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ObjectivesHigh-need, high-cost (HNHC) patients represent a small proportion of patients in the US, but result in disproportionately higher healthcare utilization. Teaching Internal Medicine (IM) resident trainees to provide high value care for HNHC patients is critical. We sought to improve resident attitudes and increase clinical skills associated with treating HNHC patients by creating a curriculum that leveraged the UCLA Extensivist Program, a patient-centered medical home for HNHC patients.MethodsWe developed a curriculum for PGY-2 and PGY-3 IM residents centered on caring for HNHC patients over the course of 6, 4h sessions during 1 academic year. Participants completed pre- and post-intervention surveys assessing self-rated attitudes and skills associated with caring for an HNHC patient population.ResultsTwenty-one IM residents completed the curriculum and 41 were in the control group. There were no statistically significant differences in assessed attitudes and skills, but there were trends of improvement, including a decrease in participants who agreed or strongly agreed they felt overwhelmed when seeing patients for posthospital discharge follow up (45.0% pre- to 41.7% post-intervention) and an increase in participants who agreed or strongly agreed they have the skills to successfully transition HNHC patients between inpatient and ambulatory settings (20.0% pre- to 33.3% post-intervention). Participants reported better understanding of resources available to HNHC patients, effective coordination of transitions of care, and comprehensive assessment of social determinants of health.ConclusionA curriculum to improve resident attitudes and skills associated with caring for HNHC patients was successfully implemented in an IM program at a large academic medical center. The curriculum may be adapted for other training programs; long-term training woven throughout training may be important to significantly improve resident education on how to care for HNHC patients.

Mingyue Sun, Weiqiang Xiao, Qingxia Xu Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Qingxia Xu, Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Dongming Road No. 127, Zhengzhou, Henan Province, People’s Republic of China, Tel +860371-65587147, Email qxiaxu@126.comObjective: Klebsiella michiganensis is an emerging pathogen. In this context, we characterised a strain fxq isolated from a cerebrospinal fluid specimen of a patient with tentorial meningioma, and the K. michiganensis isolate produced carbapenemases of KPC and NDM types.Methods: The Phoenix 100 Automated Microbiology System, MALDI-TOF and whole-genome sequencing were used to identify the species. Anti-microbial susceptibility testing was also conducted with the Phoenix 100. The plasmid locations of the blaKPC-2 and blaNDM-1 genes were determined by S1-nuclease pulsed-field gel electrophoresis and Southern blot. The transfer capacity of plasmids carrying blaKPC-2 and blaNDM-1 was investigated by conjugation experiments, and the resistance plasmid stability was evaluated by culture and subculture. K. michiganensis subtypes were identified by multi-locus sequence typing. We performed whole-genome sequencing to confirm species, characterise plasmids and analyse core genes.Results: fxq was originally identified as Klebsiella oxytoca and showed resistance to imipenem and meropenem, but whole-genome sequencing identified it to be K. michiganensis. The strain fxq belonged to the novel sequence type 202 (ST202) and carried the blaKPC-2 and blaNDM-1 genes located on the pB_KPC InFIA and pE_NDM IncU plasmids, respectively. The blaKPC-2-carrying plasmid was successfully transferred to Escherichia coli EC600 by conjugation, whereas the blaNDM-1 gene on the pE_NDM plasmid was not. The pB_KPC and pE_NDM plasmids demonstrated high stability.Conclusion: This work is the first report on a carbapenem-resistant clinical isolate K. michiganensis ST202 harbouring the blaKPC-2 and blaNDM-1 genes encoded by the IncFIA and IncU plasmids, respectively.Keywords: Klebsiella michiganensis, IncU plasmid, carbapenemase gene, NDM, KPC

Mingjun Gong,1 Min Sun,1 Yaqi Sun,2 Lijuan Jin,1 Shen Li3 1Sports Training College, Tianjin University of Sport, Tianjin, People’s Republic of China; 2Mental Health Institute, Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3Psychoneuromodulation Center, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Shen Li, Psychoneuromodulation Center, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, No. 13, Liulin Road, Hexi District, Tianjin, 300222, People’s Republic of China, Tel +86-22-88188875, Email lishen@tmu.edu.cnObjective: Using meta-analysis to comprehensively and quantitatively evaluate the impact of acute sleep deprivation on different sports performance of athletes, this study aims to provide scientific guidance for coaches in optimizing and adjusting training and competition arrangements.Methods: Establishing literature inclusion and exclusion criteria, we conducted searches in both Chinese and English databases. Using stata 14.0, we analyzed 75 indicators from 27 included literature, focusing on three aspects: the impact of acute sleep deprivation on overall athletic performance, the impact on sporting performance across various athletic abilities, and the disparities in athletic performance between morning and afternoon following acute sleep deprivation.Results: The effect size of acute sleep deprivation on overall athletic performance was − 0.56 (P< 0.05). Sub-analyses revealed effect sizes of − 0.23 (P< 0.05) for whole night sleep deprivation, − 1.17 (P< 0.05) for partial sleep deprivation at the end of the night, and − 0.25 (P> 0.05) for partial sleep deprivation in the beginning of the night. The effect sizes of acute sleep deprivation on high intensity intermittent exercise, skill control, speed, aerobic endurance, and explosive power indicators were − 1.57, − 1.06, − 0.67, − 0.54, and − 0.39 respectively (P< 0.05). The effect sizes of acute sleep deprivation on the overall athletic performance in the morning and afternoon were − 0.30, and − 1.11, respectively (P< 0.05).Conclusion: Acute sleep deprivation significantly impairs the overall athletic performance of athletes, with a more pronounced negative impact observed with partial sleep deprivation at the end of the night. Various types of exercise performance are adversely affected by acute sleep deprivation, with magnitude of impact ranking high intensity intermittent, skill control, speed, aerobic endurance, and explosive power. Following acute sleep deprivation, athletes’ overall sporting performance in the afternoon is inferior to that in the morning.Keywords: acute sleep deprivation, athletes, athletic ability, sporting performance, meta-analysis

