Search

Abstract Background The global health crisis of obesity has prompted a need for better indicators of abdominal obesity than body mass index, with sagittal abdominal diameter emerging as a potential candidate. Nonetheless, the association between sagittal abdominal diameter-to-height ratio (SADHtR) and mortality remains inadequately established. Our objective was to contribute novel evidence to this association. Methods This study encompassed 12,572 participants aged 18–80 years from the National Health and Nutrition Examination Survey 2011–2016. Mortality data were tracked until December 31, 2019. Weighted multivariable Cox proportional hazard models were employed to evaluate the association between SADHtR and all-cause mortality, with subgroup analyses conducted for result robustness. Results Following a median follow-up period of 69 months, each standard deviation (SD) increase in SADHtR was consistently associated with a higher risk of all-cause mortality across three models, yielding a hazard ratio (HR) and 95% confidence interval (CI) of 1.51(1.29,1.76) in model 3. Additionally, compared to the first tertile of SADHtR, the third tertile exhibited a higher risk for all-cause mortality, with HRs(95%CIs) of 1.58(1.25,2.01) in model 1, 2.01(1.33,3.02) in model 2, and 1.74(1.19,2.57) in model 3. Notably, subgroup analysis revealed persistent positive associations between SADHtR and all-cause mortality among subgroups based on age-at-risk (

Abstract Background This study explored the influence of type 2 diabetes and impaired glucose tolerance (IGT) on the risk of the multimorbidity cluster of cardiovascular disease (CVD) and cancer. Methods A total of 1629 participants in the Da Qing Diabetes Prevention Outcome Study were recruited in the present analysis, including normal glucose tolerance (NGT, N = 492), IGT (N = 540), and newly diagnosed type 2 diabetes (N = 597) groups. Cox proportional hazards analyses were performed to assess the relationship between NGT, IGT, and newly diagnosed type 2 diabetes and the risk of the multimorbidity cluster of CVD and cancer. Results The incidence rates for multimorbidity cluster CVD and cancer were 1.25, 3.17, and 3.23 per 1000 person-years in people with NGT, IGT, and the newly diagnosed type 2 diabetes groups, respectively, over 34-year follow-up. Cox analysis revealed that diabetes status (as time-dependent variable) was significantly associated with the subsequent increased risk of multimorbidity cluster of CVD and cancer compared with non-diabetes (hazard ratios [HR] = 2.55, 95% confidence interval [CI] 1.51–4.31) after adjustment of potential confounders. Similar analysis showed that this risk was significantly higher in the IGT and newly diagnosed type 2 diabetes groups compared with NGT, with HR of 3.28 (95% CI 1.83–5.87) and HR of 3.90 (95% CI 2.14–7.09), respectively. Whereas compared diabetes with IGT group, this risk was not significantly different. Conclusions Similar to newly diagnosed type 2 diabetes, IGT is significantly associated with an increased risk of the multimorbidity cluster of CVD and cancer compared with NGT. This finding highlights the urgent need for an active detection of IGT and effective prevention and management of diabetes.

Abstract Background GM3 synthase deficiency (GM3SD) is an autosomal recessive disorder resulting from mutations in the ST3GAL5 gene. It is characterized by intellectual disability, microcephaly, psychomotor and developmental delay, hearing and visual impairments, and changes in skin pigmentation. This study aims to broaden the genetic mutation spectrum of GM3SD through the report of a de novo mutation and a comprehensive summary of GM3SD phenotype to aid in genetic counseling and prenatal diagnosis. Results Compound heterozygous variants in ST3GAL5 (NM_003896.4: c.1000delC, p.Arg334Glufs*15 and c.207-1G > T, p.Cys70Glufs*81) were identified via trio-whole exome sequencing (trio-WES) and confirmed pathogenic through functional experiments. Notably, c.207-1G > T was a newly discovered variant. Additionally, previously reported GM3SD mutations were classified into R288X and non-R288X, revealing that R288X mutations were more likely to manifest developmental, emotional abnormalities, and severe feeding difficulties. Conclusions This study reveals a novel mutation in ST3GAL5 and provides a comprehensive overview of GM3SD phenotype, aiding in the diagnosis and genetic counseling of GM3SD in clinical practice.

Abstract Background The clinical application of mesenchymal stem cells (MSCs) in myocardial infarction (MI) is severely hampered by their poor survival. Pretreatment is a key strategy that has been adopted to promote their therapeutic efficacy. This study aimed to investigate the benefit of growth differentiation factor 15-pretreated MSCs (GDF15-MSCs) in enhancing cardiac repair following MI and to determine the underlying mechanisms. Methods MSCs with or without GDF15 pretreatment were exposed to serum deprivation and hypoxia (SD/H) challenge. Apoptosis of MSCs was assessed by TUNEL staining. The conditioned media (CM) of MSCs and GDF15-MSCs was collected by centrifugation. MSCs and GDF15-MSCs were transplanted into the peri-infarct region in a mouse model of MI. Cardiac function, fibrosis and MSC survival were examined 4 weeks after MSC transplantation. Results Pretreatment with GDF15 greatly reduced SD/H-induced apoptosis of MSCs via inhibition of reactive oxygen species (ROS) generation by attenuating mitochondrial fission. Mechanistically, GDF15 pretreatment ameliorated mitochondrial fission of MSCs under SD/H challenge by activating the AMPK pathway. These effects were partially abrogated by AMPK inhibitor. Pretreatment with GDF15 also promoted paracrine effects of MSCs in vitro, evidenced by improving tube formation of HUVECs, and inhibited the apoptosis of cardiomyocytes induced by SD/H. At 4 weeks after transplantation, compared with MSCs, GDF15 pretreatment strongly promoted the survival of MSCs in the ischemic heart with consequent enhanced cardiac function, reduced cardiac fibrosis and increased angiogenesis. Conclusions Our study showed that pretreatment with GDF15 promoted the cardioprotective effects of MSCs in MI via regulation of pro-survival signaling and paracrine actions. GDF15 pretreatment is an effective approach to enhance the therapeutic efficacy of MSCs in ischemic heart disease.

Abstract Background Sporting success relies not only on athletes’ physical qualities but also involves psychological, technical, and environmental factors. Given the lack of effective tools to comprehensively measure sporting success in the Chinese context, this study aimed to validate the Chinese version of the Sport Success Scale (SSS-C). Methods A total of 604 adolescent basketball players, comprising 301 (49.8%) males and 303 (50.2%) females aged between 12 and 19 (M = 15.53, SD = 1.42), were recruited from secondary schools across 17 cities in Shandong Province, China, to answer the questionnaire, which measured their views on 29 items through a six-point Likert scale. The SSS was translated into Chinese language (SSS-C) using forward-backward translation techniques. Confirmatory Factor Analysis (CFA) was performed using Mplus 8.0 software to assess the structural validity of SSS-C. The reliability and convergent validity were also evaluated. Results CFA results demonstrated an excellent fit to the hypothesized six-factor model based on the fit indices (CFI = 0.997, TLI = 0.997, RMSEA = 0.016 [90% CI: 0.005, 0.022], SRMR = 0.018). All items displayed significant factor loadings above 0.40, supporting the robustness of the model. The SSS-C exhibited high internal consistency reliability (Cronbach’s α ranged from 0.95 to 0.96; Composite Reliability ranged from 0.95 to 0.96) and strong convergent validity (Average Variance Extracted values > 0.50). Conclusion The SSS-C with 29 items was a valid and reliable instrument for comprehensively assessing sport success among Chinese adolescent athletes. The multidimensional approach of the SSS-C provides a new perspective for understanding the psychological factors contributing to athletes’ success, which can inform the development of targeted interventions.

