Heat stroke is a heat-related illness caused by an imbalance between the body's heat production and heat dissipation,which could lead to multiple organ dysfunction syndrome with a high mortality rate.Rapid and effective reduction of core body temperature is key to successful treatment.This article reviews recent progress in the treatment of heat stroke,including new understandings of organ injury mechanisms,the timing,velocity and goals of cooling treatment,evaluation and selection of traditional cooling techniques(such as cold water immersion),and scientific evaluation of new cooling technologies(such as blood purification technology and intravascular heat exchange cooling technology),aiming to promote understanding and treatment of heat stroke.

Computational approaches,encompassing both physics-based and machine learning(ML)methodolo-gies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychi-atric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxi-cological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter re-uptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC50)values of 0.753 μM,0.542 μM,and 1.210 μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were con-ducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.

Antibody humanization is critical to reduce immunogenicity and enhance efficacy in the preclinical phase of the development of therapeutic antibodies originated from animal models.Computational suggestions have long been desired,but available tools focused on immunogenicity calculation of whole antibody sequences and sequence segments,missing the individual residue sites.This study introduces Site-specific Immunogenicity for Therapeutic Antibody(SITA),a novel computational framework that predicts B-cell immunogenicity score for not only the overall antibody,but also individual residues,based on a comprehensive set of amino acid descriptors characterizing physicochemical and spatial features for antibody structures.A transfer-learning-inspired framework was purposely adopted to overcome the scarcity of Antibody-Antibody structural complexes.On an independent testing dataset derived from 13 Antibody-Antibody structural complexes,SITA successfully predicted the epitope sites for Antibody-Antibody structures with a receiver operating characteristic(ROC)-area unver the ROC curve(AUC)of 0.85 and a precision-recall(PR)-AUC of 0.305 at the residue level.Furthermore,the SITA score can significantly distinguish immunogenicity levels of whole human antibodies,therapeutic antibodies and non-human-derived antibodies.More importantly,analysis of an additional 25 thera-peutic antibodies revealed that over 70％of them were detected with decreased immunogenicity after modification compared to their parent variants.Among these,nearly 66％antibodies successfully iden-tified actual modification sites from the top five sites with the highest SITA scores,suggesting the ability of SITA scores for guide the humanization of antibody.Overall,these findings highlight the potential of SITA in optimizing immunogenicity assessments during the process of therapeutic antibody design.

Objective:To investigate the brain iron status in the sensorimotor cortex of patients with chronic low back pain (CLBP) and its relationship with changes in resting-state functional connectivity (RS-FC).Methods:This was a cross-sectional study. Thirty-two patients with CLBP (CLBP group) who were treated at Wuxi People′s Hospital Affiliated to Nanjing Medical University from July 2023 to March 2024 and 30 age-and gender-matched healthy volunteers (control group) were prospectively included. All subjects underwent pain and neuropsychological assessments and head MRI examinations, including conventional sequences, quantitative susceptibility mapping (QSM), and blood oxygen level-dependent (BOLD) functional MRI. QSM values of the sensorimotor cortex and the left middle frontal gyrus, right inferior temporal gyrus, right olfactory cortex, and right posterior cingulate gyrus were extracted using the ANTs toolkit. The bilateral postcentral gyrus and posterior portion of the bilateral precentral gyrus in the sensorimotor cortex were selected as seed points using SPM software to extract the average time series of BOLD signals and evaluate the changes in RS-FC values with other brain regions. Two-sample t-tests were used to compare the differences in QSM values and RS-FC values between the two groups. Pearson correlation analysis was used to analyze the correlation between iron deposition in key brain regions and RS-FC values and clinical scale scores. Results:The QSM values in the posterior portion of the bilateral precentral gyrus and the left postcentral gyrus in the CLBP group were significantly higher than those in the control group ( t=2.17, P=0.009; t=4.44, P<0.001), and the QSM value in the left postcentral gyrus was positively correlated with pain-related scale scores ( P<0.05). Compared with the control group, the QSM values in the left orbital part of the middle frontal gyrus ( t=2.22, P=0.031) and the right inferior temporal gyrus ( t=2.98, P=0.004) were increased, while the QSM values in the right olfactory cortex ( t=2.54, P=0.014) and the right posterior cingulate gyrus ( t=2.70, P=0.009) were decreased in the CLBP group. Compared with the control group, the RS-FC values between the left postcentral gyrus, the posterior part of the bilateral precentral gyrus, and the left superior frontal gyrus were increased in the CLBP group ( P<0.001), the RS-FC value between the right postcentral gyrus and the right precuneus was increased ( P<0.001). The RS-FC of the bilateral motor cortex and the left dorsolateral superior frontal gyrus was positively correlated with the QSM values of the bilateral motor cortex ( r=0.444, P=0.015). Conclusion:Iron deposition in the sensorimotor cortex (posterior portion of the bilateral precentral gyrus and the left postcentral gyrus) is increased in CLBP patients and is correlated with abnormal functional connectivity within and between brain regions.