Weiwei Guan,1,2 Congyue Zhang,1 Tongguo Miao,1 Chen Dong,1 Lu Li,1 Xiwei Yuan,1 Dandan Zhao,1 Rong Ai,1 Xiaoxiao Zhang,1 Mengjiao Sun,1 Haiyan Kang,2,&ast; Yuemin Nan1,&ast; 1Department of Traditional and Western Medical Hepatology, Hebei Medical University Third Hospital & Hebei International Joint Research Center for Liver Cancer Molecular Diagnosis, Hebei International Science and Technology Cooperation Base, Shijiazhuang, Hebei Province, 050051, People’s Republic of China; 2Department of Liver Disease, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei, 050023, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuemin Nan, Department of Traditional and Western Medical Hepatology, Hebei Medical University Third Hospital & Hebei International Joint Research Center for Liver Cancer Molecular Diagnosis, Hebei International Science and Technology Cooperation Base, No. 139, Ziqiang Road, Shijiazhuang, Hebei Province, 050051, People’s Republic of China, Tel +86 18533112266, Email nanyuemin@163.com Haiyan Kang, Department of Liver Disease, The Fifth Hospital of Shijiazhuang, Hebei Medical University, No. 42, Tanan Road, Shijiazhuang, Hebei Province, 050023, People’s Republic of China, Tel +86 13315952782, Email kanghaiyan1976@126.comPurpose: Long noncoding RNAs (lncRNAs) might be closely associated with hepatocellular carcinoma (HCC) progression and could serve as diagnostic and prognostic markers. This study aimed to investigate lncRNA-based diagnostic biomarkers for hepatitis B virus (HBV)-associated HCC.Materials and Methods: High‐throughput transcriptome sequencing was conducted on the liver tissues of 15 patients with HBV-associated liver diseases (5 with chronic hepatitis B [CHB], 5 with liver cirrhosis [LC], and 5 with HCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze lncRNA expressions. Potential diagnostic performance for HBV-associated HCC screening was evaluated.Results: Through trend analysis and functional analysis, we found that 8 lncRNAs were gradually upregulated and 1 lncRNA was progressively downregulated by regulation of target mRNAs and downstream HCC-associated signaling pathways. The validation of dysregulated lncRNAs in peripheral blood mononuclear cells (PBMCs) and HCC tissues by qRT-PCR revealed that ADAMTSL4-AS1, SOCS2-AS1, and AC067931 were significantly increased in HCC compared with CHB and cirrhosis. Moreover, differentially expressed lncRNAs were aberrantly elevated in Huh7, Hep3B, HepG2, and HepG2.215 cells compared with LX2 cells. Furthermore, ADAMTSL4-AS1, SOCS2-AS1, and AC067931 were identified as novel biomarkers for HBV-associated HCC. For distinguishing HCC from CHB, ADAMTSL4-AS1, AC067931, and SOCS2-AS1 combined with alpha-fetoprotein (AFP) had an area under the curve (AUC) of 0.945 (sensitivity, 83.9%; specificity, 89.8%). Similarly, for distinguishing HCC from LC, this combination had an AUC of 0.871 (sensitivity, 91.1%; specificity, 68.2%). Furthermore, this combination showed the highest diagnostic ability to distinguish HCC from CHB and LC (AUC, 0.905; sensitivity, 91.1%; specificity, 75.3%). In particular, this combination identified AFP-negative (AFP < 20 ng/mL) (AUC = 0.814), small (AUC = 0.909), and early stage (AUC = 0.863) tumors.Conclusion: ADAMTSL4-AS1, SOCS2-AS1, and AC067931 combined with AFP in PBMCs may serve as a noninvasive diagnostic biomarker for HBV-associated HCC, especially AFP-negative, small, and early stage HCC.Keywords: ADAMTSL4-AS1, AC067931, SOCS2-AS1, HBV-associated HCC, diagnostic biomarkers

Min Sun,1 Guanchi Yan,2 Siming Sun,3 Xiaonan Li,1 Wei Sun,4 Yuehui Wang1 1Department of Geriatrics, The First Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 3Department of Clinical Research, The First Hospital of Jilin University, Changchun, People’s Republic of China; 4Education Department, The First Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Yuehui Wang, Department of Geriatrics, The First Hospital of Jilin University, No. 1 Xinmin Street, Chaoyang District, Changchun, Jilin, 130061, People’s Republic of China, Tel +86-13614303457, Email yuehuiwang300@jlu.edu.cn Wei Sun, Education Department, The First Hospital of Jilin University, No. 1 Xinmin Street, Chaoyang District, Changchun, Jilin, 130061, People’s Republic of China, Tel +86-16604302962, Email 18504381676@163.comBackground: Serum trace elements and oxidative stress factors are related to diabetic microvascular complications. The study was to investigate the complex relationship between trace elements, oxidative stress factors, and the severity of microvascular complications of diabetes in older adults.Methods: The present study included patients with or without type 2 diabetes, and blood glucose, blood lipids, trace elements (iron, magnesium, zinc), oxidative stress factors (malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC)) were evaluated. Risk factors for the severity of diabetic microvascular complications in older adults with diabetes were also estimated.Results: There were statistically significant differences in fasting blood glucose (FBG), triglycerides (TG), low density lipoprotein (LDL), glycated hemoglobin (HbAlc), MDA, NO, SOD, T-AOC, magnesium, and zinc between the two groups (P< 0.05). Iron (rZinc = 0.147, rSOD = 0.180, rT-AOC = 0.193, P < 0.05) was positively correlated with zinc, SOD and T-AOC. Iron was negatively correlated with MDA (rMDA = − 0.146, P < 0.05). Magnesium was positively correlated with SOD (rMagnesium = 0.147, P < 0.05). Zinc (rSOD = 0.616, rT-AOC = 0.575, P < 0.01) was positively correlated with SOD and T-AOC. Zinc (rMDA =− 0.636, rNO=− 0.616, P< 0.01) was positively correlated with MDA and negatively correlated with NO. The course of disease (18.653, [5.726; 60.764], P < 0.01), FBG (1.265, [1.059; 1.511], P < 0.05), HbAlc (1.545, [1.431; 1.680], P < 0.01), MDA (2.989, [1.900; 4.702], P < 0.01) were risk factor for the severity of diabetic microvascular complications. Zinc (0.680, [0.503; 0.919], P < 0.05) and SOD (0.820, [0.698; 0.964], P < 0.05) were protective factors for the severity of diabetic microvascular complications.Conclusion: Serum trace elements are related to oxidative stress levels in older adults with type 2 diabetes. The more stable trace element in older adults with diabetes, the lower the oxidative stress and the fewer microvascular complications of diabetes.Keywords: type 2 diabetes mellitus, older adults, trace elements, diabetic microvascular complications, oxidative stress

Mingyue Sun, Zhuoyou Chen Department of Neurology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213000, People’s Republic of ChinaCorrespondence: Zhuoyou Chen, Email neuro1972@163.comAbstract: Alzheimer’s disease (AD) is the most common neurodegenerative illness, characterized by memory loss and cognitive decline, accounting for 60– 80% of dementia cases. AD is characterized by senile plaques made up of amyloid β (Aβ) protein, intracellular neurofibrillary tangles caused by hyperphosphorylation of tau protein linked with microtubules, and neuronal loss. Currently, therapeutic treatments and nanotechnological developments are effective in treating the symptoms of AD, but a cure for the illness has not yet been found. Recently, the increased study of extracellular vesicles (EVs) has led to a growing awareness of their significant involvement in neurodegenerative disorders, including AD. Exosomes are small extracellular vesicles that transport various components including messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive compounds from one cell to another, facilitating information transmission and material movement. There is growing evidence indicating that exosomes have complex functions in AD. Exosomes may have a dual role in Alzheimer’s disease by contributing to neuronal death and also helping to alleviate the pathological progression of the disease. Therefore, the primary aim of this review is to outline the updated understandings on exosomes biogenesis and many functions of exosomes in the generation, conveyance, distribution, and elimination of hazardous proteins related to Alzheimer’s disease. This review is intended to provide novel insights for understanding the development, specific treatment, and early detection of Alzheimer’s disease.Keywords: Alzheimer’s disease, exosomes, pathogenesis, diagnosis, treatment

