.Keywords: patients with dementia, multiple chronic diseases, behavior and psychological symptoms of dementia, mood symptom, caregiving burden, dementia collaborative care team, apriori algorithm

Yu-Chi Tu,&ast; Yu-Mei Wang,&ast; Li-Jun Yao Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Jun Yao, Email ljyao@hust.edu.cnAbstract: DNA can be used for precise construction of complex and flexible micro-nanostructures, including DNA origami, frame nucleic acids, and DNA hydrogels. DNA nanomaterials have good biocompatibility and can enter macrophages via scavenger receptor-mediated endocytosis. DNA nanomaterials can be uniquely and flexibly designed to ensure efficient uptake by macrophages, which represents a novel strategy to regulate macrophage function. With the development of nanotechnology, major advances have been made in the design and manufacturing of DNA nanomaterials for clinical therapy. In diseases accompanied by macrophage disturbances including tumor, infectious diseases, arthritis, fibrosis, acute lung injury, and atherosclerosis, DNA nanomaterials received considerable attention as potential treatments. However, we lack sufficient information to guarantee precise targeting of macrophages by DNA nanomaterials, which precludes their therapeutic applications. In this review, we summarize recent studies of macrophage-targeting DNA nanomaterials and discuss the limitations and challenges of this approach with regard to its potential use as a biological therapy.Keywords: macrophages, DNA nanomaterials, therapy, macrophage-related diseases

Shi-hao Zhao,1 Wen-hui Wang,1 Yu-cong Liang,1 Kai-xin Zhang,1 Kuan Chen,1 Hong-ling Wang,2 Xiang-qi Wang2 1Acupuncture and Moxibustion Massage College, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450046, People’s Republic of China; 2Department of Oncology, Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450008, People’s Republic of ChinaCorrespondence: Xiang-qi Wang, Email wangxiangqi777@163.comAbstract: Baihe Gujin decoction is one of the most commonly used decoction in traditional Chinese medicine for the treatment of lung cancer. It can nourish yin and moisten the lung as well as prevent phlegm from forming and stop coughing. On the one hand, Baihe Gujin decoction is characterized with extensive application, proven efficacy, a long history, and high safety. On the other hand, Baihe Gujin decoction can induce apoptosis of tumor cells, improve immune function and inhibit inflammation. The main anti-tumor components of this include kaempferol, quercetin, isorhamnetin, glycyrrhizin and β-sitosterol. Clinically, Baihe Gujin decoction can improve the adverse reactions caused by radiotherapy, chemotherapy and immunotherapy for lung cancer, enhance the quality of life of patients, and prolong their survival time. At present, there are a large number of clinical and basic researches on the treatment of lung cancer with Baihe Gujin decoction. In this paper, we mainly discussed the treatment of lung cancer with Baihe Gujin decoction through analyzing basic and clinical researches at home and abroad in the past 20 years. Through the discussion, we aimed to probe deeper into Baihe Gujin decoction for the treatment of lung cancer, thereby providing a broader idea for clinical diagnosis and treatment of lung cancer.Keywords: Baihe Gujin decoction, lung cancer, traditional Chinese medicine, basic research, clinical study

Yul Hee Kim,1 Han-Seul Kim,1 Hyeung Kyoo Kim,2 Soo Young Kim,2 Jeonghun Lee,2 You Chan Kim,1 Young Joon Park1 1Department of Dermatology, Ajou University School of Medicine, Suwon, Republic of Korea; 2Department of Surgery, Ajou University School of Medicine, Suwon, Republic of KoreaCorrespondence: Young Joon Park, Department of Dermatology, Ajou University Hospital, 164, World Cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-Do, Suwon, Republic of Korea, Tel +82-31-219-5187, Email aro@ajou.ac.krPurpose: Early intervention of surgical scars with a pulsed dye laser is known to effectively prevent pathologic scars. Despite multiple reports on the effectiveness of the treatment, very few studies have demonstrated its appropriate initiation timing. In this study, our objective was to determine the optimal timing for initiating laser treatment following thyroidectomy.Methods: This study retrospectively analyzed 91 patients undergoing pulsed dye laser treatment post-thyroidectomy, grouping them by treatment initiation timing. The patients underwent treatment at intervals of 3– 4 weeks with at least five sessions. Those with a high pliability score were injected with intralesional corticosteroids. The Antera 3D® skin imaging analyzer was used to assess biophysical parameters.Results: The total Vancouver Scar Scale score significantly reduced after treatment in all groups. The Vancouver Scar Scale score reduction rate was significantly higher after treatment in the group for which the treatment was initiated within 3 weeks of surgery. The pigmentation and erythema score analyzed by Antera 3D® was also lower in this group.Conclusion: Early intervention using a pulsed dye laser within 3 weeks of thyroidectomy can substantially inhibit pathological scar development, providing physicians with a guide for optimal treatment commencement.Keywords: hypertrophic scars, laser treatment of scar, scar, pulsed dye laser

