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Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

BOUT++ turbulence simulations were performed to investigate the impact of turbulence spreading on the edge localized mode (ELM) size and divertor heat flux width $({\lambda _q})$ broadening in small ELM regimes. This study is motivated by EAST experiments. BOUT++ linear simulations of a pedestal radial electric field (Er) scan show that the dominant toroidal number mode (n) shifts from high-n to low-n, with a narrow mode spectrum, and the maximum linear growth rate increases as the pedestal Er well deepens. The nonlinear simulations show that as the net E × B pedestal flow increases, the pressure fluctuation level and its inward penetration beyond the top of the pedestal both increase. This leads to a transition from small ELMs to large ELMs. Both inward and outward turbulence spreading are sensitive to the scrape-off-layer (SOL) plasma profiles. The inward turbulence spreading increases for the steep SOL profiles, leading to increasing pedestal energy loss in the small ELM regime. The SOL width $({\lambda _q})$ is significantly broadened progressing from the ELM-free to small ELM regime, due to the onset of strong radial turbulent transport. The extent of the SOL width $({\lambda _q})$ broadening depends strongly on outward turbulence spreading. The fluctuation energy intensity flux ${\varGamma _\varepsilon }$ at the separatrix can be enhanced by increasing either pedestal Er flow shear or local SOL pressure gradient. The ${\lambda _q}$ is broadened as the fluctuation energy intensity flux ${\varGamma _\varepsilon }$ at the last close flux surface (LCFS) increases. Local SOL E × B flow shear will restrain outward turbulence spreading and the associated heat flux width broadening. Operating in H-mode with small ELMs has the potential to solve two critical problems: reducing the ELM size and broadening the SOL width.

Yimy F Medina,1,2 Cindy V Mendieta,1,3 Natalia Prieto,2 María Laura Acosta Felquer,4 Enrique R Soriano4 1Department of Clinical Epidemiology and Biostatistics, PhD Program in Clinical Epidemiology, Pontificia Universidad Javeriana, Bogotá, Colombia; 2Department of Internal Medicine, Rheumatology Unit, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia; 3Nutrition and Biochemistry Department, Faculty of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia; 4Internal Medicine Department, Rheumatology Section, Internal Medicine Service, Instituto Universitario Hospital Italiano, Buenos Aires, ArgentinaCorrespondence: Yimy F Medina, Email yimfmedinav@unal.edu.coIntroduction: A consensus is a general agreement among group members that is pivotal in gathering expert input for classification, diagnostic criteria, and guideline development. However, the absence of established methodological standards presents challenges in conducting and analyzing these studies.Objective: This scoping review explored the evidence on essential elements in consensus studies to create a list of candidate items for a standardized reporting tool. This tool is intended to improve the critical appraisal and methodological rigor of consensus studies.Methods: A systematic scoping review was conducted using predetermined criteria for study selecting studies and extracting data. A comprehensive literature search was performed without imposing date restrictions, covering multiple databases, including Medline, Embase, LILACS, SciELO, and up to March 2022. We included only English-language publications and excluded incomplete articles and conference reports. The risk of bias was assessed using the CASP checklist, and the study selection and data extraction were performed independently by two researchers in duplicate.Results: We identified 8360 references; 20 publications were included for data extraction. The majority (70%) used the Delphi method, and the remainder (30%) employed the modified Delphi method. Inconsistencies in reporting conflicts of interest and consensus timing were observed. Other methodologies, such as RAND/UCLA and Nominal Group Technique were excluded due to methodological limitations. Most studies exhibited a low risk of bias.Discussion: Our findings underscored the need for more standardization in definitions, methodology, and reporting within consensus studies. To address these gaps, we developed a checklist of key reporting items aimed at improving the planning, execution, and reporting consensus studies. Although the developed checklist requires validation, it offers a practical framework to enhance methodological transparency and reliability.Conclusion: Deficiencies and variability in consensus methodologies reporting underscore the need for a standardized approach. We propose the adoption of a checklist to strengthen the robustness of consensus studies, supporting advances in classification, diagnostic criteria, and guideline development.Keywords: consensus study, reporting guidelines, scoping review, methodology, completeness of reporting, excellent reporting

Lwin Moe Aung,1 Ting-Yi Renn,1 Jerry Chin-Yi Lin,1,2 Eisner Salamanca,1 Yi-Fan Wu,1,3 Yu-Hwa Pan,1,4,5 Nai-Chia Teng,1,6 Haw-Ming Huang,1 Ying-Sui Sun,7 Wei-Jen Chang1,8 1School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; 2Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA; 3Department of Biomedical Engineering, Ming-Chuan University, Taoyuan, Taiwan; 4Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan; 5School of Dentistry, College of Medicine, China Medical University, Taichung, Taiwan; 6Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan; 7School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; 8Dental Department, Shuang-Ho Hospital, Taipei Medical University, Taipei, TaiwanCorrespondence: Wei-Jen Chang; Ying-Sui Sun, Email cweijen1@tmu.edu.tw; yingsuisun@tmu.edu.twPurpose: Nano-engineering techniques have significantly enhanced the various aspects of dentistry, with notable advancements, especially in dental implant surface modification. Dental implants are among the most significant and highly successful developments in contemporary dentistry. The use of nanotechnology for surface modification of zirconia ceramic implant increases interaction with surrounding bone cells, and ultimately leading to increase osseointegration.Materials and Methods: Glow discharge plasma was utilized to graft allylamine and fibronectin nanoproteins onto the surface of zirconia implants. A total of 18 implants were placed in right and left femurs of nine New Zealand rabbits. Implant stability test (IST), 3D bone reconstruction and micro-CT (μCT) analysis, bone-implant contact (BIC) from histomorphometry analysis, and osteogenic gene expression were analyzed after scarification at 4, 8, and 12 weeks.Results: IST results demonstrated a significant secondary stability gain at the end of 12 weeks. The surface-treated group obtained a gradual increase in marginal bone level. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis revealed increased expression of osteogenic genes of alkaline phosphatase (ALP) and transcription factor SP7 (SP7) biomarkers at 4 weeks. Osteoprotegerin (OPG) expression increased at 8 weeks, while runt-related transcription factor 2 (RUNX2), collagen 1A1 (COL1), bone sialoprotein (BSP), and receptor activator of nuclear factor κ B (RANK) exhibited the highest expression at 12 weeks. Importantly, histomorphometric analysis of BIC indicated that new bone formation was significantly higher in the A50F10 group compared to the control group at 12 weeks (P < 0.001).Conclusion: Based on the above findings, we conclude that the nanorough zirconia implant surface grafted with fibronectin nanoproteins prominently stimulated cellular activity and improved osseointegration properties. These results evidence its potential for future applications in dental implant surface modifications. Keywords: nano-roughness, surface modification, glow discharge plasma, zirconia implants, osseointegration, fibronectin

Lin-Feng Guo,&ast; Ya-Qing Dai,&ast; Yi-Feng Yu, San-Gang Wu Department of Radiation Oncology, Xiamen Cancer Quality Control Center, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi-Feng Yu; San-Gang Wu, Department of Radiation Oncology, Xiamen Cancer Quality Control Center, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, People’s Republic of China, Email yuyfeng001@sina.com; wusg@xmu.edu.cnPurpose: To investigate the prognostic implications of gender in nasopharyngeal carcinoma (NPC) utilizing data from two independent cohorts: the Xiamen (XM)-NPC cohort (an endemic area in China) and the United States Surveillance, Epidemiology, and End Results (SEER)-NPC cohort (a non-endemic area).Methods: We included patients diagnosed with NPC from both the XM-NPC and SEER-NPC cohorts. Statistical analysis involved the chi-square test, Kaplan-Meier method, and multivariate Cox regression analyses.Results: The study identified 728 patients in the XM-NPC cohort and 2237 in the SEER cohort. In the XM-NPC cohort, 515 (70.7%) were male and 213 (29.3%) were female. In the SEER-NPC cohort, 1597 (71.4%) were male and 640 (28.6%) were female. The male-to-female ratio peaked at ≤ 25 years (2.33) and 46– 55 years (2.79) in the XM-NPC cohort, and at ≤ 25 years (2.07) and 56– 65 years (3.24) in the SEER-NPC cohort. The lowest ratios were observed among patients aged 26– 35 years in both cohorts (XM-NPC: 1.64; SEER-NPC:1.38). In the XM-NPC cohort, females had significantly better overall survival (P=0.022) and distant metastasis-free survival (P=0.038) compared to males. Similarly, in the SEER-NPC cohort, gender was found to be an independent prognostic factor for overall survival, with females showing better outcomes (P=0.038). Consistent trends were observed in patients aged > 45 years in both cohorts, while survival outcomes were comparable between genders in patients aged ≤ 45 years.Conclusion: Gender independently influences survival outcomes of NPC in both endemic and non-endemic areas.Keywords: nasopharyngeal carcinoma, gender, SEER, Chinese, outcome