Mengjuan Sun,1,&ast; Jun Wei,1,&ast; Yanhui Su,1,&ast; Yangjingwan He,1 Liang Ge,1 Yan Shen,1 Bohui Xu,2 Yanlong Bi,3 Chunli Zheng1 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China; 2School of Pharmacy, Nantong University, Nantong, People’s Republic of China; 3Pediatric Intensive Care Unit, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunli Zheng; Yanlong Bi, Email zhengchunli@cpu.edu.cn; pulong123@163.comPurpose: The purpose of this study is to address the high mortality and poor prognosis associated with Acute Respiratory Distress Syndrome (ARDS), conditions characterized by acute and progressive respiratory failure. The primary goal was to prolong drug circulation time, increase drug accumulation in the lungs, and minimize drug-related side effects.Methods: Simvastatin (SIM) was used as the model drug in this study. Employing a red blood cell surface-loaded nanoparticle drug delivery technique, pH-responsive cationic nanoparticles loaded with SIM were non-covalently adsorbed onto the surface of red blood cells (RBC), creating a novel drug delivery system (RBC@SIM-PEI-PPNPs).Results: The RBC@SIM-PEI-PPNPs delivery system effectively extended the drug’s circulation time, providing an extended therapeutic window. Additionally, this method substantially improved the targeted accumulation of SIM in lung tissues, thereby enhancing the drug’s efficacy in treating ARDS and impeding its progression to ARDS. Crucially, the system showed a reduced risk of adverse drug reactions.Conclusion: RBC@SIM-PEI-PPNPs demonstrates promise in ARDS and ARDS treatment. This innovative approach successfully overcomes the limitations associated with SIM’s poor solubility and low bioavailability, resulting in improved therapeutic outcomes and fewer drug-related side effects. This research holds significant clinical implications and highlights its potential for broader application in drug delivery and lung disease treatment.Keywords: acute lung injury, simvastatin, respiratory distress syndrome, pH response

Ting Yang,1,2 Yanan Du,1 Mingzhen Sun,1 Jingjing Meng,1 Yiyi Li1 1School of Health Services Management, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China; 2Intelligent Interconnected Systems Laboratory of Anhui Province (Hefei University of Technology), Hefei, Anhui, 230009, People’s Republic of ChinaCorrespondence: Ting Yang, Email yangting@ahmu.edu.cnAbstract: Over the past decade, the global outbreaks of SARS, influenza A (H1N1), COVID-19, and other major infectious diseases have exposed the insufficient capacity for emergency disposal of medical waste in numerous countries and regions. Particularly during epidemics of major infectious diseases, medical waste exhibits new characteristics such as accelerated growth rate, heightened risk level, and more stringent disposal requirements. Consequently, there is an urgent need for advanced theoretical approaches that can perceive, predict, evaluate, and control risks associated with safe disposal throughout the entire process in a timely, accurate, efficient, and comprehensive manner. This article provides a systematic review of relevant research on collection, storage, transportation, and disposal of medical waste throughout its entirety to illustrate the current state of safe disposal practices. Building upon this foundation and leveraging emerging information technologies like Internet of Things (IoT), cloud computing, big data analytics, and artificial intelligence (AI), we deeply contemplate future research directions with an aim to minimize risks across all stages of medical waste disposal while offering valuable references and decision support to further advance safe disposal practices.Keywords: medical waste, safe disposal, major infectious diseases, progress and challenges

Yaohui Yi, Meng Sun, Jiachen Lu, Xiaofeng Dou, Yingying Yu, Ling Zhou School of Public Health, Dalian Medical University, Dalian City, Liaoning Province, People’s Republic of ChinaCorrespondence: Ling Zhou, School of Public Health, Dalian Medical University, Dalian City, Liaoning Province, People’s Republic of China, Tel +86-411-8611-0368, Email zhouling0609@163.comBackground: As future health workers, medical students’ attitudes towards tuberculosis (TB) patients can impact TB control. However, in China, there is a lack of well-quantified assessment regarding the stigma among medical students towards TB patients. Therefore, this study aimed to validate the Chinese version of the Tuberculosis related-Stigma Scale (TSS) in medical students and to apply the scale to measure stigma and its determinants.Methods: A total of 1035 eligible medical students participated in the cross-sectional questionnaire. Exploratory factor analyses (EFA) and confirmatory factor analyses (CFA) were first conducted to test Chinese version of the TSS construct validity, and then internal consistency was assessed using Cronbach’s α. Finally, multiple linear regression analyses were conducted to identify predictors of stigma.Results: EFA extracted two factors (“Social distance” and “Exclusionary sentiments”). The CFA further confirmed the two-factor construct. The internal consistency, convergent and divergent validity of the adapted Chinese version of the TSS was acceptable. Furthermore, Whether one has received TB health education and whether know a person with TB are associated with all dimensions of TB stigma, while differences in sex and place of residence play different roles in influencing the different dimensions of stigma.Conclusion: The adapted Chinese version of the TSS can be used to assess the level of stigma among medical students in China towards tuberculosis patients. When implementing future interventions to reduce stigma associated with TB, special attention should be given to medical students from urban areas, of male gender, who have not received TB health education, and no know a person with TB. However, these two dimensions (“Social distance” and “Exclusionary sentiments”) are impacted by different determinants and should therefore be addressed separately when designing, implementing, and evaluating measures to reduce stigma.Keywords: tuberculosis related-stigma scale, medical student, psychometrics, determinants

Chunyan Yang,&ast; Hao Tian,&ast; Guixing Xu, Qin Luo, Mingsheng Sun, Fanrong Liang Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fanrong Liang, Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No. 37 Shi’er Qiao Road, Chengdu, Sichuan, 610075, People’s Republic of China, Email acuresearch@126.comPurpose: The effect of acupuncture as adjunctive therapy for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) was controversial. Thus, we aimed to evaluate the effects of acupuncture for treating AECOPD.Methods: Eight databases were searched from database inception to July 30, 2023. All RCTs compared acupuncture plus conventional western medicine with conventional western medicine alone were included. Outcomes were quality of life, lung function, blood oxygen condition, exercise capacity, daily symptoms, duration of hospitalization, and adverse events. The statistical analyses were conducted using Stata 17.0, and methodological quality was measured by the Cochrane bias risk assessment tool. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of evidence.Results: Twelve studies including 915 patients were included. Compared with conventional western medicine alone, acupuncture combined with conventional western therapy significantly improved quality of life (CAT: MD: − 3.25; 95% CI: − 3.73 to − 2.78, P< 0.001) and arterial blood gas (PaCO2: MD: − 1.85; 95% CI: − 2.74 to − 0.95, P< 0.001; PaO2: MD: 5.15; 95% CI: 1.22 to 9.07, P = 0.01). And for lung function, statistical benefits were found in FEV1/FVC (MD: 4.66; 95% CI: 2.21 to 7.12, P< 0.001), but no difference was seen for FEV1% (MD: 1.83; 95% CI: − 0.17 to 3.83, P = 0.073). There was no significant improvement in exercise capacity (6MWD: MD: 96.69; 95% CI: − 0.60 to 193.98, P = 0.051), hospitalization duration (MD: − 5.70; 95% CI: − 11.97 to 0.58, P = 0.075), and dyspnea (mMRC: MD: − 0.19; 95% CI: − 0.61 to 0.63, P = 0.376) between two groups. Overall bias for CAT and mMRC was in “high” risk, FEV1%, FEV1/FVC, PaCO2, and PaO2 was in “some concern” and 1 RCT assessing hospitalization duration was in “low” risk. And the overall assessments were either moderate, low or very low certainty. Seven trials performed safety assessment of acupuncture, and no serious adverse events were reported.Conclusion: Acupuncture might have auxiliary effects on AECOPD. However, the quality of the evidence is limited, and more high-quality RCTs are needed to be performed in the future.Keywords: acute exacerbation of chronic obstructive pulmonary disease, acupuncture, systematic review, meta-analysis