Abstract AIMS This study investigated the status and influencing factors of organizational silence among 624 nurses in general hospitals in eastern coastal cities of China. Methods This study followed STROBE guidelines. During the period from January to April 2024, the researchers investigated 624 clinical in-service nurses in terms of general information, employee silence behavior, work engagement, and peer support, and analyzed the related factors affecting nurses’ organizational silence. Results The total average score of nurses’ organizational silence was (33.88 ± 6.88), and the total score of work engagement was (69.23 ± 10.76); The total score of the colleague support scale was (90.02 ± 13.72), which was at the medium level. Univariate analysis showed that the scores of organizational silence of 610 nurses had statistical differences in departments, employment methods and professional titles (P

Abstract Background Despite being preventable and curable, leprosy remains endemic in some undeveloped regions, including China. Wenshan Zhuang and Miao Autonomous Prefecture (Wenshan prefecture) currently bears the highest leprosy burden in China. In this ecological study, we aimed to analyze the epidemiological characteristics as well as identify and visualize the high-risk townships of Wenshan prefecture using the most updated leprosy data from 2010 to 2022. Methods Geographical information system combined with spatial scan statistics was used for newly detected leprosy cases abstracted from the Leprosy Management Information System in China. Global Moran’s I index was used to uncover the spatial pattern of leprosy at the township level. Spatial scan statistics, encompassing purely temporal, purely spatial, spatial variation in temporal trends, and space-time analysis, were implemented for detecting the risk clusters. Results Between 2010 and 2022, Wenshan prefecture detected 532 new leprosy cases, comprising 352 (66.17%) males and 180 (33.83%) females. The aggregated time primarily occurred between October 2010 and March 2014. The distribution pattern of newly detected leprosy cases was spatially clustered. We identified four high-risk spatial clusters encompassing 54.51% of the new cases. Furthermore, spatial variation in temporal trends highlighted one cluster as a potential high-risk area. Finally, two space-time clusters were detected, and the most likely cluster was predominantly located in the central and northwest regions of Wenshan prefecture, spanning from January 2010 to September 2013. Conclusions In this ecology study, we characterized the epidemiological features and temporal and spatial patterns of leprosy in Wenshan prefecture using the most recent leprosy data between 2010 and 2022. Our findings offer scientific insights into the epidemiological profiles and spatiotemporal dynamics of leprosy in Wenshan prefecture. Clinicians and policymakers should pay particular attention to the identified clusters for the prevention and control of leprosy.

Abstract Background Early postoperative mobilization is important for enhanced recovery but can be hindered by orthostatic intolerance. However, study on postoperative orthostatic intolerance in thoracoscopic lung resection is limited. Thus, this investigation aims to examine the prevalence and variables contributing to orthostatic intolerance on the first day following thoracoscopic lung cancer resection. Methods A prospective observational study was conducted from February 01 to May 05, 2023, at the First Affiliated Hospital of Chongqing Medical University. Typically, 215 subjects subjected to thoracoscopic lung resection were enrolled in this study. Their general information, disease, and treatment information were collected, and the occurrence of orthostatic intolerance was recorded. Results Typically, 64 patients (29.77%) demonstrated orthostatic intolerance during early mobilization, and 43.75% failed to walk. The prevalence of nausea, dizziness, and impaired vision was 60.94%, 92.19%, and 25.00%, respectively, and no patient experienced syncope. The factors shown to be independently linked with orthostatic intolerance were being female (OR = 2.98, 1.53 to 5.82) and high pain level during sitting (OR = 2.69, 1.79 to 4.04). Individuals with orthostatic intolerance had a longer postoperative hospital stay with a mean of 5.42 days against 4.25 days (p = 0.003). Conclusions Orthostatic intolerance was prevalent following thoracoscopic lung cancer resection and affected patients’ capability to mobilize and prolonged postoperative hospitalization. Being female and having high pain levels during sitting were identified as independent factors for orthostatic intolerance. This suggests that more emphasis should be given to risky patients, and for these groups, we may optimize pain management to adjust the risk of emerging orthostatic intolerance, facilitating early mobilization and early postoperative rehabilitation.

Abstract Background Medical fear is a common psychological reaction in hospitalized children, especially during radiotherapy for central nervous system (CNS) cancers. This fear not only causes negative emotions such as anxiety and depression but also affects children’s quality of life and treatment outcomes. It is exacerbated by factors such as unfamiliar environments during radiation therapy and separation from parents. Child Life, as a professional service, offers physical and mental support to children through medical understanding and psychological preparation, addressing their social and psychological needs, among other things. This study aims to construct a comprehensive Child Life intervention program (CCLIP), consisting of four key components: psychological adjustment and preparation, therapeutic play, pain management and coping strategies, and family support. The integration of effective intervention methods aims to reduce medical fear in children undergoing radiotherapy, promote psychological well-being, improve treatment compliance, and enhance quality of life. Methods This study is a protocol for a randomized controlled trial. Using a random number table method, we plan to recruit 38 eligible children who meet the inclusion criteria and then randomize them into two distinct groups: the intervention group and the control group. The intervention group will receive the CCLIP, and the control group will receive standardized care. Data will be collected through questionnaires and on-site assessments during the one-month intervention period at four distinct time points: the day of admission (T0), the first radiotherapy positioning (T1), mid-radiotherapy (T2), and postradiotherapy (T3). The primary outcome measure is the effectiveness of the CCLIP in reducing medical fear among children receiving radiation treatment for CNS cancers. Secondary outcomes include anxiety, depression, radiation adherence, quality of life among children, and parental satisfaction. Discussion This study aims to alleviate medical fear among children with CNS tumors undergoing radiotherapy through the implementation of the CCLIP while enhancing their mental health and quality of life. The expected outcomes of this research include providing effective intervention strategies for clinical practice, improving the treatment experience and long-term prognosis of children, and having positive impacts on children and their families. Trial registration This study is registered at the Chinese Clinical Trial Registry, ChiCTR2400082622. Registered 2 April, 2024.

Abstract Background and objective Community-acquired pneumonia (CAP) is a common respiratory disease that frequently requires hospitalisation, and is a significant cause of death worldwide. This study aimed to evaluate the usefulness of alpha-1-antichymotrypsin (AACT) as a diagnostic and prognostic biomarker of CAP. Methods We conducted a multicentre prospective cohort study in patients hospitalised with CAP. Plasma AACT levels were measured using a quantitative enzyme-linked immunosorbent assay. Receiver-operating characteristic (ROC) curves and Cox proportional hazards regression were used to assess the association between plasma AACT levels and CAP diagnosis and prognosis. Results A total of 274 patients with CAP were enrolled in the study. AACT levels were elevated in patients with CAP, especially those with severe CAP and non-survivors. The area under the curve (AUC) of AACT and CRP for diagnosing CAP was 0.755 and 0.843. Cox regression showed that CURB-65 and AACT levels were independent predictors of 30-day mortality. ROC curves showed that plasma AACT levels had the highest accuracy for predicting acute respiratory distress syndrome (ARDS), with an AUC of 0.862. Combining AACT with Pneumonia Severity Index and CURB-65 significantly improved their predictive accuracy for predicting 30-day mortality. Conclusion Plasma AACT levels are elevated in patients with CAP, but plasma AACT level is inferior to the C-reactive protein level for diagnosing CAP. The AACT level can reliably predict the occurrence of ARDS and 30-day mortality in patients with CAP.

Abstract Background After a 920-day hiatus, COVID-19 resurged in the Tibet Autonomous Region of China in August 2022. This study compares the characteristics of COVID-19 between high-altitude residents and newcomers, as well as between newcomers and lowlanders. Methods This multi-center cohort study conducted at the Third People’s Hospital of Tibet Autonomous Region and Beijing University Shenzhen Hospital, included 520 high-altitude resident patients, 53 high-altitude newcomer patients, and 265 lowlander patients infected with the Omicron variant. Initially, we documented epidemiological, clinical, and treatment data across varying residency at admission. We compared the severity of COVID-19 and various laboratory indicators, including hemoglobin concentration and SpO2%, over a 14-day period from the date of the first positive nucleic acid test, as well as the differences in treatment methods and disease outcomes between highlanders and high-altitude newcomers. We also compared several characteristics of COVID-19 between high-altitude newcomers and lowlanders. Univariate analysis, multivariable logistic regression, and the generalized linear mixed model were utilized for the analysis. Results No fatalities were observed. The study found no significant differences in COVID-19 severity or in the physiological measures of hemoglobin concentration and SpO2% between high-altitude and lowland residents. Similarly, there were no statistically significant differences in the values or trends of hemoglobin and SpO2% between high-altitude residents and newcomers throughout the 14-day observation period. However, compared to age- and sex-matched lowlander patients (1:5 ratio), high-altitude newcomers exhibited higher heart rates, respiratory rates, and average hemoglobin concentrations, along with lower platelet counts. There were no significant differences in hospital stays between the two groups. Conclusions High-altitude residents and newcomer patients exhibit clinical similarities. However, the clinical characteristics of high-altitude newcomers and lowlander patients differ due to the impact of the high-altitude environment. These results highlight potential considerations for public health strategies in high-altitude regions such as Tibet.