Xuan Wang,1,&ast; Jing-Xian Hu,2,&ast; Ying Wang,1 Fang Wang,1 Xuan Wu,1 Fei Wang,1 Yan-Chao Zhao,1 Xiao-Lan Wang,2 Li-Li Zhang2 1Second Department of Hepatology Center for Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 2Department of Nursing, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Li Zhang; Jing-Xian Hu, Department of Nursing, Beijing Youan Hospital, Capital Medical University, No. 8 of Xitoutiao, Youanmen wai, FengtaiDistrict, Beijing, 100069, People’s Republic of China, Email zhanglyliy@163.com; 819211326@mail.ccmu.edu.cnObjective: This study explores the correlation between coping style, quality of life, and illness uncertainty in the family caregivers of patients with liver cancer.Methods: Employing convenience sampling, 210 family caregivers of patients with liver cancer who met the admission criteria were selected from a grade A infectious disease hospital in Beijing between January and December 2022. A cross-sectional survey was conducted using the Simplified Coping Style Questionnaire, Caregiver Quality of Life, and the Mishel Uncertainty in Illness Scale for Family Members. This study analysed the correlations between coping styles, quality of life, and illness uncertainty in these caregivers.Results: The study found that family caregivers of patients with liver cancer had average scores for illness uncertainty (83.44 ± 11.86), coping style (33.19 ± 9.79; both positive [23.02 ± 6.81] and negative [10.17 ± 5.05]), and quality of life (169.53 ± 32.46). A negative association was observed between illness uncertainty in these caregivers and positive coping style (r = − 0.207, p = 0.003), physical status (r = − 0.182, p = 0.008), psychological status (r = − 0.200, p = 0.004), and social adaptation (r = − 0.229, p = 0.001).Conclusion: The study concludes that illness uncertainty in family caregivers of patients with liver cancer is at a moderate level. Furthermore, there is a notable correlation between illness uncertainty, coping style, and quality of life in these caregivers.Keywords: liver cancer, family caregivers, uncertainty in illness, coping style, quality of life

Jing-Chun Xia,1,2,&ast; Yu-Cheng Huang,1,2,&ast; Ke Wu,1,2 Jian Pang,1,2 Ying Shi1,2 1Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Pang; Ying Shi, Email pangjian@shutcm.edu.cn; shiying1974@126.comPurpose: Chinese herbal medicine and electroacupuncture (EA) have been used to control pain for many decades in China. We aim to explore the efficacy of intervening patients whose discogenic sciatica symptoms lasting longer than 3 months with these conservative treatments.Patients and Methods: This is a single-center, parallel-group, patient-unblinded Randomized Controlled Trial (RCT) with blinded outcome assessment and statistician. One hundred and twenty-four patients will be assigned randomly into 2 groups including conservative treatment group (Shenxie Zhitong capsule combined with EA treatment) and Nonsteroidal Anti-inflammatory Drugs (Nonsteroidal Anti-inflammatory Drugs, NSAIDs) control group (Celecoxib) in a 1:1 ratio. The trial involves a 4-week treatment along with follow-up for 6 months. The primary outcome is the leg pain intensity measured by the visual analogue scale (VAS) at 6 months after randomization. Secondary outcomes include leg pain intensity at other time points, back pain intensity, leg pain and back pain frequency, functional status, quality of life, return to work status and satisfaction of patients. Adverse events will also be recorded.Strengths and Limitations of This Study: Through this study, we want to observe the efficacy of electroacupuncture combined with Chinese herbal medicine on pain intensity for chronic sciatica secondary to Lumbar Disc Herniation. If the final results are favorable, it is expected to be a safe, economical, and effective treatment for patients. The study design has the following limitations: the setup of control group was less than perfect; patients and doctors could not be blinded in this trial; we skipped the feasibility study. We have tried our best to minimize adverse impacts.Trial Registration: ChiCTR2300070884 (Chinese Clinical Trial Registry, http://www.chictr.org.cn, registered on 25th April 2023).Keywords: sciatica of lumbar disc herniation, shenxie zhitong capsule, electroacupuncture treatment, celecoxib, single-center randomized controlled trial, protocol

Introduction: To describe the duration of survival among bone tumour patients with endoprosthesis reconstruction and to determine frequency of implant failure, revision of surgery, and amputation after endoprosthesis reconstruction. Materials and methods: A retrospective cross-sectional review of all patients with either primary bone tumour or secondary bone metastases treated with en bloc resection and endoprosthesis reconstruction from January 2008 to December 2020. Results: A total of 35 failures were recorded among the 27 (48.2%) patients with endoprostheses. Some of the patients suffered from one to 3 types of modes of failure on different timelines during the course of the disease. Up to 8 patients suffered from more than one type of failure throughout the course of the disease. Out of all modes of failure, local recurrence (type 5 failure) was the most common, accounting for 25.0% of all failure cases. Four patients (7.1%) eventually underwent amputation, which were either due to infection (2 patients) or disease progression causing local recurrence (2 patients). Conclusion: The overall result of endoprosthesis reconstruction performed in our centre was compatible with other centres around the world. Moreover, limb salvage surgery should be performed carefully in a selected patient group to maximise the benefits of surgery.