Hongjuan Wang,1 Rongzhi Li,1 Lin Ge,2 Fan Xu,1 James Allen Wiley,3 Siyuan Tang,1 Mei Sun1,4 1Xiangya School of Nursing, Central South University, Changsha, Hunan Province, People’s Republic of China; 2Department of Alcohol Addiction and Internet Addiction, Brain Hospital of Hunan Province (The Second People’s Hospital of Hunan Province), Changsha, Hunan Province, People’s Republic of China; 3Department of Family and Community Medicine and Institute for Health Policy Research, University of California, San Francisco, CA, USA; 4School of Nursing, Changsha Medical University, Changsha, Hunan Province, People’s Republic of ChinaCorrespondence: Siyuan Tang; Mei Sun, Xiangya School of Nursing, Central South University, Changsha, Hunan Province, 410013, People’s Republic of China, Email sytang263@csu.edu.cn; smnjw2008@126.comBackground: Sleep-related outcomes in people with diabetes are poor, which is closely linked to reducing the development of diabetes. Cognitive behavioral therapy (CBT) based intervention presents innovative solutions that can help improve sleep-related outcomes.Aim: This synthesis aims to assess the effectiveness of CBT-based intervention compared to controls in Randomized Controlled Trials (RCTs) for sleep-related outcomes among people with diabetes.Methods: Eight electronic databases were systematically searched: PubMed, EMBASE, Cochrane library, Web of Science, PsycINFO, CINAHL, China National Knowledge Infrastructure (CNKI), and Wan Fang database. We examined CBT-based intervention’s effectiveness on sleep-related outcomes in people with diabetes in RCTs identified in these databases from their inception to 1st November 2023, and updated on 15 January 2024. The risk of bias was assessed using the Cochrane Risk of Bias tool by two reviewers. The meta-analysis of included studies was conducted by RevMan 5.3 software.Results: Seven studies in total (n = 2633 participants) were included in this systematic review based on our inclusion criteria. The systematic review found CBT-based intervention significantly improved sleep quality (Pittsburgh Sleep Quality Index, PSQI scores) at immediate post-intervention [95% CI=(− 1.31 to -0.32), p = 0.001], six months [95% CI=(− 0.75 to − 0.22), p = 0.0003], and 12 months [95% CI=(− 0.72 to − 0.24), < 0.0001], compared to control groups. Furthermore, our findings demonstrated that six sessions [95% CI= (− 0.38 to − 0.13), p < 0.0001] or more than six sessions [95% CI=(− 1.76 to − 0.02), p = 0.05] of CBT-based intervention could improve sleep quality compared to controls (I2=0%). Interestingly, CBT-based intervention improves total sleep time at post-intervention in people with diabetes compared to the control group [95% CI= (− 0.57 to − 0.12), p = 0.003]. However, there was no significant that CBT-based intervention is beneficial to time to fall asleep [95% CI (− 1.89 to 0.43), p = 0.22] and sleep efficiency [95% CI (− 1.27 to 0.27), p = 0.20] after intervention, compared to control group.Conclusion: CBT-based intervention appears to have a beneficial effect on improving sleep quality and total sleep time among people with diabetes. CBT-based intervention could be considered a strategy among healthcare providers to enhance sleep quality and total sleep time for people with diabetes. More RCTs with rigorous designs and long-term follow-up are warranted to provide conclusive evidence of the CBT-based intervention on sleep-related outcomes and to explore the mechanisms by which the CBT-based interventions improve sleep-related outcomes.Keywords: diabetes, cognitive behavioral therapy, sleep, systematic review, meta-analysis

Man Sun,1 Huan Zhang,1 Jiayi Liu,1 Jiayi Chen,1 Yaxin Cui,1 Simiao Wang,1 Xiangyu Zhang,2 Zhaogang Yang1 1School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China; 2Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, 310020, People’s Republic of ChinaCorrespondence: Xiangyu Zhang; Zhaogang Yang, Tel/Fax +86-431-85155320, Email 3314023@zju.edu.cn; zhaogangyang@jlu.edu.cnAbstract: Recently, gene therapy has become a subject of considerable research and has been widely evaluated in various disease models. Though it is considered as a stand-alone agent for COVID-19 vaccination, gene therapy is still suffering from the following drawbacks during its translation from the bench to the bedside: the high sensitivity of exogenous nucleic acids to enzymatic degradation; the severe side effects induced either by exogenous nucleic acids or components in the formulation; and the difficulty to cross the barriers before reaching the therapeutic target. Therefore, for the successful application of gene therapy, a safe and reliable transport vector is urgently needed. Extracellular vesicles (EVs) are the ideal candidate for the delivery of gene drugs owing to their low immunogenicity, good biocompatibility and low toxicity. To better understand the properties of EVs and their advantages as gene drug delivery vehicles, this review covers from the origin of EVs to the methods of EVs generation, as well as the common methods of isolation and purification in research, with their pros and cons discussed. Meanwhile, the engineering of EVs for gene drugs is also highlighted. In addition, this paper also presents the progress in the EVs-mediated delivery of microRNAs, small interfering RNAs, messenger RNAs, plasmids, and antisense oligonucleotides. We believe this review will provide a theoretical basis for the development of gene drugs.Keywords: extracellular vesicles, gene therapy, drug delivery system, gene drugs