Ying-Fei Yang,1 Yi-Jun Lin,2 Shu-Han You,3 Tien-Hsuan Lu,4 Chi-Yun Chen,5,6 Wei-Min Wang,1 Min-Pei Ling,7 Szu-Chieh Chen,8,9 Chung-Min Liao1 1Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 10617, Taiwan; 2Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, 11230, Taiwan; 3Institute of Food Safety and Risk Management, National Taiwan Ocean University, Keelung City, 20224, Taiwan; 4Department of Science Education and Application, National Taichung University of Education, Taichung, 403514, Taiwan; 5Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, Gainesville, FL, 32610, USA; 6Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32608, USA; 7Department of Food Science, National Taiwan Ocean University, Keelung City, 20224, Taiwan; 8Department of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan; 9Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung, 40201, TaiwanCorrespondence: Chung-Min Liao, Department of Bioenvironmental Systems Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei, 10617, Taiwan, Email cmliao@ntu.edu.twBackground: The emergence and progression of highly divergent SARS-CoV-2 variants have posed increased risks to global public health, triggering the significant impacts on countermeasures since 2020. However, in addition to vaccination, the effectiveness of non-pharmaceutical interventions, such as social distancing, masking, or hand washing, on different variants of concern (VOC) remains largely unknown.Objective: This study provides a mechanistic approach by implementing a control measure model and a risk assessment framework to quantify the impacts of control measure combinations on the transmissions of five VOC (Alpha, Beta, Delta, Gamma, and Omicron), along with a different perspective of risk assessment application.Materials and Methods: We applied uncontrollable ratios as an indicator by adopting basic reproduction number (R0) data collected from a regional-scale survey. A risk assessment strategy was established by constructing VOC-specific dose-response profiles to implicate practical uses in risk characterization when exposure data are available.Results: We found that social distancing alone was ineffective without vaccination in almost all countries and VOC when the median R0 was greater than two. Our results indicated that Omicron could not be contained, even when all control measure combinations were applied, due to its low threshold of infectivity (~3× 10− 4 plague-forming unit (PFU) mL− 1).Conclusion: To facilitate better decision-making in future interventions, we provide a comprehensive evaluation of how combined control measures impact on different countries and various VOC. Our findings indicate the potential application of threshold estimates of infectivity in the context of risk communication and policymaking for controlling future emerging SARS-CoV-2 variant infections.Keywords: SARS-CoV-2, variants of concern, basic reproduction number, modeling, non-pharmaceutical interventions, infection risk

Jia-Yu Liu,1 Chia-Hung Yen,2,3 Ya-Fan Lin,4 Yin-Hsun Feng,5 Yi-Ping Fang1,6,7 1School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Chemistry, National Dong Hwa University, Hualien, Taiwan; 5Division of Hematology and Oncology, Department of Internal Medicine, ChiMei Medical Center, Tainan, Taiwan; 6Regeneration Medicine and Cell Therapy Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence: Yi-Ping Fang, School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, San Ming District, Kaohsiung, 80708, Taiwan, Tel +886 7 3121101 ext. 2261, Email ypfang@kmu.edu.twBackground: Belinostat, a histone deacetylase inhibitor used for hematological cancer treatments, however, it caused thrombocytopenia, poor solubility, and rapid clearance. To mitigate these issues, human serum albumin (HSA) was utilized as the core material for its high protein binding affinity and self-binding capabilities. The study focused on developing belinostat-loaded HSA nanoparticles to improve solubility, extend circulation time, and reduce adverse effects.Methods: Belinostat-loaded HSA nanoparticles were synthesized using a desolvation method, optimized for size, charge, and entrapment efficiency, and characterized by molecular docking and Fourier-transform infrared spectroscopy (FTIR). Cytotoxicity was assessed in vitro against HuT-78 cells, and in vivo pharmacokinetics and toxicology studies were conducted to evaluate therapeutic efficacy and safety.Results: The prepared belinostat–HSA nanoparticles exhibited the size of 150 nm with a charge of ~− 50 mV and a high entrapment efficiency (90%). Molecular docking confirmed that belinostat and HSA had a strong binding affinity (− 9.5 kcal mol− 1), and the entrapment of belinostat within HSA nanoparticles was also confirmed via FTIR. Belinostat–HSA nanoparticles were cytotoxic against HuT-78 with the dose–response relation (1– 100 μM). The highly concentrated (100 μM) belinostat–HSA nanoparticles maintained the viability of the peripheral blood mononuclear cells with 50% survival, which did not survive when exposed to belinostat (100 μM). The belinostat–HSA nanoparticles proved suitable for intravenous administration without causing hemolysis, exhibited prolonged circulation times, and improved in vivo platelet counts significantly (p < 0.05).Conclusion: In conclusion, the belinostat-loaded HSA nanoparticles significantly enhance the solubility and half-life of belinostat, reduce its adverse hematological effects, and maintain sustained drug release. These attributes underscore the potential of belinostat-HSA nanoparticles as a viable intravenous option for the treatment of hematological malignancies. Keywords: belinostat, human serum albumin nanoparticles, peripheral T-cell lymphoma, thrombocytopenia, pharmacokinetics

Nan Huang,1– 3,&ast; Bing Lu,4,&ast; Zhuan-Zhuan Zhu,5,&ast; Xiang-Yun Zhu,1,3 Sheng Chen,1– 3 Zhi-Yi Shu,1– 3 Gai-Fang Liu,6 You-Fan Peng,7,&ast; Ling Li1– 3,&ast; 1Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, People’s Republic of China; 2Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing, Jiangsu, 210009, People’s Republic of China; 3Pancreatic Research Institute, Southeast University, Nanjing, Jiangsu, 210009, People’s Republic of China; 4Department of Endocrinology, Kunshan Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu, 215343, People’s Republic of China; 5Department of Endocrinology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, People’s Republic of China; 6Division of Gastroenterology, Hebei General Hospital, Shijiazhuang, Hebei, 050000, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Li, Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People’s Republic of China, Email lingli@seu.edu.cn You-Fan Peng, Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18 Zhongshan 2nd Road, Baise, Guangxi, 533000, People’s Republic of China, Email youfanpeng@hotmail.comPurpose: Insulin resistance is associated with kidney impairment in patients with type 2 diabetes mellitus (T2DM). The triglyceride glucose-body mass index (TyG-BMI), which combines the TyG index with body mass index (BMI), has received significant attention as a tool for evaluating insulin resistance. Thus, the aim of this study was to explore the association between TyG-BMI and kidney impairment in patients with type 2 diabetes mellitus (T2DM).Patients and Methods: The cross-sectional analysis included 1080 patients with T2DM, and data were collected retrospectively. TyG-BMI was calculated by fasting blood glucose, triglyceride, and body mass index.Results: TyG-BMI was significantly higher in T2DM patients with albuminuria than those without albuminuria (232.16 [206.52– 268.02] vs 229.83 [206.11– 255.64], p =0.023). T2DM patients with chronic kidney disease (CKD) showed a significantly higher value of TyG-BMI compared with those without CKD (232.23 [206.46– 268.28] vs 229.73 [206.11– 255.49], p=0.014). Correlation analysis showed a significantly positive association between TyG-BMI and metabolic parameters including BMI (r = 0.866, p < 0.001), TG (r = 0.630, p < 0.001), TC (r = 0.119, p < 0.001), HDL-C (r = − 0.374, p < 0.001), FBG (r = 0.297, p < 0.001), and HbA1c (r = 0.116, p < 0.001) in patients with T2DM. The binary logistic regression analysis found that TyG-BMI was an independent factor for albuminuria (OR = 1.004, 95% CI: 1.001– 1.008, p = 0.010) and CKD (OR = 1.005, 95% CI: 1.001– 1.008, p = 0.005) in patients with T2DM respectively.Conclusion: The study suggests that TyG-BMI is associated with kidney impairment in patients with T2DM. Given that TyG-BMI is a novel parameter of insulin resistance, the study results indicates that clinicians should pay close attention to screening for kidney impairment in T2DM patients with insulin resistance.Keywords: type 2 diabetes mellitus, TyG-BMI, insulin resistance, kidney impairment

Ryan S D’Souza,1 Yeng F Her,1 Nasir Hussain,2 Jay Karri,3 Michael E Schatman,4 Aaron K Calodney,5 Christopher Lam,6 Thomas Buchheit,7 Brennan J Boettcher,8 George C Chang Chien,9 Scott G Pritzlaff,10 Christopher Centeno,11 Shane A Shapiro,12 Johana Klasova,1 Jay S Grider,13 Ryan Hubbard,14 Eliana Ege,15 Shelby Johnson,8 Max H Epstein,16 Eva Kubrova,8 Mohamed Ehab Ramadan,17 Alexandra Michelle Moreira,18 Swarnima Vardhan,19 Yashar Eshraghi,20 Saba Javed,21 Newaj M Abdullah,22 Paul J Christo,17 Sudhir Diwan,23 Leslie C Hassett,24 Dawood Sayed,6 Timothy R Deer25 1Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA; 2Department of Anesthesiology, The Ohio State Wexner Medical Center, Columbus, OH, USA; 3Departments of Orthopedic Surgery and Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA; 4Department of Anesthesiology, Perioperative Care, & Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 5Precision Spine Care, Tyler, TX, USA; 6Department of Anesthesiology and Pain Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; 7Department of Anesthesiology, Duke University, Durham, NC, USA; 8Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA; 9Department of Regenerative Medicine, GCC Institute, Torrance, CA, USA; 10Department of Anesthesiology and Pain Medicine, University of California, Davis, Sacramento, CA, USA; 11Centeno-Schultz Clinic, Broomfield, CO, USA; 12Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, FL, USA; 13Department of Anesthesiology, University of Kentucky College of Medicine, Lexington, KY, USA; 14Department of Sports Medicine, Anderson Orthopedic Clinic, Arlington, VA, USA; 15Department of Physical Medicine & Rehabilitation, Baylor College of Medicine, Houston, TX, USA; 16Department of Physical Medicine & Rehabilitation, Harvard Medical School, Boston, MA, USA; 17Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, MD, USA; 18Department of Physical Medicine & Rehabilitation, University of Miami/Jackson Memorial Hospital, Miami, FL, USA; 19Department of Internal Medicine, Yale New Haven Health – Bridgeport Hospital, Bridgeport, CT, USA; 20Department of Anesthesiology & Critical Care Medicine, Ochsner Health System, New Orleans, LA, USA; 21Department of Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 22Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA; 23Department of Pain Medicine, Advanced Spine on Park Avenue, New York City, NY, USA; 24Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, USA; 25Department of Anesthesiology and Pain Medicine, West Virginia University School of Medicine, Charleston, WV, USACorrespondence: Ryan S D’Souza, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA, Tel +1-(507)-284-9696, Fax +1-(507)-266-7732, Email dsouza.ryan@mayo.eduPurpose: Injectable biologics have not only been described and developed to treat dermal wounds, cardiovascular disease, and cancer, but have also been reported to treat chronic pain conditions. Despite emerging evidence supporting regenerative medicine therapy for pain, many aspects remain controversial.Methods: The American Society of Pain and Neuroscience (ASPN) identified the educational need for an evidence-based guideline on regenerative medicine therapy for chronic pain. The executive board nominated experts spanning multiple specialties including anesthesiology, physical medicine and rehabilitation, and sports medicine based on expertise, publications, research, and clinical practice. A steering committee selected preliminary questions, which were reviewed and refined. Evidence was appraised using the United States Preventive Services Task Force (USPSTF) criteria for evidence level and degree of recommendation. Using a modified Delphi approach, consensus points were distributed to all collaborators and each collaborator voted on each point. If collaborators provided a decision of “disagree” or “abstain”, they were invited to provide a rationale in a non-blinded fashion to the committee chair, who incorporated the respective comments and distributed revised versions to the committee until consensus was achieved.Results: Sixteen questions were selected for guideline development. Questions that were addressed included type of injectable biologics and mechanism, evidence in treating chronic pain indications (eg, tendinopathy, muscular pathology, osteoarthritis, intervertebral disc disease, neuropathic pain), role in surgical augmentation, dosing, comparative efficacy between injectable biologics, peri-procedural practices to optimize therapeutic response and quality of injectate, federal regulations, and complications with mitigating strategies.Conclusion: In well-selected individuals with certain chronic pain indications, use of injectable biologics may provide superior analgesia, functionality, and/or quality of life compared to conventional medical management or placebo. Future high-quality randomized clinical trials are warranted with implementation of minimum reporting standards, standardization of preparation protocols, investigation of dose–response associations, and comparative analysis between different injectable biologics.Keywords: regenerative medicine, injectable biologics, platelet-rich plasma, mesenchymal stem cell, bone marrow aspirate concentrate, pain medicine