Objective To evaluate the rehabilitative effect of targeted sonic vibration load brushing method in stroke patients with oral phase swallowing disorders.Methods A total of 60 stroke patients with swallowing disor-ders,who hospitalized in the rehabilitation department of a Grade Ⅲ Class A hospital in Nanjing City from October 2023 to May 2024,were randomly assigned to an experimental group and a control group,with 30 patients in each group.Both groups received the conventional swallowing function training.The experimental group received targeted sonic vibration load brushing therapy,while the control group received routine oral care with manual toothbrushes.After 30 days of intervention,the swallowing function(Gugging Swallowing Screen,GUSS),modified Beck oral score,incidence of swallowing disorder-related complications,Swallowing Quality of Life(SWAL-QOL)scores,and oral care satisfaction were assessed in both groups.Results No sample detachment.After the intervention,the GUSS score for the experimental group was significantly higher than that of the control group,with a statistical difference(Z=-4.239,P＜0.001).Additionally,the modified Beck oral score and the overall complications rate related to swallowing disor-ders in the experimental group were significantly lower than those in the control group(both P＜0.05).Furthermore,the SWAL-QOL score and the oral care satisfaction score were both higher in the experimental group compared to those in the control group,with statistically significant differences(both P＜0.001).Conclusion Targeted sonic vibration load brushing method significantly improves swallowing function,enhances oral cleanliness,reduces the occurrence of swallowing disorder-related complications,and effectively improves patients' quality of life and nursing satisfaction.

Objective To explore the value of cardiopulmonary and additional ultrasound(CLAUS)protocol and point-of-care ultrasound rapid management(POCURM)protocol in etiological diagnosis of acute respiratory distress in critically ill patients in the emergency room.Methods A total of 242 patients with acute respiratory distress admitted to Jinhua City Central Hospital from January 2022 to January 2024 were selected as the research subjects.According to the final diagnosis after discharge,they were divided into cardiogenic group(n=144)and pulmonary group(n=98).Compare the CLAUS findings of two groups and accuracy of two protocols in diagnosing etiology of acute respiratory distress.Results The history of heart disease in cardiogenic group was higher than that in pulmonary group,and difference was statistically significant(P＜0.05).The lung disease history of patients in cardiogenic group was lower than that in pulmonary group,and difference was statistically significant(P＜0.05).The proportion of pleural smoothness/slight thickening,sliding presence/slight weakening,left heart dysfunction,right heart dysfunction,and B-line pulmonary ultrasound scores in cardiogenic group were higher than those in pulmonary group,and differences were statistically significant(P＜0.05).The sensitivity,specificity of POCURM protocol for diagnosing acute respiratory distress were 90.28％,91.84％.The sensitivity,specificity of CLAUS protocol for diagnosing acute respiratory distress were 96.53％,97.96％.Conclusion CLAUS regimen can effectively diagnose specific causes of acute respiratory distress in patients,with higher accuracy than POCURM regimen.