Miaomiao Sun,1– 3,&ast; Fuquan Wang,1– 3,&ast; Haopeng Li,1– 3 Mengyu Li,1– 3 Yu Wang,1– 3 Chenchen Wang,1– 3 Yan Zhang,1– 3 Dingyu Zhang,1– 4 Jianhua Li,5 Shanglong Yao1– 3 1Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, 430022, People’s Republic of China; 4Wuhan Jinyintan Hospital, Wuhan, 430023, People’s Republic of China; 5Department of Critical Care Medicine, Chongqing University Jiangjin Hospital, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shanglong Yao; Jianhua Li, Email yaoshanglong@hust.edu.cn; jianhuali2022@cqu.edu.cnBackground: Sepsis-associated acute kidney injury (SA-AKI) is a common complication in patients with sepsis, triggering high morbidity and mortality. Maresin-1 (MaR1) is a pro-resolution lipid mediator that promotes the resolution of acute inflammation and protects organs from inflammation.Methods: In this study, we established an SA-AKI model using cecal ligation and puncture (CLP) and investigated the effect and mechanism of MaR1. The blood and kidneys were harvested 24 hours after surgery. The blood biochemical/routine indicators, renal function, SA-AKI-related pathophysiological processes, and AMPK/SIRT3 signaling in septic mice were observed by histological staining, immunohistochemical staining, Western blot, qPCR, ELISA and TUNEL Assay.Results: MaR1 treatment alleviated kidney injury in septic mice, reflected in improved pathological changes in renal structure and renal function. MaR1 treatment decreased the levels of serum creatinine (sCr) and blood urea nitrogen (BUN) and the expressions of KIM-1, NGAL and TIMP-2, which were related to kidney injury, while inhibited the expressions of inflammatory factors TNF-α, IL-1β and IL-6. The expression of endoplasmic reticulum stress-related indicators p-PERK/PERK, GRP78, p-EIF2α/EIF2α, ATF4, CHOP, and pyroptosis-related indicators Caspase-1, NLRP3, GSDMD, IL-18, and IL-1β also decreased after MaR1 treatment. The mechanism may be related to the activation of the AMPK/SIRT3 signaling pathway, and an AMPK inhibitor (compound C) partially reverses MaR1’s protective effects in septic mice.Conclusion: Taken together, these findings suggest that MaR1 may partially ameliorate SA-AKI by activating the AMPK/SIRT3 signaling pathway, providing a potential new perspective for research on SA-AKI.Keywords: Maresin-1, pyroptosis, AMPK/SIRT3, endoplasmic reticulum stress, sepsis-associated acute kidney injury, inflammation

OBJECTIVES High-need, high-cost (HNHC) patients represent a small proportion of patients in the US, but result in disproportionately higher healthcare utilization. Teaching Internal Medicine (IM) resident trainees to provide high value care for HNHC patients is critical. We sought to improve resident attitudes and increase clinical skills associated with treating HNHC patients by creating a curriculum that leveraged the UCLA Extensivist Program, a patient-centered medical home for HNHC patients. METHODS We developed a curriculum for PGY-2 and PGY-3 IM residents centered on caring for HNHC patients over the course of 6, 4h sessions during 1 academic year. Participants completed pre- and post-intervention surveys assessing self-rated attitudes and skills associated with caring for an HNHC patient population. RESULTS Twenty-one IM residents completed the curriculum and 41 were in the control group. There were no statistically significant differences in assessed attitudes and skills, but there were trends of improvement, including a decrease in participants who agreed or strongly agreed they felt overwhelmed when seeing patients for posthospital discharge follow up (45.0% pre- to 41.7% post-intervention) and an increase in participants who agreed or strongly agreed they have the skills to successfully transition HNHC patients between inpatient and ambulatory settings (20.0% pre- to 33.3% post-intervention). Participants reported better understanding of resources available to HNHC patients, effective coordination of transitions of care, and comprehensive assessment of social determinants of health. CONCLUSION A curriculum to improve resident attitudes and skills associated with caring for HNHC patients was successfully implemented in an IM program at a large academic medical center. The curriculum may be adapted for other training programs; long-term training woven throughout training may be important to significantly improve resident education on how to care for HNHC patients.

Xiaodong Xu,&ast; Yuan Tao,&ast; Yitian Yang, Jiaqiang Zhang, Mingyang Sun Department of Anesthesiology and Perioperative Medicine, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiaqiang Zhang; Mingyang Sun, Department of Anesthesiology and Perioperative Medicine, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003, People’s Republic of China, Tel +0 371 6558 0728, Email zhangjiq@zzu.edu.cn; mingyangsun1986@163.comPurpose: We investigate the efficacy and safety of butorphanol in multimodal analgesia combined with dexmedetomidine and ketorolac via patient-controlled intravenous analgesia (PCIA) after hepatobiliary surgery, as compared with sufentanil.Patients and Methods: Postoperative follow-up data of hepatobiliary surgery patients in Henan Provincial People’s Hospital from March 2018 to June 2021 were collected retrospectively and divided into butorphanol group (group B) or sufentanil group (group S) according to the postoperative intravenous controlled analgesia scheme. The baseline characteristics and surgical information of the two groups were matched through propensity score matching (PSM).Results: A total of 3437 patients were screened, and PSM yielded 1816 patients after matching, including 908 in the butorphanol group and 908 in the sufentanil group. Compared with group S, the incidence of moderate-to-severe pain on the first postoperative day and the second postoperative day was lower in group B during rest (3.2% vs 10.9%, P< 0.001; 1.2% vs 4.6%, P< 0.001), and during movement (7.0% vs 18.9%, P< 0.001; 2.6% vs 8.7%, P< 0.001). Patients receiving butorphanol had a lower morphine consumption (50mg vs 120mg, P< 0.001). The bolus attempts of an analgesic pump in group B were significantly lower than in group S (1 vs 2, P< 0.001). Postoperative hospital length of stay was shortened in group B (11d vs 12d, P=0.017). The occurrence of postoperative vomiting was lower in group B (1.4% vs 3.0%, P=0.025) than in group S. However, more patients in group B experienced dizziness (0.9% vs 0.1%, P=0.019).Conclusion: Compared with sufentanil, the application of butorphanol in multimodal analgesia combined with dexmedetomidine and ketorolac via PCIA ameliorated postoperative pain after hepatobiliary surgery, with reduced opioid consumption and shorter postoperative hospital length of stay.Keywords: patient controlled intravenous analgesia, butorphanol, sufentanil, propensity score matching

Yue Zhang,1,2,&ast; Meiyan Sun,2,&ast; Hongxiang Zhao,1,2,&ast; Zhengyan Wang,2 Yanan Shi,2 Jianxin Dong,2 Kaifang Wang,3 Xi Wang,4 Xingyue Li,5 Haiyan Qi,6 Xiaoyong Zhao1,2,7 1Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 2Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China; 3Department of Anesthesia, Tangdu Hospital, Fourth Military Medical University, Xian, Shanxi Province, People’s Republic of China; 4Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 5Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People’s Republic of China; 6Department of Anesthesiology, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, People’s Republic of China; 7Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoyong Zhao; Haiyan Qi, Email xyzhao83@163.com; qihy123@163.comAbstract: Dichloroacetate (DCA) is an investigational drug used to treat lactic acidosis and malignant tumours. It works by inhibiting pyruvate dehydrogenase kinase and increasing the rate of glucose oxidation. Some studies have documented the neuroprotective benefits of DCA. By reviewing these studies, this paper shows that DCA has multiple pharmacological activities, including regulating metabolism, ameliorating oxidative stress, attenuating neuroinflammation, inhibiting apoptosis, decreasing autophagy, protecting the blood‒brain barrier, improving the function of endothelial progenitor cells, improving mitochondrial dynamics, and decreasing amyloid β-protein. In addition, DCA inhibits the enzyme that metabolizes it, which leads to peripheral neurotoxicity due to drug accumulation that may be solved by individualized drug delivery and nanovesicle delivery. In summary, in this review, we analyse the mechanisms of neuroprotection by DCA in different diseases and discuss the causes of and solutions to its adverse effects.Keywords: dichloroacetate, neuroprotection, mitochondria, energy metabolism, oxidative stress