Yan-fei Lu,1,&ast; Ji-min Wu,2,&ast; Hai-yan Lan,2 Qiao-min Xu,2 Shu-qi Shi,2 Gong-chen Duan2 1Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China; 2Department of Anesthesiology, Lishui People’s Hospital, Wenzhou Medical University Lishui Hospital, Lishui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gong-chen Duan, Department of Anesthesiology, Lishui People’s Hospital, Wenzhou Medical University Lishui Hospital, No. 1188, Liyang Street, Lishui, Zhejiang, 323000, People’s Republic of China, Tel/Fax +8618957093030, Email 981225178@qq.comBackground: Ciprofol is a new intravenous sedative / anesthetic drug. In recent years, many clinical studies have also confirmed the sedative effect of ciprofol. However, more clinical research is still needed on its clinical application characteristics in special populations.Objective: The aim of this study was to compare the clinical effects of ciprofol and propofol in general anesthesia induction of elderly patients.Methods: 60 elderly (aged ≥ 75 years) patients underwent hip fracture surgery were randomly into two groups of a 1:1 ratio. Group C (ciprofol group): 0.3mg/kg ciprofol was infused. Group P (propofol group): 1.5mg/kg propofol was infused. The observation period was from the infusion of test drug to 5 min after endotracheal intubation. The primary outcomes included the incidence of severe hypotension and hypotension during the observation period. The secondary outcomes were as follows: the success rate of general anesthesia induction, the number of additional sedation, the time of loss of consciousness (LOC), Δ MAP, Δ HR, adverse events and the frequency of vasoactive drugs used.Results: Finally, 60 subjects completed the study. Compared with Group P, the incidence of severe hypotension in Group C was lower (26.7% vs 53.3%, P = 0.035), the incidence of hypotension was also lower (36.7% vs 63.3%, P = 0.037), Δ MAP in Group C was significantly lower (31.4 ± 11.4 vs 39.6 ± 15.7, P = 0.025), the frequency of ephedrine used and the incidence of injection pain in Group C were also significantly lower.Conclusion: Ciprofol showed similar efficacy to propofol when used for general anesthesia induction in elderly patients underwent hip fracture surgery and could maintain more stable blood pressure.Keywords: Ciprofol, elderly, Hip fracture surgery, general anesthesia, hypotension

Horng-Chyuan Lin,1– 3 Meng-heng Hsieh,1,2 Yu-Lun Lo,1,2 Hung-Yu Huang,1,2 Shih-Wei Huang,1,2 Chien-Da Huang,1,2 Po-Jui Chang,1,2 Chun-Yu Lo,1,2 Ting-Yu Lin,1,2 Yueh-Fu Fang,1,2 Shu-Min Lin,1,2 Chun-Yu Lin,1,2,&ast; Ying-Huang Tsai1,2,4,&ast; 1Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Respiratory Therapy, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 4Department of Pulmonary and Critical Care Medicine, Xiamen Chang Gung Hospital, Xiamen, 361028, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chun-Yu Lin, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Kweishan, Taoyuan, 33305, Taiwan, Tel +886-3-3281200 ext. 8467, Fax +886-3-3282474, Email pitiful1984@gmail.com Ying-Huang Tsai, Department of Pulmonary and Critical Care Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung Medical Foundation and Department of Respiratory Therapy, College of Medicine, Chang Gung University, 5 Fu-Hsing Street, Kweishan, Taoyuan, 33305, Taiwan, Tel +886-3-3281200 ext. 8470, Fax +886-3-3282474, Email chestmed@cgmh.org.twBackground: Non-cystic fibrosis bronchiectasis is associated with airway pathogen colonization. We planned to investigate the inflammatory markers in patients with different airway pathogens and their correlation with disease severity.Methods: We enrolled patients aged between 20 and 75 from October 2021 to August 2022. All patients had sputum evaluation for bacterial and fungal cultures before enrollment, and were classified into four groups according to the culture results.Results: Forty-four patients with non-CF bronchiectasis and six controls were enrolled and categorized as follows: Group 1, no pathogens identified in sputum cultures (n = 14); Group 2, positive fungal culture results (n = 18); Group 3, positive P. aeruginosa culture results (n = 7); and Group 4, positive culture results for both fungi and P. aeruginosa (n = 5). Group 4 had significantly higher serum defensin α 1, IL-6 and tissue inhibitors of MMP (TIMP)-1 levels than group 1 patients. The serum levels of IL-6 and TIMP-1 were positively correlated with the FACED score and negatively correlated with distance-saturation product.Conclusion: Significantly higher levels of serum IL-6 and TIMP-1 were found in the patients who had concomitant fungal and P. aeruginosa colonization, and were closely related to clinical severity and may have important roles in disease monitoring.Keywords: TIMP-1, non-cystic fibrosis bronchiectasis, clinical severity

Yeng F Her,1 Robert A Churchill2 1Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic Alix School of Medicine, Mayo Clinic Hospital, Rochester, MN, 55905, USACorrespondence: Yeng F Her, Email her.yeng@mayo.eduAbstract: We present on a patient with complex regional pain syndrome (CRPS) following ankle surgery. Pain was refractory to both conservative and surgical measures including neurotomies, ankle fusion, hardware removal, and spinal cord stimulation (SCS) trial. A dorsal root ganglion (DRG) stimulation trial with lead placements at L4, L5, and S1 provided significant pain and functional improvement. However, during the implantation, we were able to place only two DRG leads at L4 and L5 and not S1 due to difficulties with advancing the lead to the desired location. Nonetheless, the two DRG leads provided 90% pain relief and 75% functional improvement for 9 months. However, the patient experienced pain symptoms similar to that of pre-implant without a clear trigger after 9 months despite no DRG stimulator hardware malfunction or lead migration. A decision was made to re-try implanting the S1 DRG lead, which was successful and provided significant pain relief.Keywords: DRG-stimulation, loss of efficacy, CRPS

Yi-fei Wang,1,&ast; Xiao-han Kong,1,&ast; Hui-min Tao,2,&ast; Li Tao3,&ast; 1Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210000, People’s Republic of China; 2Jiangsu Women and Children Health Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210000, People’s Republic of China; 3Nanjing Medical University, Nanjing, Jiangsu, 210000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi-fei Wang, Email happywangyf2018@163.comBackground: The triglyceride–glucose index (TyG) is a reliable indicator for predicting the prognosis of patients with coronary heart disease (CAD) after percutaneous coronary intervention (PCI). However, its influence on patients with in-stent restenosis (ISR) is unclear. This study was designed to evaluate the association between the TyG index and the occurrence of major adverse cardiovascular events (MACEs) after PCI in patients with ISR.Methods: This retrospective study included 1654 patients who underwent PCI between 2016 and 2022 at Nanjing First Hospital. Patients were stratified into three groups based on the quantile level of the TyG index. The TyG index was determined as Ln (triglycerides [mg/dL] × fasting plasma glucose [mg/dL]/2).Results: Individuals with the highest TyG index showed an increased risk of MACEs compared to those with the lowest level of the TyG index (HR 1.60; 95% CI 1.11– 2.30; P = 0.01). When analyzing the TyG index as a continuous variable, each standard deviation increase was associated with an HR of 1.51 (95% CI: 1.11– 2.05; P = 0.01). For the male subgroup and the diabetes subgroup, this trend was even more pronounced (HR 1.269; 95% CI 1.055– 1.527; P = 0.011; HR 1.385; 95% CI 1.125– 1.706; P = 0.002). Additionally, the landmark analysis showed that patients with the highest level of TyG had an increased risk of MACEs 6 months after the PCI (P = 0.019).Conclusion: Elevated TyG index is associated with increased risk of adverse cardiovascular events in patients with ISR, and the extent of increase in the risk is more significant in male patients with diabetes.Keywords: triglyceride–glucose index, percutaneous coronary intervention, in-stent restenosis