Objective:To report the nationwide surveillance results of pathogenic profiles and antimicrobial resistance patterns of Gram-positive bloodstream infections in China in 2023.Methods:The clinical isolates of Gram-posttive bacteria from blood cultures were collected in member hospitals of National Bloodstream Infection Bacterial Resistant Investigation Collaborative System（BRICS）during January to December 2023. Antimicrobial susceptibility testing was performed using the dilution method recommended by the Clinical and Laboratory Standards Institute（CLSI）. Statistical analyses were conducted using WHONET 5.6 and SPSS 25.0 software.Results:A total of 4 385 Gram-positive bacterial isolates were obtained from 60 participating center. The top five pathogens were Staphylococcus aureus（ n=1 544，35.2%），coagulase-negative Staphylococci（ n=1 441，32.9%）， Enterococcus faecium（ n=574，13.1%）， Enterococcus faecalis（ n=385，8.8%），and α-hemolytic Streptococci（ n=187，4.3%）. The prevalence of methicillin-resistant Staphylococcus aureus（MRSA）and methicillin-resistant coagulase-negative Staphylococci（MRCNS）was 26.2%（405/1 544）and 69.8%（1 006/1 441），respectively. Notably，all Staphylococci remained susceptible to glycopeptide or daptomycin. Staphylococcus aureus demonstrated excellent susceptibility（>97.0%）to cephalobiol，rifampicin，trimethoprim-sulfamethoxazole，linezolid，minocycline，tigecycline，and eravacycline. No Enterococcus exhibiting resistance to linezolid were detected. Glycopeptide resistance was uncommon but more frequent in Enterococcus faecium（resistance to vancomycin and teicoplanin：both 1.7%）compared to Enterococcus faecalis（both 0.3%）. The detection rates of MRSA and MRCNS exhibited significant regional variations across the country（ χ2=17.674 and 148.650，respectively，both P<0.001）. No vancomycin-resistant Enterococci were detected in central China. Institutional comparison demonstrated higher prevalence of MRSA（ χ2=14.111， P<0.001）and MRCNS（ χ2=4.828， P=0.028）in provincial hospitals than that in municipal hospitals. Socioeconomic analysis identified elevated detection rates of both MRSA（ χ2=18.986， P<0.001）and MRCNS（ χ2=4.477， P=0.034）in less developed regions（per capita GDP

Objective:To report the results of bacterial resistant investigation collaborative system（BRICS）on the distribution and antimicrobial resistance profile of clinical Gram-negative bacteria isolates from bloodstream infections in China in 2023，and provide reference for clinical tretment of bloodstream infections and prevention and control of bacterial resistance.Methods:The clinical isolates of Gram-negative bacteria from blood cultures in member hospitals of BRICS were collected during January 2023 to December 2023. Antibiotic susceptibility tests were conducted by agar dilution or broth dilution methods recommended by Clinical and Laboratory Standards Institute（CLSI）. WHONET 5.6 and SPSS 25.0 were used to analyze the data.Results:During the study period，11 492 strains of Gram-negative bacteria were collected from 60 hospitals，of which 10 098（87.9%）were Enterobacterales and 1 394（12.1%）were non-fermentative bacteria. The top 5 bacterial species were Escherichia coli（50.0%）， Klebsiella pneumoniae（26.1%）， Pseudomonas aeruginosa（5.1%）， Acinetobacter baumannii complex（5.0%）and Enterobacter cloacae complex（4.1%）. The ESBL-producing rates in Escherichia coli， Klebsiella pneumoniae and Proteus mirablilis were 46.8%（2 685/5 741），18.3%（549/2 999）and 44.0%（77/175），respectively. The prevalence of carbapenem-resistant Escherichia coli（CREC）and carbapenem-resistant Klebsiella pneumoniae（CRKP）were 1.3%（76/5 741）and 15.0%（450/2 999）；32.9%（25/76）and 78.0%（351/450）of CREC and CRKP were sensitive to ceftazidime/avibactam combination，respectively. 94.7%（72/76）and 90.2%（406/450）of CREC and CRKP were sensitive to aztreonam/avibactam combination. Furthermore，57.9%（44/76）and 79.1%（356/450）were sensitive to imipenem/relebactam combination. The prevalence of carbapenem-resistant Acinetobacter baumannii（CRAB）complex was 64.6%（370/573），while more than 80.0% of CRAB complex was sensitive to tigecycline，eravacycline and polymyxin B. The prevalence of carbapenem-resistant Pseudomonas aeruginosa（CRPA）was 17.0%（99/581）. There were differences in the composition ratio of Gram-negative bacteria in bloodstream infections and the prevalence of important Gram-negative bacteria resistance among different regions in China，with statistically significant differences in the prevalence of CREC，CRKP，CRPA and CRAB complex（ χ2=10.6，28.6，10.8 and 19.3， P<0.05）. The prevalence of ESBL-producing Escherichia coli， CREC，CRAB complex and CRKP were higher in provincial hospitals than those in municipal hospitals（ χ2=12.5，9.8，12.7 and 57.8，all P<0.01）. Conclusions:Gram-negative bacteria are the main pathogens causing bloodstream infections in China，and Escherichia coli is ranked in the top，while the trend of Klebsiella pneumoniae increases continuously with time. CRKP infection shows a slow upward trend，CREC infecton maintains a low prevalence level，and CRAB complex infection continues to exhibit a high prevalence rate. The composition and resistance patterns of pathogens causing bloodstream infections vary to some extent across different regions and levels of hospitals in China.

