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Objectives The purpose of this review is to summarise the evidence from a systematic review and meta-analysis of observational studies that objectively measure daily steps and health outcomes.Design This is an umbrella review.Data sources PubMed, Embase, Scopus, the Cochrane Library and Web of Science databases were searched through 31 January 2024.Eligibility We included systematic reviews of observational studies (with or without meta-analysis) that assessed the association of objectively measured daily steps with human health-related outcomes. Methodological quality was assessed using ‘A MeaSurement Tool to Assess systematic Reviews 2’.Results A total of 10 systematic reviews and 6 health outcomes were included after excluding irrelevant and duplicate studies. Higher daily steps were associated with more benefits than harms for a range of health-related outcomes, including all-cause mortality, cardiovascular event, skeletal muscle lesions, metabolic diseases and respiratory disease. A dose-response analysis showed that an increase of 500–1000 steps per day was associated with lower all-cause mortality and cardiovascular events. Beneficial associations were also found in patients with asthma and acutely hospitalised older adults. Conversely, one study within a systematic review suggested that higher daily steps (≥10 000) might be associated with an increased 52% risk of meniscal pathologies in individuals without knee osteoarthritis. However, one study within a systematic review suggested a potential increased risk of meniscal pathologies in individuals without knee osteoarthritis. Specifically, those exceeding 10 000 steps per day showed a 52% increase in risk.Conclusion The results of this study suggest that daily steps are associated with a lower risk of all-cause mortality and cardiovascular events. Future research could focus on identifying specific populations that may benefit most from increased daily steps and exploring potential mechanisms to enhance our understanding of how daily steps contribute to improved health outcomes.PROSPERO registration number CRD42022347055.

Background The majority of anti-programmed cell-death 1 (PD-1) monoclonal antibodies (mAbs) use S228P mutation IgG4 as the structural basis to avoid the activation of immune cells or complement. However, little attention has been paid to the Fc–Fc interactions between IgG4 and other IgG Fc fragments that could result in adverse effects. Fc-null IgG1 framework is a potential safer alternative to avoid the undesirable Fc–Fc interactions and Fc receptor binding derived effects observed with IgG4. This study provides a comprehensive evaluation of anti-PD-1 mAbs of these two frameworks.Methods Trastuzumab and rituximab (both IgG1), wildtype IgG1 and IgG4 were immobilized on nitrocellulose membranes, coated to microplates and biosensor chips, and bound to tumor cells as targets for Fc–Fc interactions. Wildtype IgG1 and IgG4, anti-PD-1 mAb nivolumab (IgG4 S228P), penpulimab (Fc-null IgG1), and tislelizumab (Fc-null IgG4 S228P-R409K) were assessed for their binding reactions to the immobilized IgG proteins and quantitative kinetic data were obtained. To evaluate the effects of the two anti-PD-1 mAbs on immune responses mediated by trastuzumab and rituximab in the context of combination therapy, we employed classic immune models for antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement dependent cytotoxicity. Tumor-bearing mouse models, both wildtype and humanized, were used for in vivo investigation. Furthermore, we also examined the effects of IgG1 and IgG4 on diverse immune cell populationsResults Experiments demonstrated that wildtype IgG4 and nivolumab bound to immobilized IgG through Fc–Fc interactions, diminishing antibody-dependent cell-mediated cytotoxicity and phagocytosis reactions. Quantitative analysis of kinetic parameters suggests that nivolumab and wildtype IgG4 exhibit comparable binding affinities to immobilized IgG1 in both non-denatured and denatured states. IgG4 exerted inhibitory effects on various immune cell types. Wildtype IgG4 and nivolumab both promoted tumor growth in wildtype mouse models. Conversely, wildtype IgG1, penpulimab, and tislelizumab did not show similar adverse effects.Conclusions Fc-null IgG1 represents a safer choice for anti-PD-1 immunotherapies by avoiding both the adverse Fc–Fc interactions and Fc-related immune inhibitory effects of IgG4. Fc-null IgG4 S228P-R409K and Fc-null IgG1 displayed similar structural properties and benefits. This study contributes to the understanding of immunotherapy resistance and the advancement of safer immune therapies for cancer.