Jia-Wen Xie,1,2 Yin-Feng Guo,1,2 Ya-Wen Zheng,1,3 Mao Wang,1,2 Qiu-Yan Xu,1,2 Yu-Yan Chen,1,2 Li-Rong Lin1,2,4 1Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 3Prenatal Diagnosis Center, Zhangzhou Municipal Hospital Affiliated to Fujian Medical University, Zhangzhou, People’s Republic of China; 4Department of Basic Medical Science, Xiamen Medical College, Xiamen, People’s Republic of ChinaCorrespondence: Yu-Yan Chen; Li-Rong Lin, Centre of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, 361004, People’s Republic of China, Tel +86-592-2993041, Fax +86-592-2993043, Email chenyuyan@xmu.edu.cn; linlirong@xmu.edu.cnPurpose: Accurate differentiation between early and late latent syphilis stages is pivotal for patient management and treatment strategies. Nontreponemal IgM antibodies have shown potential in discriminating latent syphilis staging by differentiating syphilis activity. This study aimed to develop a predictive nomogram model for latent syphilis staging based on nontreponemal IgM antibodies.Patients and Methods: We explored the correlation between nontreponemal IgM antibodies and latent syphilis staging and developed a nomogram model to predict latent syphilis staging based on 352 latent syphilis patients. Model performance was assessed using AUC, calibration curve, Hosmer–Lemeshow χ 2 statistics, C-index, Brier score, decision curve analysis, and clinical impact curve. Additionally, an external validation set was used to further assess the model’s stability.Results: Nontreponemal IgM antibodies correlated with latent syphilis staging. The constructed model demonstrated a strong discriminative capability with an AUC of 0.743. The calibration curve displayed a strong fit, key statistics including Hosmer–Lemeshow χ² at 2.440 (P=0.486), a C-index score of 0.743, and a Brier score of 0.054, all suggesting favorable model calibration performance. Decision curve analysis and clinical impact curve highlighted the model’s robust clinical applicability. The external validation set yielded an AUC of 0.776, Hosmer–Lemeshow χ² statistics of 2.440 (P=0.486), a C-index score of 0.767, and a Brier score of 0.054, further underscored the reliability of the model.Conclusion: The nontreponemal IgM antibody-based predicted model could equip clinicians with a valuable tool for the precise staging of latent syphilis and enhancing clinical decision-making.Keywords: syphilis, latent syphilis, latent syphilis staging, nontreponemal IgM antibody, predictive model

Hong-Yan Li,1,2 Hao-Yu Wang,3 Yi-Fei Duan,2,4 Yu Gou,2,4 Xiao-Qin Liu,2,4 Zheng-Xiang Gao2,4 1West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan, People’s Republic of China; 3Department of Radiology, The First People’s Hospital of Liangshan Yi Autonomous Prefecture, Xichang, Sichuan, People’s Republic of China; 4Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Zheng-Xiang Gao, Email GAOZX84@163.comAbstract: Neurosyphilis is a central nervous system infection caused by Treponema pallidum that imitates various neurological and mental disorders. Therefore, patients with this disease are prone to misdiagnoses. Here, we report a case of neurosyphilis with a psychotic disorder as the main manifestation. A young girl exhibited mental and behavioural abnormalities after a heartbreak, which manifested as alternating low mood, emotional irritability, and a lack of interest in social relations, followed by memory loss. The cerebrospinal fluid protein - Treponema pallidum particle agglutination test was positive, the toluidine red unheated serum test titre was 1:4, the white blood cell count was 5 × 10^6/L, the cerebrospinal fluid protein level was 0.97 g/L, and the brain CT was abnormal. After admission, the possibility of neurosyphilis was considered and the patient received intravenous penicillin G treatment. The patient’s clinical symptom ms improved. This case emphasises that doctors should maintain clinical suspicion of Treponema pallidum infection in adolescent patients with mental abnormalities.Keywords: neurosyphilis, case report, psychotic disorder, Treponema pallidum, syphilis

Reactor neutrino experiments play a crucial role in advancing our knowledge of neutrinos. In this Letter, the evolution of the flux and spectrum as a function of the reactor isotopic content is reported in terms of the inverse-beta-decay yield at Daya Bay with 1958 days of data and improved systematic uncertainties. These measurements are compared with two signature model predictions: the Huber-Mueller model based on the conversion method and the SM2018 model based on the summation method. The measured average flux and spectrum, as well as the flux evolution with the ^{239}Pu isotopic fraction, are inconsistent with the predictions of the Huber-Mueller model. In contrast, the SM2018 model is shown to agree with the average flux and its evolution but fails to describe the energy spectrum. Altering the predicted inverse-beta-decay spectrum from ^{239}Pu fission does not improve the agreement with the measurement for either model. The models can be brought into better agreement with the measurements if either the predicted spectrum due to ^{235}U fission is changed or the predicted ^{235}U, ^{238}U, ^{239}Pu, and ^{241}Pu spectra are changed in equal measure.

We present a new determination of the smallest neutrino mixing angle θ_{13} and the mass-squared difference Δm_{32}^{2} using a final sample of 5.55×10^{6} inverse beta-decay (IBD) candidates with the final-state neutron captured on gadolinium. This sample is selected from the complete dataset obtained by the Daya Bay reactor neutrino experiment in 3158 days of operation. Compared to the previous Daya Bay results, selection of IBD candidates has been optimized, energy calibration refined, and treatment of backgrounds further improved. The resulting oscillation parameters are sin^{2}2θ_{13}=0.0851±0.0024, Δm_{32}^{2}=(2.466±0.060)×10^{-3}  eV^{2} for the normal mass ordering or Δm_{32}^{2}=-(2.571±0.060)×10^{-3}  eV^{2} for the inverted mass ordering.

Bjoern Schwander,1 Katharina Klesper,2 Siegbert Rossol,3 Ken Herrmann,4 York Francis Zoellner5 1Department of Health Economics & Outcomes Research, AHEAD GmbH, Bietigheim-Bissingen, Baden-Württemberg, Germany; 2Department of Health Economics & Epidemiology, ECON-EPI, Meerbusch, Nordrhein-Westfalen, Germany; 3Medical Clinic, Krankenhaus Nordwest, Frankfurt a.M., Hessen, Germany; 4Department of Nuclear Medicine, University of Duisburg-Essen, and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Nordrhein-Westfalen, Germany; 5Department of Health Sciences, University of Applied Sciences Hamburg, Hamburg, GermanyCorrespondence: Bjoern Schwander, AHEAD Gmbh, Wilhelm-Leibl-Straße 7, Bietigheim-Bissingen, D-74321, Germany, Tel + 49 1577 194 8125, Email bjoern.schwander@ahead-net.dePurpose: To compare personalized dosimetry with yttrium-90 (90Y)-loaded glass microspheres (SIRT) vs atezolizumab and bevacizumab (A+B) in hepatocellular carcinoma (HCC) treatment in terms of cost-effectiveness and budget impact from a German statutory health insurance (SHI) perspective.Patients and Methods: Cost-effectiveness analysis (CEA) and budget impact analysis (BIA) models were developed in MS Excel. The available key studies (IMbrave150 and DOSISPHERE-01) suggest that both strategies are comparable in terms of progression-free survival and overall survival in HCC, but a difference in severe adverse events (SAE) in favor of SIRT was observed. Accordingly, the CEA model investigates the endpoints “cost per SAE avoided” and “cost per quality-adjusted life year (QALY) gained”, whereas the BIA simulates the impact of a stepwise re-allocation of current market share to the option which emerges as more cost-effective from the CEA.Results: The model suite estimated a mean annual total per-patient costs of € 29,984 for SIRT, compared to € 75,725 for A+B. SIRT was associated with a lower number of SAE and a higher number of QALYs compared to A+B. Switching additionally 25% of the eligible patients (&ap;500) from systemic therapy to SIRT could generate annual savings of approximately € 22.6 million Euros to the SHI.Conclusion: SIRT was identified as dominant treatment strategy. SIRT use not only saves SHI expenditure compared to systemic immunotherapy but also yields extra QALYs. This positions SIRT as the dominant and more cost-effective treatment strategy for patients with HCC. The savings to the SHI system, derived from the BIA conducted, become increasingly significant with rising adoption rates of SIRT.Keywords: selective internal radiation therapy, atezolizumab, bevacizumab, hepatocellular carcinoma, cost-effectiveness, budget impact

Guo-Wang Yang,1,2 Hao Cheng,1,2 Xiao-Yang Song,3 Yu-Fan Yang,1,2 Hong Liu,4 Fu-Hai Ji,1,2 Ke Peng1,2 1Department of Anaesthesiology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Institute of Anaesthesiology, Soochow University, Suzhou, Jiangsu, People’s Republic of China; 3Department of Anaesthesiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, People’s Republic of China; 4Department of Anaesthesiology and Pain Medicine, University of California Davis Health, Sacramento, CA, USACorrespondence: Ke Peng, Department of Anaesthesiology, the First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou, Jiangsu, 215006, People’s Republic of China, Tel +86-15962155989, Email pengke0422@163.comPurpose: Oxycodone is a potent μ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery.Methods: In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0– 24 h postoperatively, assessed using the numerical rating scale (0– 10) with a minimal clinically important difference of 1.Results: All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=− 0.60, 95% CI, − 1.16 to − 0.03; P=0.039). Patients in the oxycodone group had a significantly lower 24-h TWA of visceral pain on coughing (2.00 [0.83] vs 2.98 [1.26]; mean difference=− 0.98, 95% CI, − 1.66 to − 0.30; P=0.006). In the subgroup analyses, the treatment effect of oxycodone vs sufentanil on the co-primary outcomes did not differ in terms of age (18– 65 years or > 65 years), sex (female or male), or type of surgery (colorectal or gastric). Secondary outcomes (24-h TWA of incisional and shoulder pain, postoperative analgesic usage, rescue analgesia, adverse events, and patient satisfaction) were comparable between groups.Conclusion: For patients undergoing major laparoscopic gastrointestinal surgery, oxycodone-based multimodal analgesia reduced postoperative visceral pain in a statistically significant but not clinically important manner.Trial Registration: Chinese Clinical Trial Registry (ChiCTR2100052085).Keywords: laparoscopic gastrointestinal surgery, oxycodone, patient-controlled analgesia, visceral pain