Ni Meng, Xiaolong Cheng, Mengyao Sun, Yushan Zhang, Xueke Sun, Xifu Liu, Jing Chen Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Anti-Tumor Molecular Target Technology Innovation Center; Hebei Research Center of the Basic Discipline of Cell Biology; College of Life Science, Hebei Normal University, Shijiazhuang, 050024, People’s Republic of ChinaCorrespondence: Jing Chen; Xifu Liu, Email jingchen@hebtu.edu.cn; xfliu@hebtu.edu.cnIntroduction: The monkeypox (Mpox) virus epidemic presents a significant risk to global public health security. A35R, a crucial constituent of EEV, plays a pivotal role in virus transmission, serves as a vital target for vaccine development, and has potential for serological detection. Currently, there is a dearth of research on nanobodies targeting A35R. The purpose of this study is to identify specific nanobodies target A35R, so as to provide new antibody candidates for Mpox vaccine development and diagnostic kit development.Methods: Three nanobodies specific to the monkeypox virus protein A35R were screened from a naïve phage display library. After four rounds of panning, positive phage clones were identified by enzyme-linked immunosorbent assay (ELISA). Further, the nanobody fusion protein was constructed in pNFCG1-IgG1-Fc vector and expressed in HEK293F cells and purified by affinity chromatography. The specificity and affinity of the nanobodies were identified by ELISA. The binding kinetics of the VHH antibody to A35R were assessed via employment of a bio-layer interferometry (BLI) apparatus, thereby determining the nanobodies affinity.Results: The three purified nanobodies showed specific high-affinity binding MPXV A35R, of them, VHH-1 had the best antigen binding affinity (EC50 = 0.010 ug/mL). In addition, VHH-1 on Protein A biosensor can bind Mpox virus A35R, with an affinity constant of 54 nM as determined in BLI assay.Conclusion: In sum, we has obtained three nanobody strains against Mpox virus A35R with significant affinity and specificity, therefore laying an essential foundation for further research as well as the applications of diagnostic and therapeutic tools of Mpox virus.Keywords: monkeypox virus, A35R, nanobody, phage display library

Xing Zhang,1,&ast; Yuanyuan Song,1,&ast; Hongyang Gong,1,&ast; Chunyan Wu,1 Binquan Wang,1 Wenxuan Chen,2 Jiawei Hu,2 Hanhui Xiang,2 Ke Zhang,1 Mingkuan Sun1 1Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2The Second Clinical Medical School, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingkuan Sun, Department of Toxicology, School of Public Health, Nanjing Medical University, No. 101 Longmian Avenue, Jiangning District, Nanjing, 211166, People’s Republic of China, Email sunmk@njmu.edu.cnAbstract: The increasing use of titanium dioxide nanoparticles (TiO2 NPs) across various fields has led to a growing concern regarding their environmental contamination and inevitable human exposure. Consequently, significant research efforts have been directed toward understanding the effects of TiO2 NPs on both humans and the environment. Notably, TiO2 NPs exposure has been associated with multiple impairments of the nervous system. This review aims to provide an overview of the documented neurotoxic effects of TiO2 NPs in different species and in vitro models. Following exposure, TiO2 NPs can reach the brain, although the specific mechanism and quantity of particles that cross the blood-brain barrier (BBB) remain unclear. Exposure to TiO2 NPs has been shown to induce oxidative stress, promote neuroinflammation, disrupt brain biochemistry, and ultimately impair neuronal function and structure. Subsequent neuronal damage may contribute to various behavioral disorders and play a significant role in the onset and progression of neurodevelopmental or neurodegenerative diseases. Moreover, the neurotoxic potential of TiO2 NPs can be influenced by various factors, including exposure characteristics and the physicochemical properties of the TiO2 NPs. However, a systematic comparison of the neurotoxic effects of TiO2 NPs with different characteristics under various exposure conditions is still lacking. Additionally, our understanding of the underlying neurotoxic mechanisms exerted by TiO2 NPs remains incomplete and fragmented. Given these knowledge gaps, it is imperative to further investigate the neurotoxic hazards and risks associated with exposure to TiO2 NPs. Keywords: TiO2 NPs, neurotoxic effects, oxidative stress, neuronal damage, neurotoxic mechanisms

Cong Xia,1 Ting Wei,2,3 Qi Tang,2,3 Hongying Zheng,2,3 Mei Sun,2,3 Gang Chen,2,3 Jun Lv2,3 1School of Health Management Anhui Medical University, Hefei, People’s Republic of China; 2School of Public Health, Fudan University, Shanghai, People’s Republic of China; 3China Research Center on Disability, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Gang Chen; Jun Lv, School of Public Health, Fudan University, 130 Dong’an Road, Xuhui District, Shanghai, 200032, People’s Republic of China, Tel +86-13661432703 ; +86-13671684324, Email gchen@shmu.edu.cn; lujun@shmu.edu.cnPurpose: To investigate the family support, anxiety, depression, health-related quality of life (HRQoL), and their associations among parents and grandparents of children with disabilities.Methods: This is a cross-sectional study and a total of 327 family caregivers were included. Chi-square test, Mann–Whitney U-test, and two independent t-test were used to identify the intergenerational differences in sociodemographic characteristics, received family support, anxiety, depression, and HRQoL. Eight generalized linear models were developed to examine the associations in both generations.Results: Parents and grandparents were most in need of rehabilitation and financial support, but both populations received the least amount of financial support. 33.6% and 36.1% of family caregivers had the risk of anxiety and depression and found no significant intergenerational differences. As for HRQoL, intergenerational differences were found in the physical component score, but not found in the mental component score. Among parents, childcare support of respite care and household tasks assistance was negatively associated with their depression (p< 0.05), professional support of appropriate surgery for children (p< 0.05) and psychological support from professional psychologists (p< 0.01) were negatively associated with their anxiety and depression, psychological support from relatives and friends was negatively associated with their depression (p< 0.05) whereas was positively associated with their mental HRQoL (p< 0.01). As for grandparents, financial support for daily living expenses was negatively associated with depression (p< 0.05), and psychological support from families was negatively associated with depression (p< 0.05) whereas was positively associated with mental HRQoL (p< 0.05). However, no relationship was found between family support and anxiety among grandparents. Notably, no association was found between family support and physical HRQoL among both populations.Conclusion: Both parents and grandparents had high risks of anxiety, depression and low levels of mental HRQoL. To efficiently improve psychological health, care providers and policymakers may consider intergenerational differences and provide targeted family support.Keywords: mental health, health-related quality of life, family support, children with disabilities, intergenerational differences