Abstract Thyroid cancer (TC) is a significant global healthcare burden. However, the lack of comprehensive data has impeded our understanding of its global impact. We aimed to examine the burden of TC and its trends at the global, regional, and national levels using data stratified by sociodemographic index (SDI), sex, and age. Data on TC, including incidence, mortality, and disability-adjusted life-years (DALYs) from 1990 to 2021, were obtained from the Global Burden of Disease Study 2021. Estimated annual percentage changes (EAPCs) were calculated to assess the incidence rate, mortality, and DALYs trends. The incidence, mortality, and DALYs of TC in 2021 were 249,538 (95% uncertainty interval: 223,290–274,638), 44,799 (39,925–48,541), and 646,741 (599,119–717,357), respectively. The age-standardized incidence rate (ASIR) in 2021 was 2.914 (2.607–3.213), with an EAPC of 1.25 (1.14–1.37) compared to 1990. In 2021, the age-standardized death rate (ASDR) was 0.53 (0.47–0.575) and age-standardized DALYs rate was 14.571 (12.783–16.115). Compared with 1990, the EAPCs of ASDR and age-standardized DALYs rate showed decreasing trends, at − 0.24 (− 0.27 to − 0.21) and − 0.14 (− 0.17 to − 0.11), respectively. Low SDI regions showed the highest ASDR and age-standardized DALYs rate, at 0.642 (0.516–0.799) and 17.976 (14.18–23.06), respectively. Low-middle SDI regions had the highest EAPCs for ASDR and age-standardized DALYs rate, at 0.74 (0.71–0.78) and 0.67 (0.63–0.7), respectively. Females exhibited decreasing trend in ASDR and age-standardized DALYs rate, with EAPCs of − 0.58 (− 0.61 to − 0.55) and − 0.45 (− 0.47 to − 0.42), respectively. In contrast, males showed an increasing trend in ASDR and age-standardized DALYs rate, with EAPCs of 0.41 (0.35–0.46) for both. In high-income regions, most countries with decreased annual changes in deaths experience increasing age-related deaths. Over the past few decades, a notable increase in TC incidence and decreased mortality has been observed globally. Regions characterized by lower SDI, male sex, and an aging population exhibited no improvement in TC mortality. Effective resource allocation, meticulous control of risk factors, and tailored interventions are crucial for addressing these issues.

Abstract Background Ischemic stroke (IS) is a major cause of death and disability worldwide. Genetic factors are important risk factors for the development of IS. The quinone oxidoreductase 1 gene (NQO1) has antioxidant, anti-inflammatory, and cytoprotective properties. Thus, in this study, we investigated the relationship between NQO1 gene polymorphism and the risk of IS. Methods Peripheral blood was collected from 143 patients with IS and 124 the control groups in Yunnan, China, and NQO1 rs2917673, rs689455, and rs1800566 were genotyped. Logistic regression was used to analyze the relationship between the three NQO1 loci and IS susceptibility. The difference in the expression levels of NQO1 between the control groups and IS groups was verified using public databases and enzyme-linked immunosorbent assay. Results The rs2917673 locus increased the risk of IS by 2.375 times in TT genotype carriers under the co-dominance model compared with CC carriers and was statistically associated with the risk of IS (OR = 2.375, 95% CI = 1.017–5.546, P = 0.046). In the recessive model, TT genotype carriers increased IS risk by 2.407 times compared with CC/CT carriers and were statistically associated with the risk of IS (OR = 2.407, 95% CI = 1.073–5.396, P = 0.033). Conclusions NQO1 rs2917673 polymorphism is significantly associated with IS. Mutant TT carriers are risk factors for IS.

Abstract Purpose Early ambulation is an important step in accelerating post-joint replacement surgery recovery. However, there is limited research on populations who are unable to walk immediately after the operation. The purpose of this study was to determine the factors influencing postoperative ambulation in total knee arthroplasty (TKA) patients. Methods Primary TKA patients were included in this retrospective study. All patients were divided into two groups. Patients who began walking within 24 h were categorized as the early ambulation group, while patients who began walking after 24 h were classified as the late ambulation group. Recorded demographic data included age, gender, body mass index (BMI), clinical diagnosis, and comorbidities. Hematological parameters potentially affecting patients’ preoperative physical condition were also documented. Additionally, intraoperative metrics such as surgical time, surgical side, tourniquet time, intraoperative blood loss, the placement of drains, and prosthetic model were recorded. Results A total of 453 patients (79.0% female, 21.0% male) were included in this study. The average age of all patients was 68.5±7.9 years, ranging from 36 to 87 years, with an average BMI of 27.2±9.9 kg/ $$\mathrm {m^{2}}$$ m 2 . The mean postoperative ambulation time was 1.6 days, with a range of 0–4 days. In univariate group comparisons, an increase in postoperative time to ambulation was significantly associated with a history of heart disease ( $$P

Abstract Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1–STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions. Graphical abstract The schematic figure depicts a mechanism model of the STAT1–STING axis in HFpEF (this figure was drawn using FigDraw software).

Abstract Background Excessive visceral adipose tissue (VAT) is associated with a spectrum of diseases, including diabetes, cancer, and cardiovascular diseases. Remnant cholesterol (RC), denoting cholesterol within triglyceride-rich lipoproteins and their metabolic byproducts, has been identified as a key contributor to cardiovascular diseases and related mortality. However, the association between the VAT and RC remains unclear. In this study, the objective is to provide new evidence regarding the association between VAT and RC concentrations. Methods 4727 individuals aged 18–59 were selected from the National Health and Nutrition Examination Survey conducted between 2011 and 2018 as study participants. This study utilized several weighted linear regression models and a restricted cubic spline (RCS) to explore the association and potential nonlinearities between VAT and RC. Subgroup analyses were performed to determine the consistency of findings. Results The mean VAT value was 103.82 ± 1.42 cm2, and the median RC value was 18 mg/dl. VAT demonstrated a positive association with RC in a fully adjusted model, with a β and 95% confidence interval (CI) of 0.09 (0.08, 0.11) after adjustment for potential confounders. Analysis using RCS revealed a nonlinear association between the VAT area and RC (P

Abstract Background Benefit finding is the search for positive meaning from traumatic events, such as cancer. It can help caregivers have a positive experience in the caregiving process, relieve negative emotions, and reduce caregiving stress. The aim of this study was to explore benefit finding among caregivers of patients with advanced cancer in their palliative caregiving journey. Methods An exploratory qualitative design of phenomenology was used. Semistructured interviews were conducted with 19 caregivers of palliative care patients with advanced cancer. The Colaizzi 7-step analysis was used to analyse, summarize, and extract themes from the interview data. Results The study identified five themes of caregiver benefit finding in the caregiving process: personal growth, strengthened relationships with patients, adjustment and adaptation, perceived social support, and perceived meaning in life. Most caregivers reported a closer, more dependent relationship with the patient, and only one caregiver did not report any positive changes. Conclusions Caregivers of palliative care patients with advanced cancer can have positive experiences in their care. Healthcare professionals should focus on supporting caregivers and helping them find positive experiences to cope with the challenges of caregiving and improve their quality of life.