Xuan Wang,1,&ast; Yi-Fan Wang,2,&ast; Shi-Jun Wang1 1Department of Gynecology, Xuanwu Hospital Capital Medical University, Beijing, 100053, People’s Republic of China; 2Department of Gynecology, Beijing Youan Hospital Capital Medical University, Beijing, 100069, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shi-Jun Wang, Department of Gynecology, Xuanwu Hospital Capital Medical University, No. 45 of Changchun Street, Xicheng District, Beijing, 100053, People’s Republic of China, Tel + 86 15001119089, Email wangshijundr058@outlook.comObjective: In this study, we investigated the value of molecular typing combined with integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) semi-quantitative indices in endometrial cancer risk stratification.Methods: A retrospective study was conducted on 86 patients who were pathologically diagnosed with endometrial cancer and underwent surgical treatment after curettage at the Department of Obstetrics and Gynecology, Xuanwu Hospital, Capital Medical University between January 2017 and March 2023. Prior to surgery, each patient underwent integrated PET/MRI examination. The postoperative samples were subjected to pathological diagnosis, immunohistochemistry, and POLE gene sequencing. The differences in clinicopathological features between the four molecular subtypes and the differences in integrated PET/MRI semi-quantitative indexes (SUV max, ADC min) between the four molecular subtypes were analyzed. The cutoff value of molecular typing combined with integrated PET/MRI semi-quantitative indices for endometrial cancer risk stratification was determined.Results: There were statistically significant differences in pathological types and tumor grades among the four molecular subtypes of endometrial cancer. The values of the four integrated PET/MRI semi-quantitative indices (SUV max and ADC min) of the molecular subtypes were statistically different. The SUV max was greater in the p53abn mutation group than in the POLE mutation group (P < 0.05). The ADC minimum of the POLE mutation group and the MMR-d group was lower than the NSMP group (P

Shu Jiao Zhang,1,2,&ast; Yi Fei Zhang,1,2,&ast; Xue Hui Bai,1,2 Meng Qi Zhou,1,2 Ze Yu Zhang,1,2 Shuai Xing Zhang,1,2 Zi Jing Cao,1,2 Lin Wang,1,2 Shao Wei Ding,1,2 Hui Juan Zheng,1,2 Yu Ning Liu,1– 3 Guo Yong Yu,1 Wei Jing Liu1– 3 1Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Key Laboratory of Chinese Internal Medicine of Ministry of Education, Beijing Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Renal Research Institution of Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guo Yong Yu, Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Beijing, Dongcheng District, 100700, People’s Republic of China, Email 18901133535@163.com Wei Jing Liu, Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, Tel/Fax +86-010-84013190, Email 1977@hotmail.comBackground: Acteoside, an active ingredient found in various medicinal herbs, is effective in the treatment of diabetic kidney disease (DKD); however, the intrinsic pharmacological mechanism of action of acteoside in the treatment of DKD remains unclear. This study utilizes a combined approach of network pharmacology and experimental validation to investigate the potential molecular mechanism systematically.Methods: First, acteoside potential targets and DKD-associated targets were aggregated from public databases. Subsequently, utilizing protein-protein interaction (PPI) networks, alongside GO and KEGG pathway enrichment analyses, we established target-pathway networks to identify core potential therapeutic targets and pathways. Further, molecular docking facilitated the confirmation of interactions between acteoside and central targets. Finally, the conjectured molecular mechanisms of acteoside against DKD were verified through experimentation on unilateral nephrectomy combined with streptozotocin (STZ) rat model. The underlying downstream mechanisms were further investigated.Results: Network pharmacology identified 129 potential intersected targets of acteoside for DKD treatment, including targets such as AKT1, TNF, Casp3, MMP9, SRC, IGF1, EGFR, HRAS, CASP8, and MAPK8. Enrichment analyses indicated the PI3K-Akt, MAPK, Metabolic, and Relaxin signaling pathways could be involved in this therapeutic context. Molecular docking revealed high-affinity binding of acteoside to PIK3R1, AKT1, and NF-κB1. In vivo studies validated the therapeutic efficacy of acteoside, demonstrating reduced blood glucose levels, improved serum Scr and BUN levels, decreased 24-hour urinary total protein (P< 0.05), alongside mitigated podocyte injury (P< 0.05) and ameliorated renal pathological lesions. Furthermore, this finding indicates that acteoside inhibits the expression of pyroptosis markers NLRP3, Caspase-1, IL-1β, and IL-18 through the modulation of the PI3K/AKT/NF-κB pathway.Conclusion: Acteoside demonstrates renoprotective effects in DKD by regulating the PI3K/AKT/NF-κB signaling pathway and alleviating pyroptosis. This study explores the pharmacological mechanism underlying acteoside’s efficacy in DKD treatment, providing a foundation for further basic and clinical research.Keywords: DKD, acteoside, network pharmacology, experimental verification

Samar Abdelazim Ahmed,1,2 Nagwa N Hegazy,3 Hebat Allah Ahmed Amin,4 Mariam IM Ismail,5 Yasser Fouad Alakid,6 Archana Prabu Kumar7 1Dubai Medical College for Girls, Dubai, United Arab Emirates; 2Forensic Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 3Family Medicine Department, Faculty of Medicine, Menoufia University (MU), Menoufia, Egypt; 4Pathology Department, Faculty of Medicine, Helwan University, Helwan, Egypt; 5Faculty of Medicine, Delta University, Dakahlia, Egypt; 6Forensic Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 7Medical Education Department, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, BahrainCorrespondence: Samar Abdelazim Ahmed, Email Prof.samar@dmcg.eduBackground: Culture is an essential component that governs all aspects of human behavior. Superstition is an irrational belief observed in almost all cultures. It is linked to one or more factors like supernatural powers, good luck, bad omen, fiction, illegitimate activity, absurd narration, folk tales, or practice without any rational basis.Methods: A cross-sectional social experiment was conducted to evaluate the effect of cultural appropriation as a tool to enhance medical knowledge acquisition and attitudinal development in medical education. The experiment was designed to target a non-medical population. Four superstition-oriented videos were developed with 20 scientific pieces of information related to forensic medicine. A data collection sheet was developed on Microsoft form with 16 questions was distributed on the participants.Results: Out of the 986 participants, 763 (77.5%) watched the whole set of videos. About 55– 95% of responders demonstrated knowledge acquisition of all the questions. There was a statistically significant difference between those who watched the videos and those who did not. When participants were asked about the most important information they remember from the videos, their answers fell into two main categories; information related to core scientific knowledge (80% of participants) and information not related to the core knowledge (16% of respondents). The top three areas for the reasons why people wanted to watch the videos were curiosity, knowledge, and career. A change in attitudes was reported among the participants where 80% of responders demonstrated curiosity to know more about this world, 46% responders reported developing more respect for the forensic physician and 43% revealed their ignorance about this great hidden world.Conclusion: Cultural appropriation could be a needed strategy to accommodate for upscale in education. Learners might validate that learning happens through a door that adopts not only honours their culture and adapts to it.Keywords: contextualization, knowledge acquisition, medical education

EuTe4 is a van der Waals material exhibiting a charge density wave (CDW) with a large thermal hysteresis in the resistivity and CDW gap. In this paper, we systematically study the electronic structure and transport properties of EuTe4 using high-resolution angle-resolved photoemission spectroscopy (ARPES), magnetoresistance (MR) measurements, and scanning tunneling microscopy (STM). We observe a CDW gap of ∼200meV at low temperatures that persists up to 400 K, suggesting that the CDW transition occurs at a much higher temperature. The ARPES intensity near the Fermi level shows large thermal hysteretic behavior, consistent with the resistivity measurement. The hysteresis in the resistivity measurement does not change under a magnetic field up to 7 T, excluding the thermal magnetic hysteretic effect. Instead, the surface topography measured with STM shows surface domains with different CDW trimerization directions, which may be important for the thermal hysteretic behavior. Interestingly, we reveal a large negative MR at low temperatures that can be associated with the canting of magnetically ordered Eu spins. Our results shed light on the understanding of magnetic, transport, and electronic properties of EuTe4.

Recent quasi-two-dimensional (quasi-2D) systems with judicious exploitation of the atomic monolayer or few-layer architecture exhibit unprecedented physical properties that challenge the conventional wisdom on condensed matter physics. Here we show that the infinite layer SrCuO2 (SCO), a topical cuprate Mott insulator in bulk form, can manifest an unexpected metallic state in the quasi-2D limit when SCO is grown on TiO2-terminated SrTiO3 (STO) substrates. The sheet resistance does not conform to Landau's Fermi liquid paradigm. Hard x-ray core-level photoemission spectra demonstrate a definitive Fermi level that resembles the hole doped metal. Soft x-ray absorption spectroscopy also reveals features analogous to those of a hole doped Mott insulator. Based on these results, we conclude that the hole doping does not occur at the interfaces between SCO and STO; instead, it comes from the transient layers between the chain-type and the planar-type structures within the SCO slab. The present work reveals a metallic state in the infinite layer SCO and invites further examination to elucidate the spatial extent of this state.

Objective and Approach Sedative-hypnotic medications are associated with harms such as delirium and falls, and may be overprescribed in hospitals. Measuring potentially inappropriate in-hospital sedative-hypnotic prescriptions requires distinguishing new initiations from pre-hospital prescriptions, but pre-hospital medications may not be captured in hospital data. To quantify physician- and hospital-level variation in sedative-hypnotic prescribing, we use linked data between GEMINI (which includes EMR data from >1.8 million admissions across 30 hospitals, approximately 60% of medical inpatient beds in Ontario) and ICES (which houses administrative healthcare databases, including outpatient prescriptions for adults ≥65 years). We will validate whether data in hospital clinical notes or pharmacy records can reliably identify pre-hospital prescriptions. Results Using provincial health insurance number, 98.1% of GEMINI records could successfully be linked deterministically to ICES. Our exploratory sedative-hypnotic cohort included 90,806 general medicine patients treated by 437 physicians from 17 hospitals across Ontario from 2021-2022. Median age was 72 years and 48.7% were female. The proportion of patients receiving a new sedative-hypnotic prescription varied markedly across hospitals (median 0.21, range 0.04-0.41) and across physicians within hospitals (median within-hospital difference between lowest and highest prescriber: 0.18, range of within-hospital differences 0.07-0.67). Validation of new rather than continued prescriptions is underway. Full results will be ready for presentation at the conference. Conclusion Sedative-hypnotic prescribing is common and highly variable in hospitals across Ontario, indicating an opportunity to improve patient safety. Implications Based on these analyses, the province of Ontario has made reducing in-hospital sedative-hypnotic prescribing a provincial priority for 2023-2024.