Objectives To explore associations between adverse birth outcomes and childhood overweight at 3–8 years of age.Design A prospective cohort study.Setting Six central urban districts of Tianjin, China.Participants 1681 woman–child pairs.Methods 1681 woman–child pairs were followed up for 8 years in Tianjin, China. Demographic and clinical information including birth outcomes was collected longitudinally, commencing from first antenatal care visit till postpartum period. Offspring height and weight were measured at 3–8 years of age. High and low weight/length ratios (WLR) at birth were, respectively, defined as ≥90th and ≤10th gestational week and sex-specific percentiles. Overweight for children at 3–5 and 6–8 years of age were, respectively, defined as body mass index (BMI)-for-age and -sex above the 2 z-score and 1 z-score curves of the WHO’s child growth standards. Binary logistic regression analysis was used to obtain ORs and 95% CI with a stepwise backward selection method to select independent predictors.Primary outcomes measures Childhood overweight.Results Of 1681 children, 10.7% (n=179) and 27.8% (n=468) developed overweight at 3–5 and 6–8 years of age, respectively. Large for gestational age (LGA) was associated with increased risk of overweight at 3–5 years of age (aOR: 1.86, 95% CI: 1.27 to 2.72) while high WLR at birth was associated with increased risk of overweight at 6–8 years of age (1.82, 1.41 to 2.34). Low WLR at birth was associated with decreased risk of overweight at 6–8 years of age (0.52, 0.30 to 0.90).Conclusions LGA and high WLR at birth predicted childhood overweight at 3–5 and 6–8 years of age, respectively. Low WLR at birth was associated with decreased risk of childhood overweight at 6–8 years of age.

Background Antineoplastic chemotherapies are dramatically efficient when they provoke immunogenic cell death (ICD), thus inducing an antitumor immune response and even tumor elimination. However, activated caspases, the hallmark of most cancer chemotherapeutic agents, render apoptosis immunologically silent. Whether they are dispensable for chemotherapy-induced cell death and the apoptotic clearance of cells in vivo is still elusive.Methods A rational cell-based anticancer drug library screening was performed to explore the immunogenic apoptosis pathway and therapeutic targets under apoptotic caspase inhibition. Based on this screening, the potential of caspase inhibition in enhancing chemotherapy-induced antitumor immunity and the mechanism of actions was investigated by various cells and mouse models.Results Heat shock protein 90 (Hsp90) inhibition activates caspases in tumor cells to produce abundant genomic and mitochondrial DNA fragments and results in cell apoptosis. Meanwhile, it hijacks Caspase-9 signaling to suppress intrinsic DNA sensing. Pharmacological blockade or genetic deletion of Caspase-9 causes tumor cells to secrete interferon (IFN)-β via tumor intrinsic mitochondrial DNA/the second messenger cyclic GMP–AMP (cGAS) /stimulator of interferon genes (STING) pathway without impairing Hsp90 inhibition-induced cell death. Importantly, both Caspase-9 and Hsp90 inhibition triggers an ICD, leading to the release of numerous damage-associated molecular patterns such as high-mobility group box protein 1, ATP and type I IFNs in vitro and remarkable antitumor effects in vivo. Moreover, the combination treatment also induces adaptive resistance by upregulating programmed death-ligand 1 (PD-L1). Additional PD-L1 blockade can further overcome this acquired immune resistance and achieve complete tumor regression.Conclusions Blockade of Caspase-9 signaling selectively provokes Hsp90-based chemotherapy-mediated tumor innate sensing, leading to CD8+ T cell-dependent tumor control. Our findings implicate that pharmacological modulation of caspase pathway increases the tumor-intrinsic innate sensing and immunogenicity of chemotherapy-induced apoptosis, and synergizes with immunotherapy to overcome adaptive resistance.

Introduction Impaired physical function is relatively common in children/adolescents with chronic kidney disease (CKD), affecting not only patients’ daily lives but also the efficiency of later treatment and rehabilitation. Exercise is a recognised intervention to improve physical function and quality of life in adult patients with CKD. However, implementing this strategy in paediatric/adolescent populations remains relatively limited. For exercise training to be widely delivered as part of paediatric public health policy, a better understanding of the physical function and the impact of exercise interventions in children/adolescents with CKD is needed.Methods and analysis A systematic review and meta-analysis will be conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to compare physical function in children/adolescents with CKD with healthy controls and the impact of exercise interventions on their outcomes. The systematic review will search the following databases: PubMed, Embase, Scopus and Web of Science. We will use the Risk Of Bias In Non-Randomised Studies-of Interventions and the second edition of the Cochrane Risk of Bias to assess the quality of the literature. Where feasible, we will conduct random effects meta-analyses where appropriate. If possible, we will conduct subgroup analyses to explore potential sources of heterogeneity.Ethics and dissemination Due to the nature of the protocol, ethical approval is not required. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to disseminate the study results through publication and conference presentations.PROSPERO registrationnumber CRD42023416208.