Abstract Chronic hepatitis B poses a significant global burden, modulating immune cells, leading to chronic inflammation and long-term damage. Due to its hepatotropism, the hepatitis B virus (HBV) cannot infect other cells. The mechanisms underlying the intercellular communication among different liver cells in HBV-infected individuals and the immune microenvironment imbalance remain elusive. Exosomes, as important intercellular communication and cargo transportation tools between HBV-infected hepatocytes and immune cells, have been shown to assist in HBV cargo transportation and regulate the immune microenvironment. However, the role of exosomes in hepatitis B has only gradually received attention in recent years. Minimal literature has systematically elaborated on the role of exosomes in reshaping the immune microenvironment of the liver. This review unfolds sequentially based on the biological processes of exosomes: exosomes’ biogenesis, release, transport, uptake by recipient cells, and their impact on recipient cells. We delineate how HBV influences the biogenesis of exosomes, utilizing exosomal covert transmission, and reshapes the hepatic immune microenvironment. And based on the characteristics and functions of exosomes, potential applications of exosomes in hepatitis B are summarized and predicted. Graphical Abstract

Abstract Objective Polycystic ovary syndrome (PCOS) is an endocrine gynecological disease affecting many women of reproductive age. Clomiphene is the first-line treatment for PCOS patients, but most individuals may be resistant to it. This study aims to assess the efficacy of dexamethasone and clomiphene in the treatment of PCOS patients, and to provide a theoretical basis for clinicians to study and treat PCOS. Methods Chinese and English databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WanFang Medical Network, and VIP Information Chinese Journal Service Platform (VIP) were searched from the inception to January 2023. Review Manager and Stata software were used for meta- analysis. The risk of bias of eligible studies were assessed using Cochrane’s risk of bias tool. Publication bias was assessed by funnel plots, Begg’s and Egger’s tests. Results A total of 12 literatures were finally included, with a total of 1270 PCOS patients. Compared with the control group, dexamethasone combined with clomiphene could significantly improve pregnancy (RR = 1.71, P

Abstract Background Widespread exposure to phthalates may raise the probability of various diseases. However, the association of phthalate metabolites with periodontitis remains unclear. Methods Totally 3402 participants from the National Health and Nutrition Examination Survey (NHANES) 2009 to 2014 cycles were enrolled in the cross-sectional investigation. We utilized weighted logistic regression to evaluate the association of ten phthalate metabolites with periodontitis. Restricted cubic spline analysis was applied to investigate potential nonlinear relationships. Results The weighted prevalence of periodontitis in the study was 42.37%. A one standard deviation (SD) rise in log-transformed levels of mono-2-ethyl-5-carboxypenty phthalate (MECPP), mono-n-butyl phthalate (MnBP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-isobutyl phthalate (MiBP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-benzyl phthalate (MBzP) was associated with higher odds of periodontitis, with odds ratios (95% confidence intervals) of 1.08 (1.02-1.14), 1.07 (1.02-1.11), 1.10 (1.05-1.15), 1.05 (1.01-1.09), 1.09 (1.04-1.14), and 1.08 (1.03-1.13), respectively. Individuals with the highest quartile concentrations of MECPP, MnBP, MEHHP, MEOHP, and MBzP were associated with 32%, 20%, 30%, 25%, and 26% increased odds of periodontitis, respectively, compared to those with the lowest quartile. Additionally, mono-(3-carboxypropyl) phthalate (MCPP) demonstrated an interesting inverted J-shaped relationship with periodontitis. Conclusions The findings indicate an association of certain phthalate metabolites with periodontitis among US adults.

Abstract Background COVID-19 has been shown to increase the risk of extracorporeal coagulation during hemodialysis in patients, but the underlying mechanism remains unclear. This study aimed to investigate the effect and mechanism of COVID-19 on the risk of extracorporeal coagulation in patients with chronic kidney disease undergoing hemodialysis. Methods A retrospective analysis of the extracorporeal coagulation status of 339 hemodialysis patients at our center before and after COVID-19 infection was performed, including subgroup analyses. Post-infection blood composition was analyzed by protein spectrometry and ELISA. Results Compared to the pre-COVID-19 infection period, COVID-19-induced extracorporeal coagulation predominantly occurred in patients with severe/critical symptoms. Further proteomic analysis demonstrated that in patients with severe/critical symptoms, the coagulation cascade reaction, platelet activation, inflammation, and oxidative stress-related pathways were significantly amplified compared to those in patients with no/mild symptoms. Notably, the vWF/FBLN5 pathway, which is associated with inflammation, vascular injury, and coagulation, was significantly upregulated. Conclusions Patients with severe/critical COVID-19 symptoms are at a higher risk of extracorporeal coagulation during hemodialysis, which is associated with the upregulation of the vWF/FBLN5 signaling pathway. These findings highlight the importance of early anticoagulant therapy initiation in COVID-19 patients with severe/critical symptoms, particularly those undergoing hemodialysis. Additionally, vWF/FBLN5 upregulation may be a novel mechanism for virus-associated thrombosis/coagulation.

Abstract Background The development of antiretroviral therapy broadly extends the life expectancy of persons living with HIV (PLHIV). However, stigma and discrimination are still great threat to these individuals and the world's public health care system. Accurate and reproducible measures are prerequisites for robust results. Therefore, it is essential to choose an acceptable measure with satisfactory psychometric properties to assess stigma and discrimination. There has been no systematic review of different stigma and discrimination tools in the field of HIV care. Researchers and clinical practitioners do not have a solid reference for selecting stigma and discrimination measurement tools. Methods We systematically searched English and Chinese databases, including PubMed, EMBASE, CINAHL, Web of Science, PsycINFO, ProQuest Dissertations and Theses, The Cochrane Library, CNKI,, and Wanfang, to obtain literature about stigma and discrimination measurement tools that have been developed and applied in the field of HIV. The search period was from 1st January, 1996 to 22nd November 2021. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guideline (2018 version) was applied to assess the risk of bias for each involved study and summarize the psychometric properties of each tool. The modified version of the Grading of Recommendations Assessment, Development, and, Evaluation (GRADE) method was used to grade the evidence and develop recommendations. Results We included 45 studies and 19 PROMs for HIV/AIDS-related stigma and discrimination among PLHIV. All studies had sufficient methodological quality in content validity, structural validity, internal consistency, and the hypothesis testing of structural validity. Limited evidence was found for cross-cultural validity, stability, and criterion validity. No relevant evidence was found concerning measurement error and responsiveness. The Internalized AIDS-related Stigma Scale (IARSS), Internalized HIV Stigma Scale (IHSS), and Wright's HIV stigma scale (WHSS) are recommended for use. Conclusions This study recommends three PROMs for different stigma and discrimination scenarios, including IARSS for its good quality and convenience, IHSS for its broader range of items, higher sensitivity, and greater precision, and WHSS for its comprehensive and quick screening. Researchers should also consider the relevance and feasibility of the measurements before putting them into practice. Systematic review registration PROSPERO CRD42022308579

Abstract Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-β-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment. Graphical Abstract

Abstract Background The link between low grip strength, diminished physical performance, and adverse health outcomes in older adults has been well-established. However, the impact of older adults who cannot complete these tests on disability and mortality rates remains unexplored without longitudinal study. Methods We collected data from the China Health and Retirement Longitudinal Study (CHARLS). Participants aged 60–101 were enrolled at baseline. We analyzed the prevalence of populations unable to complete handgrip strength (HGS), gait speed (GS), and five times chair stand test (FTCST). Completing risk models were used to estimate the risk of mortality and disability over seven years. Results A total of 3,768 participants were included in the analysis. The percentage of older adults unable to complete the GS and FTCST tests increased notably with age, from 2.68 to 8.90% and 2.60–20.42%, respectively. The proportion of older people unable to perform the HGS was relatively stable, ranging from 1.40 to 3.66%. Compared to older adults who can complete these tests, those who cannot perform FTCST face a significantly higher risk of mortality, with 49.1% higher risk [hazard ratio (HR) = 1.491, 95% CI = 1.156, 1.922; subdistribution hazard ratio (SHR) = 1.491, 95%CI = 1.135,1.958)]. Participants who were unable to complete the GS test had a higher risk of developing ADL disability, regardless of whether they were compared to the lowest-performing group (HR = 1.411, 95%CI = 1.037,1.920; SHR = 1.356, 95%CI = 1.030,1.785) or those who can complete the GS (HR = 1.727, 95%CI = 1.302,2.292; SHR = 1.541, 95%CI = 1.196,1.986). No statistically significant difference in the risk of developing ADL disability among older adults who were unable to complete the HGS test compared with either the poorest performing group (HR = 0.982, 95% CI = 0.578, 1.666; SHR = 1.025, 95% CI = 0.639, 1.642) or those who were able to complete the HGS test (HR = 1.008, 95% CI = 0.601, 1.688; SHR = 0.981, 95% CI = 0.619, 1.553). The risk of all-cause mortality was not significantly different for older adults who were unable to complete the HGS test compared to those with the worst performance (HR = 1.196, 95%CI = 0.709–2.020; SHR = 1.196, 95%CI = 0.674, 2.124) or those who were able to complete the test (HR = 1.462, 95%CI = 0.872–2.450; SHR = 1.462, 95%CI = 0.821,2.605). Conclusion The risks of adverse events faced by older adults unable to complete the tests vary, indicating the necessity for future research to conduct separate analyses on this high-risk population.