Reading acquisition is a prolonged learning process relying on language development starting in utero. Behavioral longitudinal studies reveal prospective associations between infant language abilities and preschool/kindergarten phonological development that relates to subsequent reading performance. While recent pediatric neuroimaging work has begun to characterize the neural network underlying language development in infants, how this neural network scaffolds long-term language and reading acquisition remains unknown. We addressed this question in a 7-year longitudinal study from infancy to school-age. Seventy-six infants completed resting-state fMRI scanning, and underwent standardized language assessments in kindergarten. Of this larger cohort, forty-one were further assessed on their emergent word reading abilities after receiving formal reading instructions. Hierarchical clustering analyses identified a modular infant language network in which functional connectivity (FC) of the inferior frontal module prospectively correlated with kindergarten-age phonological skills and emergent word reading abilities. These correlations were obtained when controlling for infant age at scan, nonverbal IQ and parental education. Furthermore, kindergarten-age phonological skills mediated the relationship between infant FC and school-age reading abilities, implying a critical mid-way milestone for long-term reading development from infancy. Overall, our findings illuminate the neurobiological mechanisms by which infant language capacities could scaffold long-term reading acquisition.

BackgroundThere is significant interest in treatment de-escalation for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV+ OPSCC patients.MethodsWe created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes.FindingsA three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10-5) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation.InterpretationWith additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV+ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned.FundingCIHR, European Union, and the NIH.

Loss-of-function CYP2C19 variants are associated with increased cumulative ischemic outcomes warranting CYP2C19 genotyping prior to clopidogrel administration. TAILOR-PCI was an international, multicenter (40 sites), prospective, randomized trial comparing rapid point of care (POC) genotype-guided vs. conventional anti-platelet therapy. The performance of buccal-based rapid CYP2C19 genotyping performed by non-laboratory-trained staff in TAILOR-PCI was assessed. Pre-trial training and evaluation involved rapid genotyping of 373 oral samples, with 99.5% (371/373) concordance with Sanger sequencing. During TAILOR-PCI, 5302 patients undergoing PCI were randomized to POC rapid CYP2C19 *2, *3, and *17 genotyping versus no genotyping. At 12 months post-PCI, TaqMan genotyping determined 99.1% (2,364/2,385) concordance with the POC results, with 90.7-98.8% sensitivity and 99.2-99.6% specificity. In conclusion, non-laboratory personnel can be successfully trained for on-site instrument operation and POC rapid genotyping with analytical accuracy and precision across multiple international centers, thereby supporting POC genotyping in patient-care settings, such as the cardiac catheterization laboratory.Clinical Trial Registration: https://www.clinicalTrials.gov (Identifier: NCT01742117).

Yeng F Her,1 Ryan T McWilliams,2 Erik A Ovrom,3 James C Watson1 1Department of Anesthesiology and Perioperative Medicine, Mayo Clinic Hospital, Rochester, MN, USA; 2Family Medicine, Alaska Native Medical Center, Anchorage, AK, USA; 3Mayo Clinic Alix School of Medicine, Mayo Clinic Hospital, Rochester, MN, USACorrespondence: Yeng F Her, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic Hospital, Rochester, MN, USA, Email her.yeng@mayo.eduAbstract: Arachnoiditis is difficult to treat. Patients are often left frustrated after many failed trials of conservative therapies without symptom resolution. Surgery may provide symptom relief for a short period of time, but their pain often returned. Herein, we present three cases of acute arachnoiditis following three different pain procedures: epidural blood patch, IDDS implant, and epidural steroid injection. The patients were diagnosed and treated with corticosteroids within 10 days of the procedure. Two patients were treated with the same oral steroid regiment, while the third patient was treated with both oral and IV steroid. All three patients had good outcomes at the completion of their steroid therapy. This case series may provide insight into treating acute and subacute arachnoiditis from pain interventions.Keywords: arachnoiditis, epidural blood patch, intrathecal pain pump, epidural steroid injection, corticosteroid therapy

Yuan-Qin Du,1,&ast; Bin Yuan,1,&ast; Yi-Xian Ye,1 Feng-ling Zhou,1 Hong Liu,1 Jing-Jing Huang,2 Yan-Fei Wei3,4 1Graduate School, Guangxi University of Traditional Chinese Medicine, Nanning, 530200, People’s Republic of China; 2The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530024, People’s Republic of China; 3Department of Physiology, Guangxi University of Traditional Chinese Medicine, Nanning, 530200, People’s Republic of China; 4Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Nanning, 530200, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan-Fei Wei, Department of Physiology, Guangxi University of Traditional Chinese Medicine, No. 13 Wu He Road, Nanning, 530200, People’s Republic of China, Tel/Fax +86-771-4733794, Email weiyanfei@gxtcmu.edu.cnBackground/Aims: Plumbagin (PL) has been shown to effe ctively inhibit autophagy, suppressing invasion and migration of hepatocellular carcinoma (HCC) cells. However, the specific mechanism remains unclear. This study aimed to investigate the effect of PL on tumor growth factor (TGF)-β-induced epithelial-mesenchymal transition (EMT) in HCC.Methods: Huh-7 cells were cultured, and in vivo models of EMT and HCC-associated lung metastasis were developed through tail vein and in situ injections of tumor cells. In vivo imaging and hematoxylin and eosin staining were used to evaluate HCC modeling and lung metastasis. After PL intervention, the expression levels of Snail, vimentin, E-cadherin, and N-cadherin in the liver were evaluated through immunohistochemistry and Western blot. An in vitro TGF-β-induced cell EMT model was used to detect Snail, vimentin, E-cadherin, and N-cadherin mRNA levels through a polymerase chain reaction. Their protein levels were detected by immunofluorescence staining and Western blot.Results: In vivo experiments demonstrated that PL significantly reduced the expression of Snail, vimentin, and N-cadherin, while increasing the expression of E-cadherin at the protein levels, effectively inhibiting HCC and lung metastasis. In vitro experiments confirmed that PL up-regulated epithelial cell markers, down-regulated mesenchymal cell markers, and inhibited EMT levels in HCC cells.Conclusion: PL inhibits Snail expression, up-regulates E-cadherin expression, and down-regulates N-cadherin and vimentin expression, preventing EMT in HCC cells and reducing lung metastasis.Keywords: plumbagin, hepatocellular carcinoma, epithelial-mesenchymal transition, pulmonary metastasis, Snail

Qian-Qian Liao,1,&ast; Yan-Ju Mo,2,&ast; Ke-Wei Zhu,3,4,&ast; Feng Gao,2 Bin Huang,2 Peng Chen,4 Feng-Tian Jing,5 Xuan Jiang,6 Hong-Zhen Xu,1 Yan-Feng Tang,7 Li-Wei Chu,8 Hai-Ling Huang,1 Wen-Li Wang,8 Fang-Ning Wei,9 Dan-Dan Huang,9 Bin-Jing Zhao,9 Jia Chen,9 Hao Zhang1 1Department of Pharmacy, People’s Hospital of Guilin, Guilin, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, People’s Hospital of Guilin, Guilin, People’s Republic of China; 3GuangZhou BaiYunShan Pharmaceutical Holdings CO.,LTD. BaiYunShan Pharmaceutical General Factory, Guangzhou, People’s Republic of China; 4Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 5Department of Respiratory Medicine, Xing An County People’ Hospital, Guilin, People’s Republic of China; 6Department of Hospital Infection Management, People’s Hospital of Guilin, Guilin, People’s Republic of China; 7Department of Geriatrics, People’s Hospital of Guilin, Guilin, People’s Republic of China; 8Department of Laboratory Medicine, People’s Hospital of Guilin, Guilin, People’s Republic of China; 9School of Clinical Pharmacy, Guilin Medical University, Guilin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke-Wei Zhu, GuangZhou BaiYunShan Pharmaceutical Holdings CO.,LTD. BaiYunShan Pharmaceutical General Factory, No. 88 Yunxiang Road Tonghe Street, Baiyun District, Guangzhou, Guangdong Province, 510515, People’s Republic of China, Tel +86-020-87062636, Fax +86-020-87095309, Email zhukew2018@outlook.comPurpose: The study comprehensively evaluated the prognostic roles of the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR), and eosinophil-to-lymphocyte ratio (ELR) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD).Patients and Methods: Six hundred and nineteen patients with AECOPD and 300 healthy volunteers were retrospectively included into the study. The clinical characteristics of the patients with AECOPD and the complete blood counts (CBCs) of the healthy volunteers were collected. The associations of PLR, NLR, MLR, BLR, and ELR with airflow limitation, hospital length of stay (LOS), C-reactive protein (CRP), and in-hospital mortality in patients with AECOPD were analyzed.Results: Compared with the healthy volunteers, PLR, NLR, MLR, BLR, and ELR were all elevated in COPD patients under stable condition. PLR, NLR, MLR, and BLR were further elevated while ELR was lowered during exacerbation. In the patients with AECOPD, PLR, NLR, and MLR were positively correlated with hospital LOS as well as CRP. In contrast, ELR was negatively correlated with hospital LOS as well as CRP. Elevated PLR, NLR, and MLR were all associated with more severe airflow limitation in AECOPD. Elevated PLR, NLR, and MLR were all associated with increased in-hospital mortality while elevated ELR was associated with decreased in-hospital mortality. Binary logistic regression analysis showed that smoking history, FEV1% predicted, pneumonia, pulmonary heart disease (PHD), uric acid (UA), albumin, and MLR were significant independent predictors ofin-hospital mortality. These predictors along with ELR were used to construct a nomogram for predicting in-hospital mortality in AECOPD. The nomogram had a C-index of 0.850 (95% CI: 0.799– 0.901), and the calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) further demonstrated its good predictive value and clinical applicability.Conclusion: In summary, PLR, NLR, MLR, and ELR served as useful biomarkers in patients with AECOPD.Keywords: healthy volunteers, in-hospital mortality, length of stay, nomogram, pneumonia, pulmonary heart disease