Introduction In China, older adults have the highest incidence of type 2 diabetes mellitus (T2DM). Bone, joint and physical endurance limit the types of exercise available to older adults with T2DM. Baduanjin is recommended and encouraged as an exercise option. However, Baduanjin exercise alone cannot account for the loss of muscle mass. Resistance training is recommended in the guidelines and offers new options for increasing muscle strength. The purpose of this study is to compare the effects of Elastic-band Baduanjin exercise training with those of Baduanjin alone.Methods and analysis This study is a reworking exercise programme, consisting of Baduanjin combined with elastic band resistance exercise training. A 12-week randomised controlled trial will be conducted. Patients aged 60–80 years with T2DM will be assigned to the Elastic-band Baduanjin (intervention) and Baduanjin (control) groups using cluster random sampling. A sample of 70 participants will be conducted. Indicators of muscle strength, body composition, blood glucose and balance function will be collected before and after the intervention. Meanwhile, exercise will be monitored using the International Physical Activity Questionnaire.Ethics and dissemination The trial was approved by the Chinese Ethics Committee of Registering Clinical Trials on 19 June 2022 (ChiECRCT20220210). The research results will be published in peer-­reviewed publications.Trial registration number Chinese Clinical Trials Registry (ChiCTR2200062424).

Introduction Surgery is one of the main approaches for the comprehensive treatment of early and locally advanced non-small cell lung cancer (NSCLC). This study conducts a nationwide multicentre study to explore factors that could influence the outcomes of patients with I–IIIA NSCLC who underwent curable surgery in real-world scenarios.Methods and analysis All patients diagnosed with NSCLC between January 2013 and December 2020 will be identified from 30 large public medical services centres in mainland China. The algorithm of natural language processing and artificial intelligence techniques were used to extract data from electronic health records of enrolled patients who fulfil the inclusion criteria. Six categories of parameters are collected and stored from the electronic records, then the parameters will be structured as a high-quality structured case report form. The code book will be compiled and each parameter will be classified and designated a code. In addition, the study retrieves the survival status and causes of death of patients from the Chinese Centre for Disease Control and Prevention. The primary endpoints are overall survival and the secondary endpoint is disease-free survival. Finally, an online platform is formed for data queries and the original records will be stored as secure electronic documents.Ethics and dissemination The study has been approved by the Ethical Committee of the Chinese Academy of Medical Sciences. Study findings will be disseminated via presentations at conferences and publications in open-access journals. This study has been registered in the Chinese Trial Register (ChiCTR2100052773) on 11 May 2021, http://www.chictr.org.cn/showproj.aspx?proj=136659.Trial registration number ChiCTR2100052773.

Objective Evidence suggests that both serum uric acid (SUA) and high-density lipoprotein cholesterol (HDL-C) are risk factors for chronic kidney disease (CKD). The SUA-to-HDL-C ratio (UHR) has recently attracted attention as a new biomarker to evaluate the role between inflammatory and anti-inflammatory substances. Thus, we explored the association between UHR and CKD in a large Chinese population.Design A cross-sectional study.Setting Annual health check-up population in Nanjing.Participants 19 458 individuals who underwent an annual health check-up in 2019 were included in our study.Main outcome measure CKD was diagnosed according to an estimated glomerular filtration rate (eGFR)

Introduction Globally, rheumatic heart disease (RHD) is an important cause of acquired heart disease in children and adolescents. Clinical trials on RHD treatment with Traditional Chinese Medicine (TCM) or integrated medicine are gradually increasing in China. However, because the outcomes of clinical trials are subject to heterogeneity and selective reporting, similar studies cannot be merged and compared, complicating assessing the effectiveness and safety of TCM, and diminishing the value of clinical trials. Therefore, there is an urgent need to design a TCM or integrated medicine core outcome set (COS) for RHD.Methods and analysis The development of this study will take place in four stages under the direction of a multidisciplinary advisory board. (1) Establishing a comprehensive outcomes checklist through a systematic review of previously published research, retrieval of clinical trial registration centres, patient’s semistructured interviews, and clinician’s questionnaire surveys; (2) Screen stakeholder groups from various fields to participate in the Delphi survey; (3) Two e-Delphi surveys will be conducted to determine the outcomes of various concerned stakeholder groups; (4) Hold a face-to-face consensus meeting to develop the COS-TCM-RHD.Ethics and dissemination The ethical approval for this study has been obtained from the Tianjin University of Traditional Chinese Medicine Ethics Committee (TJUTCM-EC20210008). The findings will be disseminated in peer-reviewed journals and meetings.Trial registration number This study has been registered at the Core Outcome Measures in Effectiveness Trials (COMET) database (Registration #1743).