Abstract Background For chronic hepatitis B virus (HBV) infection patients, increasing evidence has demonstrated the effectiveness of expanding the indications and applicable population for antiviral therapy. However, the expanded indication of antiviral therapy for hepatocellular carcinoma (HCC) remains to be further explored. Methods 196 HBV-related HCC patients who received radical hepatectomy and nucleos(t)ide analogues (NAs) therapy at Sichuan Provincial People’s Hospital were enrolled in this study. HCC recurrence, overall survival (OS), early virological (VR) and biochemical responses (BR) of patients were compared between different NAs therapy and the use of anti-programmed cell death protein 1 (PD-1) therapy. Results NAs therapy at different timing of surgery was a strong independent risk factor for postoperative recurrence and overall mortality of HBV-related HCC patients. Furthermore, in HCC patients who received postoperative anti-PD-1 therapy, patients with HBV DNA

Abstract Background Impaired collateral formation is a major factor contributing to poor prognosis in type 2 diabetes mellitus (T2DM) patients with atherosclerotic cardiovascular disease. However, the current pharmacological treatments for improving collateral formation remain unsatisfactory. The induction of endothelial autophagy and the elimination of reactive oxygen species (ROS) represent potential therapeutic targets for enhancing endothelial angiogenesis and facilitating collateral formation. This study investigates the potential of molybdenum disulfide nanodots (MoS2 NDs) for enhancing collateral formation and improving prognosis. Results Our study shows that MoS2 NDs significantly enhance collateral formation in ischemic tissues of diabetic mice, improving effective blood resupply. Additionally, MoS2 NDs boost the proliferation, migration, and tube formation of endothelial cells under high glucose/hypoxia conditions in vitro. Mechanistically, the beneficial effects of MoS2 NDs on collateral formation not only depend on their known scavenging properties of ROS (H2O2, •O2 -, and •OH) but also primarily involve a molecular pathway, cAMP/PKA-NR4A2, which promotes autophagy and contributes to mitigating damage in diabetic endothelial cells. Conclusions Overall, this study investigated the specific mechanism by which MoS2 NDs mediated autophagy activation and highlighted the synergy between autophagy activation and antioxidation, thus suggesting that an economic and biocompatible nano-agent with dual therapeutic functions is highly preferable for promoting collateral formation in a diabetic context, thus, highlighting their therapeutic potential. Graphical Abstract

Abstract Background Despite many efforts to control leprosy worldwide, it is still a significant public health problem in low- and middle-income regions. It has been endemic in China for thousands of years, and southwest China has the highest leprosy burden in the country. Methods This observational study was conducted with all newly detected leprosy cases in southwest China from 2010 to 2020. Data were extracted from the Leprosy Management Information System (LEPMIS) database in China. The Joinpoint model was used to determine the time trends in the study area. Spatial autocorrelation statistics was performed to understand spatial distribution of leprosy cases. Spatial scan statistics was applied to identify significant clusters with high rate. Results A total of 4801 newly detected leprosy cases were reported in southwest China over 11 years. The temporal trends declined stably. The new case detection rate (NCDR) dropped from 4.38/1,000,000 population in 2010 to 1.25/1,000,000 population in 2020, with an average decrease of 12.24% (95% CI: −14.0 to − 10.5; P

Abstract Background About 25% of pregnant women experience bleeding in the early stage, and half of them eventually progress to pregnancy loss. Progesterone serves as a useful biomarker to predict miscarriage in threatened miscarriage, yet its performance is still debated. Aim To evaluate the performance of single serum progesterone predicting miscarriage in early pregnant patients with threatened miscarriage. Method The online database was searched to yield the literature using the terms of ‘Abortion’, ‘Miscarriage’, and ‘serum Progesterone’, including PubMed, Scopus, Embase, Cochrane library, and China national knowledge infrastructure. Receiver operating characteristic (ROC) curve, likelihood ratio (LLR) and diagnostic odds ratio (DOR) and 95% confidence interval (CI) were computed. Publication bias was assessed by the deeks funnel plot asymmetry test. Subgroup analyses were conducted according to the progesterone level (

Abstract Objective To investigate the association between circulating secretoneurin (SN) and angiographic coronary collateralization in stable angina patients with chronic coronary total occlusion (CTO). Methods SN concentrations in serum were measured in 641 stable angina patients with CTO by radioimmunoassay. The status of coronary collaterals from the contra-lateral vessel was visually estimated using the Rentrop grading system, and was categorized into poor (grade 0 or 1) or good (grade 2 or 3) collateralization. Results Serum SN levels were significantly higher in patients with good coronary collaterals compared to those with poor collaterals (175.23 ± 52.09 pmol/L vs. 143.29 ± 42.01 pmol/L, P

Abstract Background Osteoporosis (OP) is a progressive metabolic disorder that is difficult to cure clinically. The molecular mechanisms of OP urgently need to be further examined. This study was designed to explore the potential function of circ_0027885 during osteogenic differentiation, as well as the systematic interactions among circ_0027885, miR-203-3p and runt-related transcription factor 2 (RUNX2). Methods Relative levels of circ_0027885, miR-203-3p and RUNX2 were analyzed with RT-qPCR and western blotting. Alizarin red staining was performed to detect the mineralization ability under the control of circ_0027885 and miR-203-3p. Dual-luciferase reporter gene assay was conducted to examine the combination among circ_0027885, miR-203-3p and RUNX2. Results Our research demonstrated that circ_0027885 was significantly increased during hBMSCs differentiation. Overexpression of circ_0027885 notably facilitated osteogenic differentiation and upregulated RUNX2 expression, while knockdown of circ_0027885 reversed the above results. Through prediction on bioinformatics analysis, miR-203-3p was the target binding circ_0027885, and RUNX2 was the potential target of miR-203-3p. Subsequently, these changes induced by the overexpression of circ_0027885 were reversed upon addition of miR-203-3p mimic. Conclusions Circ_0027885 could sponge miR-203-3p to regulate RUNX2 expression and alleviate osteoporosis progression.

Abstract Background Deep vein thrombosis (DVT) is a frequent complication following hip arthroplasty. There still has been a lack of studies analyzing the perioperative risk factors of DVT following hip arthroplasty via direct anterior approach (DAA). Methods Patients who underwent unilateral primary hip arthroplasty via DAA in our hospital from August 2015 to January 2022 were included. Patients’ data, including demographic data, clinical features, past medical history, operative data, and laboratory data, were analyzed and compared between patients with and without DVT. Logistic regression analysis was conducted to identify the independent risk factors. Receiver operating characteristic (ROC) curve analysis was used to assess the best cutoff value of continuous variables with statistical significance. Result A total of 651 patients were included. The incidence of DVT before and after hip arthroplasty was 12.7% and 6.7%, respectively. Logistic regression analysis indicated that age ≥ 65 years (OR 4.594, 95% CI 1.994–10.587), women (OR 2.331, 95% CI 1.285–4.227), and cerebral infarction (OR 1.984, 95% CI 1.138–3.460) were independent risk factors for preoperative DVT. And age ≥ 65 years (OR 4.859, 95% CI 1.062–22.226), tumor (OR 3.622, 95% CI 1.108–11.841), and preoperative D-dimer (OR 1.040, 95% CI 1.004–1.078) were risk factors for postoperative DVT. The ROC curve analysis showed that the best cutoff value of preoperative D-dimer for the diagnosis of postoperative DVT is 1.44 mg/L. Conclusions The incidence of DVT in patients undergoing DAA hip arthroplasty was low and the occurrence of DVT before and after unilateral primary hip arthroplasty performed through DAA was related to multiple factors.