Mei Sun,&ast; Yankai Wei,&ast; Chengyuan Zhang, Hong Nian, Bei Du, Ruihua Wei Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruihua Wei, Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 251 Fukang Road, Nankai District, Tianjin, 300384, People’s Republic of China, Tel/Fax +86 86428862, Email rwei@tmu.edu.cnPurpose: Sjögren’s syndrome-related dry eye (SS-related dry eye) is an intractable autoimmune disease characterized by chronic inflammation of lacrimal glands (LGs), where epigenetic factors are proven to play a crucial role in the pathogenesis of this disease. However, the alteration of DNA methylation in LGs and its role in the pathogenesis of SS-related dry eye is still unknown. Here, we performed an integrated analysis of DNA methylation and RNA-Seq data in LGs to identify novel DNA methylation-regulated differentially expressed genes (MeDEGs) in the pathogenesis of SS-related dry eye.Methods: The DNA methylation and transcription profiles of LGs in NOD mice at different stages of SS-related dry eye (4-, 8-, 12- and 16 weeks old) were generated by reduced representation bisulfite sequencing (RRBS) and RNA-Seq. The differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were analyzed by MethylKit R package and edgeR. Correlation analysis between methylation level and mRNA expression was conducted with R software. The functional correlation of DMGs and DEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, LG tissues from another litter of NOD mice were collected for methylation-specific polymerase chain reaction (MSP) and quantitative real-time PCR (qRT-PCR) to validate the methylation and expression levels of key genes. CD4+ cell infiltration of LGs was detected by immunofluorescence staining.Results: Hypermethylation of LGs was identified in NOD mice with the progression of SS-related dry eye and the DMGs were mainly enriched in the GTPases activation and Ras signaling pathway. RNA-seq analysis revealed 1321, 2549, and 3712 DEGs in the 8-, 12- and 16-week-old NOD mice compared with 4-week-old normal control mice. For GO analysis, the DEGs were mainly enriched in T cell immune responses. Further, a total of 140 MeDEGs were obtained by integrated analysis of methylome and transcriptome, which were primarily enriched in T cell activation, proliferation and differentiation. Based on the main GO terms and KEGG pathways of MeDEGs, 8 genes were screened out. The expression levels of these key genes, especially Itgal, Vav1, Irf4 and Icosl, were verified to elevate after the onset of SS-related dry eye in NOD mice and positively correlated with the extent of inflammatory cell infiltration in LGs. Immunofluorescence assay revealed that CD4+ cell infiltration dramatically increased in LGs of SS-related dry eye mice compared with the control mice. And the expression levels of four genes showed significantly positive correlation with the extent of CD4+ cell infiltration in LGs. MSP showed the hypomethylation of the Irf 4 and Itgal promoters in NOD mice with SS-related dry eye compared to control group.Conclusion: Our study revealed the critical role of epigenetic regulation of T cell immunity-related genes in the progression of SS-related dry eye and reminded us that DNA methylation-regulated genes such as Itgal, Vav1, Irf4 and Icosl may be used as new targets for SS-related dry eye therapy.Keywords: Sjögren’s syndrome-related dry eye, lacrimal gland, DNA methylation, RNA-seq, T cell-mediated immune response

Yang Qian, Chenting Cai, Mengqing Sun, Dan Lv, Yun Zhao The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of ChinaCorrespondence: Dan Lv, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, People’s Republic of China, Email fylvdan@nbu.edu.cnAbstract: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is the exacerbation of a range of respiratory symptoms during the stable phase of chronic obstructive pulmonary disease (COPD). AECOPD is thus a dangerous stage and key event in the course of COPD, as its deterioration and frequency seriously affects the quality of life of patients and shortens their survival. Acute exacerbations occur and develop due to many factors such as infection, tobacco smoke inhalation, air pollution, comorbidities, airflow limitation, various biomarkers, history of previous deterioration, natural killer cell abnormalities, immunoglobulin G deficiency, genetics, abnormal muscle and nutritional status, negative psychology, and seasonal temperature changes. There is relatively limited research on the impact of the role of standardized management on the alleviation of AECOPD. However, with the establishment of relevant prevention and management systems and the promotion of artificial intelligence technology and Internet medical approaches, long-term effective and standardized management of COPD patients may help to achieve the quality of life and disease prognosis in COPD patients and reduce the risk of AE.Keywords: chronic obstructive pulmonary disease, acute exacerbation, related risk factors

Meng Sun,1– 3,&ast; Zhouyang Wu,1– 3,&ast; Rong Wang,1– 3 Rui Xia,1– 3 Yi Sun,1– 3 Elham Esmaeili,1– 3 Zhengyuan Xia,4,5 Zhilin Wu,1– 3 Tingting Wang1– 3 1Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, People’s Republic of China; 4State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, People’s Republic of China; 5Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tingting Wang; Zhilin Wu, Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China, Tel +862785351643, Email wangtt201307@163.com; 840916@qq.comBackground: Erector spinae plane block (ESPB) is an easy and safe method for postoperative analgesia. However its effect lasts only for several hours. This trial was to investigate the effectiveness of different doses of nalbuphine as an adjuvant to ropivacaine in ESPB for patients undergoing percutaneous nephrolithotomy (PCNL).Methods: Patients scheduled for PCNL were randomized into three groups and received ultrasound-guided ESPB at T10 level for postoperative analgesia. Each subject received 28 mL of 100 mg ropivacaine solution mixed with 2 mL of normal saline (Group R), 2 mL of 10 mg nalbuphine (Group RNL), or 2 mL of 20 mg nalbuphine (Group RNH). Primary outcome was the time to first opioid demand. Secondary outcomes were morphine consumption, VAS scores within 24 h postoperatively, rescue analgesic requirements, and length of hospital stay.Results: The median [interquartile range, IQR] time to first opioid demand was significantly longer in group RNH (8.70 [6.90,14.85] h) than that of group R and group RNL (2.90 [2.00,6.30] h and 5.80 [2.95,7.00] h, respectively). VAS scores (either resting or active) within 24 h postoperatively were comparable between the three groups, with the most significant differences especially at 4, 6, 8 h. Morphine consumption at 24 h postoperatively was significant for R group vs RNH group (median difference, 9; 95% confidence interval [CI], 1.57 to 16.43; p = 0.02).Conclusions: Adding 20mg nalbuphine to ropivacaine in ESPB could significantly improve the effect of analgesia and prolong the duration of nerve blocks for PCNL.Keywords: adjuvant, erector spinae plane block, nalbuphine, percutaneous nephrolithotomy, postoperative pain