OBJECTIVE To explore the effectiveness and possible mechanism of Shangke Lengtong Patch in treating knee osteo-arthritis with cold-dampness arthralgia obstruction.METHODS A total of 70 patients who met the inclusion criteria of knee osteoar-thritis with cold-dampness arthralgia obstruction in the Orthopedics Department of Affiliated Hospital of Nanjing University of Chinese Medicine from November to December 2024 were randomly divided into an experimental group and a control group,with 35 cases in each group.During the treatment,1 case dropped out of the experimental group,3 cases dropped out of the control group,and 1 case was discontinued.The experimental group was treated with Shangke Lengtong Patch,and the control group was treated with Compound Nanxing Zhitong Ointment.The WOMAC scores and TCM syndrome scores of the two groups before and after treatment were compared to comprehensively evaluate the clinical efficacy.The changes in the expression levels of CGRP,substance P,HMGB1,IL-1β,CX-CL12,and CXCR4 in the serum of the two groups were detected by ELISA.RESULTS After 3,7,and 14 d of treatment,the WOMAC scores and TCM syndrome scores of the two groups were significantly reduced(P<0.05,P<0.01),and the score of aggrava-ted cold in the experimental group was better than that in the control group at 7 d of treatment(P<0.05);after 14 d of treatment,the expression levels of CGRP,substance P,HMGB1,IL-1β,CXCL12,and CXCR4 in the serum of the two groups were significantly re-duced(P<0.05),and there was no statistical difference between the two groups.CONCLUSION Shangke Lengtong Patch can sig-nificantly relieve the pain symptoms of knee osteoarthritis patients with cold-dampness arthralgia obstruction and improve the joint func-tion of patients.It may improve synovial inflammation by inhibiting the HMGB1/CXCL12/CXCR4 pathway,thereby exerting a thera-peutic effect.

The amino-terminal pro-C-type natriuretic peptide(NT-proCNP)is a diagnostic inflam-matory marker clinically used for diagnosing bacterial infections.This study aims to establish a phage display library of single-chain variable fragment(scFv)antibodies against canine NT-proC-NP and to screen for scFvs with high binding affinity to NT-proCNP.Initially,NT-proCNP was prepared using prokaryotic expression system and was used to immunize New Zealand White rab-bits.Upon achieving the desired serum titer,total RNA was extracted from the splenocytes of rab-bits and reverse transcribed into cDNA.Using this cDNA as a template,degenerate primers were employed to amplify the genes of the rabbit antibody light chain variable region(VL)and heavy chain variable region(VH).The VL and VH regions were spliced together to form a complete scFv fragment via overlap extension PCR.The scFv was then ligated into the phagemid pComb3XSS and electroporated into competent E.coli TG1 cells to construct a rabbit-derived anti-NT-proCNP scFv immunological library.This library underwent four rounds of enrichment and screening to isolate specific single-chain antibodies.The selected antibody was subsequently ex-pressed in a soluble form within a prokaryotic system,and its immunological activity was evalua-ted.Using phage display technology,this study successfully identified a single-chain antibody scFv-1-CNP with strong antigen-binding activity and genetic sequence characteristics of scFvs,providing a research direction for further exploration of scFv applications in the detection of NT-proCNP.