Abstract Background Atherosclerosis (AS), a significant contributor to cardiovascular disease (CVD), is steadily rising with the aging of the global population. Pyroptosis and apoptosis, both caspase-mediated cell death mechanisms, play an essential role in the occurrence and progression of AS. The human pineal gland primarily produces melatonin (MT), an indoleamine hormone with powerful anti-oxidative, anti-pyroptotic, and anti-apoptotic properties. This study examined MT’s anti-oxidative stress and anti-pyroptotic effects on human THP-1 macrophages treated with nicotine. Methods In vitro, THP-1 macrophages were induced by 1 µM nicotine to form a pyroptosis model and performed 30 mM MT for treatment. In vivo, ApoE-/- mice were administered 0.1 mg/mL nicotine solution as drinking water, and 1 mg/mL MT solution was intragastric administrated at 10 mg/kg/day. The changes in pyroptosis, apoptosis, and oxidative stress were detected. Results MT downregulated pyroptosis, whose changes were paralleled by a reduction in reactive oxygen species (ROS) production, reversal of sirtuin3 (SIRT3), and Forkhead box O3 (FOXO3α) upregulation. MT also inhibited apoptosis, mainly caused by the interaction of caspase-1 and caspase-3 proteins. Vivo studies confirmed that nicotine could accelerate plaque formation. Moreover, mice treated with MT showed a reduction in AS lesion area. Conclusions MT alleviates pyroptosis by regulating the SIRT3/FOXO3α/ROS axis and interacting with apoptosis. Importantly, our understanding of the inhibitory pathways for macrophage pyroptosis will allow us to identify other novel therapeutic targets that will help treat, prevent, and reduce AS-associated mortality.

Abstract Background Avian pathogenic Escherichia coli (APEC) causes tracheal damage and heterophilic granulocytic infiltration and inflammation in infected chicks. In this study, we infected chick tracheal tissue with strain AE17 and produced pathological sections with proteomic sequencing. We compared the results of pathological sections from the APEC-infected group with those from the PBS control group; the pathological sections from the experimental group showed hemorrhage, fibrinization, and infiltration of heterophilic granulocytes in the tracheal tissue. In order to explore the effect on proteomics on inflammation and to further search for the caus. Results The tandem mass tag-based (TMT) sequencing analysis showed 224 upregulated and 140 downregulated proteins after infection with the AE17 strain. Based on the results of KEGG in Complement and coagulation cascades, differential protein expression in the Protein export pathway was upregulated. Conclusions With these results, we found that chemokines produced by the Complement and coagulation cascades pathway may cause infiltration of heterophilic granulocytes involved in inflammation, as well as antimicrobial factors produced by the complement system to fight the infection together.These results suggest that APEC causes the infiltration of heterophilic granulocytes through the involvement of the complement system with serine protease inhibitors.

Abstract Objective Droplet digital PCR (ddPCR) is a novel assay to detect pneumocystis jjrovecii (Pj) which has been defined to be more sensitive than qPCR in recent studies. We aimed to explore whether clinical features of pneumocystis pneumonia (PCP) were associated with ddPCR copy numbers of Pj. Methods A total of 48 PCP patients were retrospectively included. Pj detection was implemented by ddPCR assay within 4 h. Bronchoalveolar fluid (BALF) samples were collected from 48 patients with molecular diagnosis as PCP via metagenomic next generation sequencing (mNGS) or quantitative PCR detection. Univariate and multivariate logistic regression were performed to screen out possible indicators for the severity of PCP. The patients were divided into two groups according to ddPCR copy numbers, and their clinical features were further analyzed. Results Pj loading was a pro rata increase with serum (1,3)-beta-D glucan, D-dimmer, neutrophil percentage, procalcitonin and BALF polymorphonuclear leucocyte percentage, while negative correlation with albumin, PaO2/FiO2, BALF cell count, and BALF lymphocyte percentage. D-dimmer and ddPCR copy number of Pj were independent indicators for moderate/severe PCP patients with PaO2/FiO2 lower than 300. We made a ROC analysis of ddPCR copy number of Pj for PaO2/FiO2 index and grouped the patients according to the cut-off value (2.75). The high copy numbers group was characterized by higher level of inflammatory markers. Compared to low copy number group, there was lower level of the total cell count while higher level of polymorphonuclear leucocyte percentage in BALF in the high copy numbers group. Different from patients with high copy numbers, those with high copy numbers had a tendency to develop more severe complications and required advanced respiratory support. Conclusion The scenarios of patients infected with high ddPCR copy numbers of Pj showed more adverse clinical conditions. Pj loading could reflect the severity of PCP to some extent.

Abstract Background We aimed to investigate the interaction between serum uric acid (SUA) levels with estimated glomerular filtration rate (eGFR) to low muscle strength (LMS) among older people in China. Methods Cohort data were obtained from China Health and Retirement Longitudinal Study (CHARLS) in 2011 and 2015. A total of 2,822 community-dwelling adults aged 60 and above were enrolled for the follow-up. Serum uric acid was collected after 8 h of fasting, and handgrip strength was measured with a dynamometer. eGFR was calculated with an equation based on the Chinese population. A generalized additive model was employed for interaction analysis and progressively adjusted confounders. Results During the follow-up, a total of 659 individuals were excluded due to the lack of grip strength data, leaving 2,163 participants for analysis. Despite the protective effect of high uric acid against low muscle strength, especially in older females, it is not statistically significant (OR = 0.69, 95%CI = 0.45–1.04, P = 0.075). Following the progressive adjustment of covariates, the association between higher eGFR and elevated SUA levels remained statistically significant in females, showing a reduced odds ratio with low muscle strength (OR = 0.82, 95%CI = 0.70–0.97, P = 0.021). However, this trend was not observed in male participants. Conclusions This Chinese population-based cohort study suggests that among older females, a higher serum uric acid level combined with a higher estimated glomerular filtration rate is linked to a reduced risk of low muscle strength. This implies that the relationship between high serum uric acid levels and the risk of low grip strength might differ by gender.

Abstract Background Real-world studies assessing the comparative effectiveness of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) as first-line targeted therapy are scarce. We analyzed the real-world persistence and effectiveness of etanercept (ETN), adalimumab (ADA), and Janus kinase inhibitors (JAKis) as first-line therapy in b/tsDMARD-naïve patients with rheumatoid arthritis (RA). Methods Adults (≥ 18 years) enrolled in the CorEvitas RA Registry and initiating ETN, ADA, or a JAKi (alone or in combination with csDMARDs) between November 2012 and June 2021 were included if they had 6 and/or 12 months’ follow-up. Treatment persistence and effectiveness outcomes including the change in Clinical Disease Activity Index (CDAI) and patient-reported outcomes (PROs) were evaluated at follow-up, adjusting for covariates using linear and logistic regression models. An exploratory analysis for patients on monotherapy was also conducted. Results Of 1059 ETN, 1327 ADA, and 581 JAKi initiators; 803 ETN, 984 ADA, and 361 JAKi initiators had 6 months’ follow-up. JAKi initiators were older and had a relatively longer disease duration than ETN or ADA initiators (mean age: 61.3 vs 54.5 and 55.5 years; mean duration of RA: 8.1 vs 5.7 and 5.6 years). Unadjusted mean improvements in CDAI and PROs were similar between the groups at 6 months, except the proportion achieving LDA, remission, and MCID in CDAI, which were numerically higher in the ETN and ADA groups vs JAKi group (LDA: 43.4% and 41.9% vs 32.5%; remission: 18.2% and 15.1% vs 11.5%; MCID: 46.5% and 47.8% vs 38.0%). Adjusted effectiveness results did not reveal statistically significant differences between treatment groups at 6 months, with an exception in MCID (odds ratio [95% CI] for JAKi vs ETN: 0.65 [0.43–0.98]). At 6 months, 68.2% of ETN, 68.5% of ADA, and 66.5% of JAKi initiators remained on therapy. The findings at 12 months’ follow-up and sensitivity analysis among monotherapy initiators also showed no differences in effectiveness outcomes between the groups. Conclusions This analysis of real-world data from the CorEvitas RA Registry did not show differences in clinical effectiveness and treatment persistence rates in b/tsDMARD-naïve patients initiating ETN, ADA, or JAKi as first-line targeted therapy either alone or in combination with csDMARDs.