Tong Wu, Da Liu, Fanhe Meng, Jing-han Lu, Yi-feng Chen, Zheng Fan Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of ChinaCorrespondence: Da Liu, Department of Orthopedics, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, People’s Republic of China, Tel +86 18940257508, Email spinecmu@163.comPurpose: Here, we introduce a novel strategy of awake unilateral biportal endoscopic (UBE) decompression, which applies conscious sedation combined with stepwise local anesthesia (LA) as an alternative to general anesthesia (GA). The study aims to evaluate the feasibility of awake UBE decompression for degenerative lumbar spinal stenosis (DLSS) in elderly patients.Patients and Methods: This retrospective study included 31 consecutive patients who received awake UBE decompression for DLSS in our institution from January 2021 to March 2022. Clinical results were evaluated using patient-reported outcomes measures (PROM) including visual analog scale for leg pain (VAS-LP), Oswestry Disability Index (ODI), and modified MacNab criteria. The anesthesia effectiveness and intraoperative experience were evaluated by intraoperative VAS and satisfaction rating system.Results: UBE decompression was successfully performed in all patients under LA combined with conscious sedation. 26 (83.9%) patients rated the intraoperative experience as satisfactory (excellent or good) and 5 (16.1%) as fair. The mean intraoperative VAS was 3.41± 1.26. The VAS and ODI at each follow-up stage after surgery were significantly improved compared to preoperative scores (p < 0.01). At the last follow-up, 28 patients (90.3%) classified the surgical outcome as good or excellent, and 3 (9.7%) as fair. There were no serious complications or adverse reactions observed in the study.Conclusion: Our preliminary results suggest that awake UBE decompression is a feasible and promising alternative for elderly patients with DLSS.Keywords: awake spinal surgery, local anesthesia, degenerative lumbar disease, biportal endoscopic spine surgery, enhanced recovery after surgery

This Letter reports the first measurement of high-energy reactor antineutrinos at Daya Bay, with nearly 9000 inverse beta decay candidates in the prompt energy region of 8-12 MeV observed over 1958 days of data collection. A multivariate analysis is used to separate 2500 signal events from background statistically. The hypothesis of no reactor antineutrinos with neutrino energy above 10 MeV is rejected with a significance of 6.2 standard deviations. A 29% antineutrino flux deficit in the prompt energy region of 8-11 MeV is observed compared to a recent model prediction. We provide the unfolded antineutrino spectrum above 7 MeV as a data-based reference for other experiments. This result provides the first direct observation of the production of antineutrinos from several high-Q_{β} isotopes in commercial reactors.

BackgroundNumerous studies of head and neck squamous cell carcinoma (HNSCC) have demonstrated disparate outcomes by race and ethnicity. Beyond known associations with socioeconomic variables, whether these are also associated with differences in tumor molecular composition has thus far been poorly explored.MethodsWe downloaded clinical and multiplatform molecular data from The Cancer Genome Atlas and other published studies. These were compared between non-Hispanic Black (n = 43) and White (n = 354) patients with non-HPV-related tumors, using multivariable models. Publicly available validation cohorts were used.ResultsBlack patients had poorer progression-free survival than White patients. Tumors of Black patients had greater copy number aberrations, and increased SFRP1 methylation and miRNA-mediated PRG4 silencing associated with poor survival. PI3K/AkT/mTOR pathway proteins were differentially expressed.ConclusionsThere are molecular differences between tumors of Black and White patients that may partially account for differences in survival. These may inform targeted treatment decisions to achieve equitable outcomes.

Cheng-Yi Hu,1 Wen-Shuai Cui,1 Yi Lei,1 Yu-Wen Tang,1 Yan-Yan Zhang,1 Qi-Min Su,1 Fang Peng,2 Yun-Fei Zeng,1 Jia-Lin Song,1 Cheng-Na Luo,1 Yan Zhou,1 Xin-Yan Li,1 Zhu-Xiang Zhao1 1Department of Infectious Diseases, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China; 2Department of Critical Care Medicine, the Third Affiliated Hospital of Guang Zhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Zhu-Xiang Zhao, Department of Infectious Diseases, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510515, People’s Republic of China, Email zhaozhuxiang@126.comPurpose: To compare the effectiveness of azvudine and nirmatrelvir/ritonavir for the treatment of coronavirus disease (COVID-19).Patients and Methods: We conducted a retrospective analysis of data from 576 patients with COVID-19, comprising 195 patients without antiviral therapy, 226 patients treated with azvudine, 114 patients treated with nirmatrelvir/ritonavir, and 41 patients were treated with azvudine and nirmatrelvir/ritonavir concurrently. We compared their symptoms, mortality rates, and the length and cost of hospitalization.Results: The incidence of symptoms was similar in patients treated with azvudine and in those treated with nirmatrelvir/ritonavir. However, among patients experiencing weakness, the duration of weakness was significantly shorter in the azvudine group than in the nirmatrelvir/ritonavir group (P=0.029). Mortality did not differ significantly between the azvudine group and the nirmatrelvir/ritonavir group (18.14% vs.10.53%, P=0.068). Among “severe patients”, the mortality rate was markedly lower in patients treated with nirmatrelvir/ritonavir than in patients treated with azvudine (16.92% vs.32.17%, P=0.026). In patients with hepatic insufficiency, those treated with nirmatrelvir/ritonavir had substantially lower mortality than those treated with azvudine (15.09% vs.34.25%, P=0.016). In addition, patients treated with nirmatrelvir/ritonavir had longer hospital stays (P=0.002) and higher hospital costs (P< 0.001) than those receiving azvudine. Compared with patients treated with nirmatrelvir/ritonavir or azvudine alone, patients taking nirmatrelvir/ritonavir and azvudine concurrently had no significant improvement in survival (P> 0.05), length of stay (P> 0.05), or hospital costs (P> 0.05).Conclusion: Azvudine is recommended for patients with non-severe COVID-19 with weakness. Nirmatrelvir/ritonavir is recommended for patients with severe COVID-19, to reduce mortality, and it could be the best choice for patients with hepatic insufficiency. The concurrent use of nirmatrelvir/ritonavir and azvudine in patients with COVID-19 could be not recommended.Keywords: azvudine, nirmatrelvir/ritonavir, COVID-19, SARS-CoV-2

Chao Yan,1,&ast; Chang Su,1,&ast; Yu-fei Ye,2 Jin Liu1 1Department of Neurosurgery, the Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, People’s Republic of China; 2Department of Neurosurgery, Qingyuan People’s Hospital, Lishui, Zhejiang, 323800, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jin Liu, Department of Neurosurgery, the Sixth Affiliated Hospital of Wenzhou Medical University, 1188 Liyang Street, Liandu District, Lishui, Zhejiang Province, 323000, People’s Republic of China, Email Liujin614@lsu.edu.cnObjective: The outcome of chronic subdural hematoma (CSDH) is influenced not only by the choice of treatment but also by various baseline characteristics. The main objective of this study is to identify the risk factors that can affect the prognosis of CSDH and develop a regression equation based on these risk factors.Methods: A total of 212 patients with CSDH were included in the study. We collected clinical data including age, gender, and so on, and radiological data including preoperative hematoma volume (V1), effusion volume 1 day after surgery (V2), gas volume 1 day after surgery (V3), and so on. These were considered independent variables, while residual volume 1 week after surgery (V4) was the dependent variable. Univariate linear regression analysis was performed to identify factors that were significantly related. Subsequently, multivariate linear regression analysis was conducted to determine the relationship between each independent variable and the dependent variable. Multiple linear regression analysis was used to obtain a regression equation predicting V4.Results: We have found that age (t = 3.109, P = 0.002), aspirin (t = 2.762, P = 0.006), hemostatic agents (haemocoagulase, t = 3.731, P < 0.001; vitamin K, t = 2.824, P = 0.005 < 0.05), V2 (t = 8.73, P < 0.001), and V3 (t = 5.968, P < 0.001) are significantly associated with V4. Furthermore, we have developed a regression equation that can predict this volume with CSDH. The fit of the model is robust with an R-squared value of 65.2% > 50%.Conclusion: Age, aspirin, hemostatic agent, V2, and V3 are significantly associated with V4. We developed a regression equation to predict this volume with CSDH.Keywords: CSDH, burr-hole and drainage, regression equation