Meiyan Sun,1,2,&ast; Xiaoyong Zhao,2,&ast; Xingyue Li,2 Chunling Wang,2 Lili Lin,3 Kaifang Wang,2 Yingui Sun,2 Wei Ye,3 Haiyan Li,3 Ye Zhang,1 Chaolu Huang2,4 1Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of China; 2Department of Anesthesiology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, 261053, People’s Republic of China; 3The First Clinical Medical College, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 4Department of Clinical Medicine, Qiandongnan Ethnic Vocational and Technical College, Kaili, 556000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ye Zhang, Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of China, Email zhangy@ahmu.edu.cn Chaolu Huang, Department of Clinical Medicine, Qiandongnan Ethnic Vocational and Technical College, Kaili, 556000, People’s Republic of China, Email huangzhaolu2020@163.comObjective: Diabetes mellitus (DM) implicates oxidative stress, apoptosis, and inflammation, all of which may contribute liver injury. Aerobic exercise is assured to positively regulate metabolism in the liver. This project was designed to investigate whether and how aerobic exercise improves DM-induced liver injury.Methods: Seven-week-old male db/db mice and age-matched m/m mice were randomly divided into a rest control group or a group that received 12 weeks of aerobic exercise by treadmill training (10 m/min). Haematoxylin and eosin (HE) staining, electron microscopy, Oil Red O staining and TUNEL assays were used to evaluate the histopathological changes in mouse liver. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TRIG), cholesterol (CHOL) were analyzed by serum biochemical analysis. Interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were analyzed via ELISA. Nuclear factor E2-associated factor-2 (Nrf2), nuclear factor κB (NF-κB) and JAK2/STAT3 pathway-related proteins were measured by immunofluorescence, Western blotting and q-PCR. F4/80 expression in liver tissues was assessed by immunohistochemistry.Results: In diabetic mice, exercise training significantly decreased the levels of serum TRIG, CHOL, IL-6, TNF-α, ALT and AST; prevented weight gain, hyperglycaemia, and impaired glucose and insulin tolerance. Morphologically, exercise mitigated the diabetes-induced increase in liver tissue microvesicles, inflammatory cells, F4/80 (macrophage marker) levels, and TUNEL-positive cells. In addition, exercise reduced the apoptosis index, which is consistent with the results for caspase-3 and Bax. Additionally, exercise significantly increased SOD activity, decreased MDA levels, activated Nrf2 and decreased the expression of NF-kB, phosphorylated JAK2 and STAT3 proteins in the livers of diabetic mice.Conclusion: This study demonstrated that aerobic exercise reversed liver dysfunction in db/db mice with T2DM by reducing oxidative stress, apoptosis and inflammation, possibly by enhancing Nrf2 expression and inhibiting the JAK2/STAT3 cascade response.Keywords: db/db mice, aerobic exercise, inflammation, apoptosis, Nrf2, JAK2/STAT3

Ya Wang,1,&ast; Jiajia Zhang,2,&ast; Xiaoyan Chen,1,&ast; Min Sun,3 Yanqing Li,4 Yanan Wang,5 Yan Gu,6 Yinyin Cai1 1Neurosurgical Intensive Care Unit, Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 2Neurosurgery Section Two, Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 3Department of Geriatrics Section Three, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 4Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 5Respiratory and Critical Care Medicine Intensive Care Unit, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 6Infection Management Office, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoyan Chen, Email CXYtdfy@126.comObjective: To develop a predictive model for assessing the risk of multidrug-resistant organisms (MDROs) infection and validate its effectiveness.We conducted a study on a total of 2516 patients admitted to the neurosurgery intensive care unit (NICU) of a Grade-III hospital in Nantong City, Jiangsu Province, China, between January 2014 and February 2022. Patients meeting the inclusion criteria were selected using convenience sampling. The patients were randomly divided into modeling and validation groups in a 7:3 ratio. To address the category imbalance, we employed the Synthetic Minority Over-sampling Technique (SMOTE) to adjust the MDROs infection ratio from 203:1558 to 812:609 in the training set. Univariate analysis and logistic regression analysis were performed to identify risk factors associated with MDROs infection in the NICU. A risk prediction model was developed, and a nomogram was created. Receiver operating characteristic (ROC) analysis was used to assess the predictive performance of the model.Patients and Methods: Results: Logistic regression analysis revealed that sex, hospitalization time, febrile time, invasive operations, postoperative prophylactic use of antibiotics, mechanical ventilator time, central venous catheter indwelling time, urethral catheter indwelling time, ALB, PLT, WBC, and L% were independent predictors of MDROs infection in the NICU. The area under the ROC curve for the training set and validation set were 0.880 (95% CI: 0.857– 0.904) and 0.831 (95% CI: 0.786– 0.876), respectively. The model’s prediction curve closely matched the ideal curve, indicating excellent predictive performance.Conclusion: The prediction model developed in this study demonstrates good accuracy in assessing the risk of MDROs infection. It serves as a valuable tool for neurosurgical intensive care practitioners, providing an objective means to effectively evaluate and target the risk of MDROs infection.Keywords: multidrug-resistant, infection, neurosurgical intensive care unit, nomogram

BackgroundThe incidence of persistent clinical symptoms and risk factors in Post-Acute Sequelae of SARS-CoV-2 (PASC) in diverse US cohorts is unclear. While there are a disproportionate share of COVID-19 deaths in older patients, ethnic minorities, and socially disadvantaged populations in the USA, little information is available on the association of these factors and PASC.ObjectiveTo evaluate the association of demographic and clinical characteristics with development of PASC.DesignProspective observational cohort of hospitalized and high-risk outpatients, April 2020 to February 2021.ParticipantsOne thousand thirty-eight adults with laboratory-confirmed symptomatic COVID-19 infection.Main measuresDevelopment of PASC determined by patient report of persistent symptoms on questionnaires conducted 60 or 90 days after COVID-19 infection or hospital discharge. Demographic and clinical factors associated with PASC.Key resultsOf 1,038 patients with longitudinal follow-up, 309 patients (29.8%) developed PASC. The most common persistent symptom was fatigue (31.4%) followed by shortness of breath (15.4%) in hospitalized patients and anosmia (15.9%) in outpatients. Hospitalization for COVID-19 (odds ratio [OR] 1.49, 95% [CI] 1.04-2.14), having diabetes (OR, 1.39; 95% CI 1.02-1.88), and higher BMI (OR, 1.02; 95% CI 1-1.04) were independently associated with PASC. Medicaid compared to commercial insurance (OR, 0.49; 95% CI 0.31-0.77) and having had an organ transplant (OR 0.44, 95% CI, 0.26-0.76) were inversely associated with PASC. Age, race/ethnicity, Social Vulnerability Index, and baseline functional status were not associated with developing PASC.ConclusionsThree in ten survivors with COVID-19 developed a subset of symptoms associated with PASC in our cohort. While ethnic minorities, older age, and social disadvantage are associated with worse acute COVID-19 infection and greater risk of death, our study found no association between these factors and PASC.

Abstract Detecting pancreatic duct adenocarcinoma (PDAC) in its early stages and predicting late‐stage patient prognosis undergoing chemotherapy is challenging. This work shows that the activation of specific oncogenes leads to elevated expression of mRNAs and their corresponding proteins in extracellular vesicles (EVs) circulating in blood. Utilizing an immune lipoplex nanoparticle (ILN) biochip assay, these findings demonstrate that glypican 1 (GPC1) mRNA expression in the exosomes‐rich (Exo) EV subpopulation and GPC1 membrane protein (mProtein) expression in the microvesicles‐rich (MV) EV subpopulation, particularly the tumor associated microvesicles (tMV), served as a viable biomarker for PDAC. A combined analysis effectively discriminated early‐stage PDAC patients from benign pancreatic diseases and healthy donors in sizable clinical from multiple hospitals. Furthermore, among late‐stage PDAC patients undergoing chemotherapy, lower GPC1 tMV‐mProtein and Exo‐mRNA expression before treatment correlated significantly with prolonged overall survival. These findings underscore the potential of vesicular GPC1 expression for early PDAC screenings and chemotherapy prognosis.