Abstract Objective To explore the effect of oral comprehensive nursing intervention on mechanically ventilated patients in ICU. Methods Select 76 cases of mechanically ventilated patients in severe ICU admitted to our hospital from January 2022 to October 2022 as the research objects, and divide them into the control group and the observation group according to the way the patients receive oral care. 38 cases each. The patients in the control group received routine nursing intervention, and the patients in the observation group received comprehensive oral nursing intervention on the basis of the nursing of the control group. The clinical index data, oropharyngeal hygiene, pH value, blood gas analysis index levels, and the occurrence and death of ventilator-associated pneumonia were compared between the two groups of patients. Results The hospitalization time of the two groups was compared (P > 0.05); the mechanical ventilation time and ICU stay time of the observation group were significantly lower than those of the control group (all, P

Abstract APEC encodes multiple virulence factors that have complex pathogenic mechanisms. In this study, we report a virulence factor named EspE3, which can be secreted from APEC. This protein was predicted to have a leucine-rich repeat domain (LRR) and may have a similar function to IpaH class effectors of the type III secretion system (T3SS). For further exploration, the regulatory correlation between the espE3 and ETT2 genes in APEC was analysed. We then assessed the pathogenicity of EspE3, detected it in APEC secretion proteins and screened the proteins of EspE3 that interact with chicken trachea epithelial cells. This study provides data on a new virulence factor for further exploring the pathogenic mechanism of APEC.

Abstract Background Prediction tools for various intraoperative bleeding events remain scarce. We aim to develop machine learning-based models and identify the most important predictors by real-world data from electronic medical records (EMRs). Methods An established database of surgical inpatients in Shanghai was utilized for analysis. A total of 51,173 inpatients were assessed for eligibility. 48,543 inpatients were obtained in the dataset and patients were divided into haemorrhage (N = 9728) and without-haemorrhage (N = 38,815) groups according to their bleeding during the procedure. Candidate predictors were selected from 27 variables, including sex (N = 48,543), age (N = 48,543), BMI (N = 48,543), renal disease (N = 26), heart disease (N = 1309), hypertension (N = 9579), diabetes (N = 4165), coagulopathy (N = 47), and other features. The models were constructed by 7 machine learning algorithms, i.e., light gradient boosting (LGB), extreme gradient boosting (XGB), cathepsin B (CatB), Ada-boosting of decision tree (AdaB), logistic regression (LR), long short-term memory (LSTM), and multilayer perception (MLP). An area under the receiver operating characteristic curve (AUC) was used to evaluate the model performance. Results The mean age of the inpatients was 53 ± 17 years, and 57.5% were male. LGB showed the best predictive performance for intraoperative bleeding combining multiple indicators (AUC = 0.933, sensitivity = 0.87, specificity = 0.85, accuracy = 0.87) compared with XGB, CatB, AdaB, LR, MLP and LSTM. The three most important predictors identified by LGB were operative time, D-dimer (DD), and age. Conclusions We proposed LGB as the best Gradient Boosting Decision Tree (GBDT) algorithm for the evaluation of intraoperative bleeding. It is considered a simple and useful tool for predicting intraoperative bleeding in clinical settings. Operative time, DD, and age should receive attention.

Abstract Background Insulin resistance (IR) is an important determinant of glucose metabolic disturbance and placental dysplasia in gestational diabetes mellitus (GDM). Calcium/calmodulin dependent protein kinase IV (CAMK4) improves insulin IR induced by a high-fat diet (HFD). The current study sought to elucidate the role and potential mechanism of CAMK4 in GDM. Methods A GDM model was established in female C57BL/6J mice via HFD feeding for one week before mating and throughout gestation. The IR was elicited by 10–6 M insulin treatment for 48 h in HTR-8/SVneo cells and mouse primary trophoblast cells. The function of CAMK4 was investigated by transfection of overexpression plasmid in HTR-8/SVneo cells and infection of lentivirus loaded with CAMK4 encoding sequence in primary trophoblast cells. Real-time PCR, western blot, cell counting kit-8, transwell, wound healing, dual-luciferase reporter assay, and liquid chromatography/mass spectrometry-based untargeted metabolomics were performed to confirm the effects of CAMK4 on trophoblast cells. Results Decreased CAMK4 expression was found in the placenta of GDM mice. CAMK4 overexpression ameliorated IR-induced viability impairment, migratory and invasive capacity inhibition, autophagy blocking, insulin signaling inactivation and glucose uptake disorder in trophoblast cells. CAMK4 also transcriptionally activated orphan nuclear receptor NUR77, and the effects of CAMK4 were abrogated by silencing of NUR77. Metabolomics analysis revealed that CAMK4 overexpression caused alterations of amino acid, lipid and carbohydrate metabolism, which were important in GDM. Conclusion Our results indicated that CAMK4/NUR77 axis may provide novel potential targets in GDM treatment.

Abstract Cancer stem cells (CSCs) are considered to be responsible for tumor recurrence and metastasis. Therefore, clarification of the mechanisms involved in CSC stemness maintenance and cell fate determination would provide a new strategy for cancer therapy. Unregulated cellular energetics has been accepted as one of the hallmarks of cancer cells, but recent studies have revealed that mitochondrial metabolism can also actively determine CSC fate by affecting nuclear stemness gene expression. Herein, from the perspective of mito-nuclear communication, we review recent progress on the influence of mitochondria on CSC potential from four aspects: metabolism, dynamics, mitochondrial homeostasis, and reactive oxygen species (ROS). Video Abstract

Abstract Background The NSD2 p.E1099K (EK) mutation is shown to be enriched in patients with relapsed acute lymphoblastic leukemia (ALL), indicating a role in clonal evolution and drug resistance. Results To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we perform Hi-C on three B-ALL cell lines heterozygous for NSD2 EK. The NSD2 mutation leads to widespread remodeling of the 3D genome, most dramatically in terms of compartment changes with a strong bias towards A compartment shifts. Systematic integration of the Hi-C data with previously published ATAC-seq, RNA-seq, and ChIP-seq data show an expansion in H3K36me2 and a shrinkage in H3K27me3 within A compartments as well as increased gene expression and chromatin accessibility. These results suggest that NSD2 EK plays a prominent role in chromatin decompaction through enrichment of H3K36me2. In contrast, we identify few changes in intra-topologically associating domain activity. While compartment changes vary across cell lines, a common core of decompacting loci are shared, driving the expression of genes/pathways previously implicated in drug resistance. We further perform RNA sequencing on a cohort of matched diagnosis/relapse ALL patients harboring the relapse-specific NSD2 EK mutation. Changes in patient gene expression upon relapse significantly correlate with core compartment changes, further implicating the role of NSD2 EK in genome decompaction. Conclusions In spite of cell-context-dependent changes mediated by EK, there appears to be a shared transcriptional program dependent on compartment shifts which could explain phenotypic differences across EK cell lines. This core program is an attractive target for therapeutic intervention.