Zhe-Feng Zhao,1,&ast; Bing-Bing Liu,1,&ast; Jian-Nan Zhang,2,&ast; Ni Shi,3,&ast; Ping Zhang,1,&ast; Gang-Zhi Yang,4 Yu-Fu Cao,4 Long-He Tian,4 Cheng-Cai Qiu,5 Yang Gao6,7 1Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 2Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 3Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 4Department of Neurosurgery, People’s Hospital of Hegang City, Hegang, Heilongjiang, People’s Republic of China; 5Department of Neurosurgery, Traditional Chinese Medicine Hospital of Jixi City, Jixi, Heilongjiang, People’s Republic of China; 6Department of Critical Care Medicine, The Sixth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 7Institute of Critical Care Medicine, The Sino Russian Medical Research Center of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhe-Feng Zhao, Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China, Email know810512@163.com Yang Gao, Department of Critical Care Medicine, The Sixth Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China, Email gaoyang0312@126.comObjective: In this study, we aimed to explore the demographic and clinical factors that could determine short- and long-term complete pain relief (CPR) in adult patients with primary trigeminal neuralgia (PTN) after microvascular decompression (MVD) to guide clinical practice.Methods: This single-center retrospective study included adult patients with PTN who underwent MVD as their initial neurosurgical procedure in the Department of Neurosurgery at the Second Affiliated Hospital of Harbin Medical University from January 2017 to December 2019 and completed a 3-year post-surgery follow-up. Demographic and clinical information was obtained from medical records. Pain relief of adult patients with PTN at various time points after sufficient decompression of trigeminal nerve (TN) during MVD was determined and classified by the patient’s subjective response and medications use. Pain relief of local patients was evaluated by outpatient follow-up at various time points, whereas that of local cases who could not return to outpatient or non-local cases was assessed through telephone or WeChat.Results: In univariate analysis, compression degree of TN and type of conflicting vessels constantly showed significant differences between the two groups at 3 months, 6 months, 1 year, 2 years, and 3 years after MVD. Compression degree of TN and type of conflicting vessels at various time points after MVD were always the related factors to CPR in logistic regression analysis, with the former having the greatest impact. The areas under the receiver operating characteristic (ROC) curve of CPR at various time points after MVD were 0.937, 0.874, 0.879, 0.864, and 0.869, respectively.Conclusion: In summary, compression degree of TN and type of conflicting vessels can determine short- and long-term CPR in adult patients with PTN after MVD.Keywords: compression degree of trigeminal nerve, type of conflicting vessels, microvascular decompression, sufficient decompression of trigeminal nerve, complete pain relief, primary trigeminal neuralgia

Fang-Yi Yu,&ast; Kua Zheng,&ast; Yin-Fang Wu,&ast; Shen-Wei Gao, Qing-Yu Weng, Chen Zhu, Yan-Ping Wu, Miao Li, Zhong-Nan Qin, Jia-Fei Lou, Zhi-Hua Chen, Song-Min Ying, Hua-Hao Shen, Wen Li Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Li, Tel +86-571-87783729, Fax +86-571-87068001, Email liwen@zju.edu.cnPurpose: This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism.Methods: We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models.Results: Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia.Conclusion: Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.Keywords: Staphylococcus aureus, pneumonia, macrophage, rapamycin, mTOR- ribosomal protein S6 signaling pathway

Shi-Tong Diao, Run Dong, Jin-Min Peng, Yan Chen, Shan Li, Shu-Hua He, Yi-Fan Wang, Bin Du, Li Weng On behalf of the China Critical Care Clinical Trials Group (CCCCTG)Medical Intensive Care Unit, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Li Weng, Medical Intensive Care Unit, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Shuai Fu Yuan, Beijing, 100730, People’s Republic of China, Email wengli@gmail.comBackground: Sepsis surveillance was important for resources allocation, prevention, and development of health policy.Objective: The aim of the study was to validate a modified International Classification of Diseases (ICD)-10 based algorithm for identifying hospitalized patients with sepsis.Methods: We retrospectively analyzed a prospective, single-center cohort of adult patients who were consecutively admitted to one medical ICU ward and ten non-ICU wards with suspected or confirmed infections during a 6-month period. A modified ICD-10 based algorithm was validated against a reference standard of Sequential Organ Failure Assessment (SOFA) score based on Sepsis-3. Sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and areas under the receiver operating characteristic curves (AUROCs) were calculated for modified ICD-10 criteria, eSOFA criteria, Martin’s criteria, and Angus’s criteria.Results: Of the 547 patients in the cohort, 332 (61%) patients met Sepsis-3 criteria and 274 (50%) met modified ICD-10 criteria. In the ICU setting, modified ICD-10 criteria had SE (84.47%), SP (88.57%), PPV (95.60), and NPV (65.96). In non-ICU settings, modified ICD-10 had SE (64.19%), SP (80.00%), PPV (80.33), and NPV (63.72). In the whole cohort, the AUROCs of modified ICD-10 criteria, eSOFA, Angus’s criteria, and Martin’s criteria were 0.76, 0.75, 0.62, and 0.62, respectively.Conclusion: This study demonstrated that modified ICD-10 criteria had higher validity compared with Angus’s criteria and Martin’s criteria. Validity of the modified ICD-10 criteria was similar to eSOFA criteria. Modified ICD-10 algorithm can be used to provide an accurate estimate of population-based sepsis burden of China.Keywords: sepsis, validation, International Classification of Diseases, administrative health data, identification

Yen-Ming Huang,1– 3 Yao-Hsing Wang,1,4 Hsun-Yu Chan,5 Yunn-Fang Ho1,2 1Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, 100025, Taiwan; 2School of Pharmacy, College of Medicine, National Taiwan University, Taipei, 100025, Taiwan; 3Department of Pharmacy, National Taiwan University Hospital, Taipei, 100229, Taiwan; 4Honest Pharmacy, Taichung, 408483, Taiwan; 5Department of Industrial Education, National Taiwan Normal University, Taipei, 106308, TaiwanCorrespondence: Hsun-Yu Chan, Department of Industrial Education, National Taiwan Normal University, Taipei, 106308, Taiwan, Tel +886 2 77493550, Email hsunyuchan@ntnu.edu.tw Yunn-Fang Ho, Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, 100025, Taiwan, Tel +886 2 33668794, Fax +886 2 33668780, Email yfho@ntu.edu.twPurpose: This study aimed to thoroughly document the process and cost factors involved in dispensing services within a community pharmacy.Methods: Using a cross-sectional design, this study incorporated a pragmatic and descriptive qualitative approach to outline pharmacists’ viewpoints on providing dispensing services in community settings. A purposive sampling was employed to recruit pharmacists from geographically different community pharmacies, spanning from March to July 2022. Semi-structured interviews with direct content analysis were conducted through face-to-face interactions to gather firsthand insights into pharmacists’ professional dispensing services. The data underwent analysis through descriptive and in vivo coding techniques to categorize, define, and label themes, thereby identifying key steps and cost components in the prescription dispensing process. The qualitative data management software, MAXQDA 2020, was utilized for data management and maintenance.Results: Ten community pharmacists participated in the study, cooperatively completing the interview process. Of these, 7 were male and 3 were female, with age ranging from 29 to 62 years. The average length of pharmacy practice experience was 11.4 years. The study revealed six integral steps in the dispensing process: (1) receiving and clarifying legality and completeness of prescriptions, (2) profiling and verifying patient prescriptions, (3) preparing prescription labels and containers, (4) dispensing right medications with right quantity, (5) inspecting dispensing accuracy, (6) handing over medications and providing counseling. Along with these processes, pharmacists emphasized that pharmacy manpower, representing a substantial portion of the associated costs, determines the success and quality of the dispensing service. Additionally, rental, utilities, consumables, and physical equipment were identified as other important cost factors associated with carrying out pharmacy dispensing services.Conclusion: The study offers a comprehensive understanding of the dispensing service workflow within community pharmacies. The findings may inform key stakeholders and policymakers about required resources for enhancing and sustaining quality dispensing services for the public in Taiwan.Keywords: community pharmacy, dispensing service, pharmacist, prescription, refill

Ji-Ren An,1,2,&ast; Qing-Feng Wang,1,&ast; Gui-Yan Sun,1 Jia-Nan Su,1 Jun-Tong Liu,1 Chi Zhang,1 Li Wang,1 Dan Teng,3 Yu-Feng Yang,1 Yan Shi1 1Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China; 2College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, People’s Republic of China; 3He University, Shenyang, 110163, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu-Feng Yang; Yan Shi, Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Huanggu District, No. 79, Mount Chong East Road, Shenyang, 110847, People’s Republic of China, Email lntcmyyf@126.com; lntcmshiyan@163.comAbstract: It is well documented that diabetes mellitus (DM) is strongly associated with cognitive decline and structural damage to the brain. Cognitive deficits appear early in DM and continue to worsen as the disease progresses, possibly due to different underlying mechanisms. Normal iron metabolism is necessary to maintain normal physiological functions of the brain, but iron deposition is one of the causes of some neurodegenerative diseases. Increasing evidence shows that iron overload not only increases the risk of DM, but also contributes to the development of cognitive impairment. The current review highlights the role of iron overload in diabetic cognitive impairment (DCI), including the specific location and regulation mechanism of iron deposition in the diabetic brain, the factors that trigger iron deposition, and the consequences of iron deposition. Finally, we also discuss possible therapies to improve DCI and brain iron deposition.Keywords: diabetic cognitive impairment, type 1 diabetes mellitus, type 2 diabetes mellitus, iron overload, iron transport, iron homeostasis

BackgroundMechanisms underlying the adiposity-cancer relationship are incompletely understood. We quantified the mediating roles of C-reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)-positive breast, endometrial, and colorectal cancer risk in postmenopausal women.MethodsWe used a case-cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case-control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis.ResultsFor breast cancer, the total effect RR for BMI ≥30 versus ≥18.5-

Magnetic fluctuations is the leading candidate for pairing in cuprate, iron-based, and heavy fermion superconductors. This view is challenged by the recent discovery of nodeless superconductivity in CeCu2Si2, and calls for a detailed understanding of the corresponding magnetic fluctuations. Here, we mapped out the magnetic excitations in superconducting (S-type) CeCu2Si2 using inelastic neutron scattering, finding a strongly asymmetric dispersion for E ≲ 1.5 meV, which at higher energies evolves into broad columnar magnetic excitations that extend to E ≳ 5 meV. While low-energy magnetic excitations exhibit marked three-dimensional characteristics, the high-energy magnetic excitations in CeCu2Si2 are almost two-dimensional, reminiscent of paramagnons found in cuprate and iron-based superconductors. By comparing our experimental findings with calculations in the random-phase approximation,we find that the magnetic excitations in CeCu2Si2 arise from quasiparticles associated with its heavy electron band, which are also responsible for superconductivity. Our results provide a basis for understanding magnetism and superconductivity in CeCu2Si2, and demonstrate the utility of neutron scattering in probing band renormalization in heavy fermion metals.