Abstract Background Vitamin E is an essential nutrient in human body famous for its antioxidant and non-antioxidant functions. However, little is known about vitamin E deficiency status in urban adults of Wuhan from central China. Our aim is to describe the distribution of both circulating and lipid-adjusted serum vitamin E concentration in urban adults of Wuhan. Methods We hypothesized that the prevalence rate of vitamin E deficiency would be low in Wuhan in consideration of the Chinese food composition. A cross-sectional study with 846 adults was performed in a single-center. Concentrations of vitamin E were measured by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). Results The median (interquartile range, IQR) of serum vitamin E concentration was 27.40 (22.89–33.20) μmol/L while that of serum vitamin E concentration adjusted by total cholesterol or the sum of cholesterol (TC) and triglyceride (TG) (the sum of cholesterol and triglyceride, TLs) were 6.20 (5.30–7.48) and 4.86 (4.10–5.65) mmol/mol, respectively. No significant difference of the circulating and TC-adjusted vitamin E concentration was found between male and female except for vitamin E/TLs. However, concentrations of vitamin E increased significantly (r = 0.137, P

Abstract Background This study aimed to develop cardiovascular disease (CVD) risk equations for Chinese patients with newly diagnosed type 2 diabetes (T2D) to predict 10-, 20-, and 30-year of risk. Methods Risk equations for forecasting the occurrence of CVD were developed using data from 601 patients with newly diagnosed T2D from the Da Qing IGT and Diabetes Study with a 30-year follow-up. The data were randomly assigned to a training and test data set. In the training data set, Cox proportional hazard regression was used to develop risk equations to predict CVD. Calibration was assessed by the slope and intercept of the line between predicted and observed probabilities of outcomes by quintile of risk, and discrimination was examined using Harrell’s C statistic in the test data set. Using the Sankey flow diagram to describe the change of CVD risk over time. Results Over the 30-year follow-up, corresponding to a 10,395 person-year follow-up time, 355 of 601 (59%) patients developed incident CVD; the incidence of CVD in the participants was 34.2 per 1,000 person-years. Age, sex, smoking status, 2-h plasma glucose level of oral glucose tolerance test, and systolic blood pressure were independent predictors. The C statistics of discrimination for the risk equations were 0.748 (95%CI, 0.710–0.782), 0.696 (95%CI, 0.655–0.704), and 0.687 (95%CI, 0.651–0.694) for 10-, 20-, and 30- year CVDs, respectively. The calibration statistics for the CVD risk equations of slope were 0.88 (P = 0.002), 0.89 (P = 0.027), and 0.94 (P = 0.039) for 10-, 20-, and 30-year CVDs, respectively. Conclusions The risk equations forecast the long-term risk of CVD in patients with newly diagnosed T2D using variables readily available in routine clinical practice. By identifying patients at high risk for long-term CVD, clinicians were able to take the required primary prevention measures.

Abstract Background Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown. Results We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated Kv1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring Kv1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice. Conclusions These results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy.

Abstract The type VI secretion system (T6SS) is a secretion apparatus widely found in pathogenic Gram-negative bacteria and is important for competition among various bacteria and host cell pathogenesis. Hcp is a core component of functional T6SS and transports toxic effectors into target cells by assembling to form tube-like structures. Studies have shown that Hcp simultaneously acts as an effector to influence cellular physiological activities; however, the mechanism of its activity in host cells remains unclear. To investigate the target of effector protein Hcp2a in a chicken fibroblast cell line, we first detected the subcellular localization of Hcp2a in DF-1 cells by indirect immunofluorescence assay. The results showed that Hcp2a protein was localized in the endoplasmic reticulum of DF-1 cells. We also used a streptavidin–biotin affinity pull-down assay combined with LC–MS/MS to screen DF-1 cell lysates for proteins that interact with Hcp2a and analyze the cellular functional pathways affected by them. The results showed that Hcp2a interacted with 52 DF-1 cellular proteins that are involved in multiple intracellular pathways. To further explore the mechanism of Hcp2a protein targeting the endoplasmic reticulum of DF-1 cells, we screened three endoplasmic reticulum-associated proteins (RSL1D1, RPS3A, and RPL23) from 52 prey proteins of Hcp2a for protein–protein molecular docking analysis. The docking analysis showed that the effector protein Hcp2a and the RPL23 protein had good complementarity. Overall, we propose that Hcp2a has strong binding activity to the RPL23 protein in DF-1 cells and this may help Hcp2a anchor to the endoplasmic reticulum in DF-1 cells.

Abstract Background CTCF is a well-established chromatin architectural protein that also plays various roles in transcriptional regulation. While CTCF biology has been extensively studied, how the domains of CTCF function to regulate transcription remains unknown. Additionally, the original auxin-inducible degron 1 (AID1) system has limitations in investigating the function of CTCF. Results We employ an improved auxin-inducible degron technology, AID2, to facilitate the study of acute depletion of CTCF while overcoming the limitations of the previous AID system. As previously observed through the AID1 system and steady-state RNA analysis, the new AID2 system combined with SLAM-seq confirms that CTCF depletion leads to modest nascent and steady-state transcript changes. A CTCF domain sgRNA library screening identifies the zinc finger (ZF) domain as the region within CTCF with the most functional relevance, including ZFs 1 and 10. Removal of ZFs 1 and 10 reveals genomic regions that independently require these ZFs for DNA binding and transcriptional regulation. Notably, loci regulated by either ZF1 or ZF10 exhibit unique CTCF binding motifs specific to each ZF. Conclusions By extensively comparing the AID1 and AID2 systems for CTCF degradation in SEM cells, we confirm that AID2 degradation is superior for achieving miniAID-tagged protein degradation without the limitations of the AID1 system. The model we create that combines AID2 depletion of CTCF with exogenous overexpression of CTCF mutants allows us to demonstrate how peripheral ZFs intricately orchestrate transcriptional regulation in a cellular context for the first time.

Abstract Liver fibrosis is a chronic liver disease with the presence of progressive wound healing response caused by liver injury. Currently, there are no approved therapies for liver fibrosis. Exosomes derived from human adipose mesenchymal stem cells (hADMSCs-Exo) have displayed a prominent therapeutic effect on liver diseases. However, few studies have evaluated therapeutic effect of hADMSCs-Exo in liver fibrosis and cirrhosis, and its precise mechanisms of action remain unclear. Herein, we investigated anti-fibrotic efficacy of hADMSCs-Exo in vitro and in vivo, and identified important metabolic changes and the detailed mechanism through transcriptomic and metabolomic profiling. We found hADMSCs-Exo could inhibit the proliferation of activated hepatic stellate cells through aggravating apoptosis and arresting G1 phase, effectively inhibiting the expression of profibrogenic proteins and epithelial-to-mesenchymal transition (EMT) in vitro. Moreover, it could significantly block collagen deposition and EMT process, improve liver function and reduce liver inflammation in liver cirrhosis mice model. The omics analysis revealed that the key mechanism of hADMSCs-Exo anti-hepatic fibrosis was the inhibition of PI3K/AKT/mTOR signaling pathway and affecting the changes of metabolites in lipid metabolism, and mainly regulating choline metabolism. CHPT1 activated by hADMSCs-Exo facilitated formation and maintenance of vesicular membranes. Thus, our study indicates that hADMSCs-Exo can attenuate hepatic stellate cell activation and suppress the progression of liver fibrosis, which holds the significant potential of hADMSCs-Exo for use as extracellular nanovesicles-based therapeutics in the treatment of liver fibrosis and possibly other intractable chronic liver diseases. Graphical Abstract

Abstract Wound healing depends largely on the remodeling of the extracellular matrix around and reorganization of tissue-resident cells. Matrix remodeling associated 7 (MXRA7) is a member of the matrix remodeling-associated gene family and is involved in matrix remodeling-associated processes, such as inflammatory neovascularization, liver injury, and autoimmune skin disease. To investigate whether and how MXRA7 participate in cutaneous wound healing, an ear-punching model was utilized in wild-type (WT) and MXRA7-deficient mice, and the dermal fibroblasts from these mice were further studied in vitro. Results showed that the MXRA7 deficiency impaired the wound healing process in mice. Quantitative PCR indicated that lack of MXRA7 impaired the expression of several extracellular matrix genes (e.g., MMP-2) and inhibited signaling pathways (e.g., STAT3) in healing ear tissues. In in vitro culture system, migration, contraction, or proliferation of fibroblasts was impaired upon MXRA7 deficiency. Pull-down and mass spectrum assay revealed that vimentin was among the proteins that bound MXRA7 proteins in cells, and further investigations indicate MXRA7 was an autocrine factor in fibroblasts that involved vimentin in certain ways, such as JNK and STAT3/STAT5 signaling pathways in our study. In conclusion, MXRA7 proteins promote wound healing through vimentin in coordinating fibroblast functions.