Objective To explore the current Chinese and English guidelines of urinary tract infection (UTI) in children and provide a summary of the recommendations of the guidelines.Methods An electronic search was conducted on databases, including Pubmed, SinoMed, Wangfang Data, CHKD,VIP, NICE, WHO, GIN and Medliveto retrieve data of the clinical practice guidelines on UTI from the establishment of the database to June 2020. Four assessors assessed the quality of guidelines using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) and evaluated the specific recommendations in guidelines.Results (1) Nine guidelines including two from the USA (AAP and A guideline for the inpatient care of children with pyelonephritis) and the remaining from EAU/ESPU, SINEPE, KHA-CARI, CPS, ISPN, NICE and CMA-CSP were explored. (2) The AGREE II evaluation demonstrated higher scores of UTI guidelines in terms of ‘scope and purpose’ (72.99%±11.19%) and ‘clarity of presentation’ (75.62%±7.75%), whereas the average scores were lower in the aspect of ‘stakeholder involvement’ (35.49%±14.41%), ‘rigour of development’ (37.05%±10.05%), ‘applicability’ (37.75%±11.98%) and ‘editorial independence’ (43.06%±48.14%). The average scores of the guidelines were as follows: SINePe (72.57%), CMA-CSP (62.96%), EAU/ESPU (59.61%), AAP (56.86%), NICE (47.54%), CPS (40.93%), KHA-CARI (38.86%), ISPN (38.63%) and A guideline for the inpatient care of children with pyelonephritis (34.72%). (3) All the selected guidelines basically reached a consensus on urine sample retention methods in older children, the antibiotic treatment course and renal and bladder ultrasonography application but lacked a conclusion on the determination of urine culture results, the choice of voiding cystourethrography and Tc-99mdimercaptosuccinicacid, and antibiotic prophylaxis.Conclusion There remains a need to improve the quality of guidelinesfor UTI in clinical practice. Existing controversies on the current guidelines of UTI in some recommendations warrant further exploration to provide more evidence on formulating more unified and practical guidelines in the future.Ethics and dissemination No ethical approval is required for this research, as it did not include patients or patient data.

Background The importance of psychosocial functioning in the assessment, diagnosis and treatment of major depressive disorder (MDD) is widely recognised. However, there is a lack of effective scales to assess psychosocial functioning in patients with MDD.Aims To develop a professional questionnaire to evaluate the psychosocial functioning of patients with MDD.Methods Using a literature review, an open-ended questionnaire survey, and patient interviews, a theoretical model of psychosocial functioning was constructed, and an initial questionnaire was formed which included four dimensions. After two rounds of testing, using items analysis and exploratory factor analysis, a finalized questionnaire was created. There were 460 patients with MDD selected from six psychiatric hospitals for formal testing using a convenience sampling method. Forty patients were randomly selected and retested one week later to evaluate the test-retest reliability of the scale. The Patient Health Questionnaire-9 (PHQ-9), Short Form of Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF), Sheehan Disability Scale (SDS), and Dysfunctional Attitudes Scale (DAS) provided major standards to check the criterion validity of this questionnaire. Correlation analysis, confirmatory factor analysis, and internal consistency reliability testing were used to examine other psychometric characteristics of the finalized questionnaire.Results The Psychosocial Functioning Questionnaire (PFQ) for patients with MDD included three dimensions: psychological cognitive functioning, subjective well-being, and social functioning, with a total of 18 items. The overall internal consistency reliability of the questionnaire was 0.957, and the test-retest reliability was 0.840. Confirmatory factor analysis showed that the model fitted well: Goodness of Fit Index (GFI)=0.888; Root Mean SquareError of Approximation (RMSEA)=0.085. The total score of PFQ was significantly correlated with the total score of PHQ-9, DAS, SDS and Q-LES-Q-SF (|r|=0.599–0.870, p

Objectives To characterise low-tier female sex workers (FSWs) who engage in commercial sex with old male clients (OMCs).Design Cross-sectional study.Setting Twenty-one counties in Zhejiang province, China.Participants A total of 2647 low-tier FSWs who participated in our survey from September to November 2013, and responded to the question regarding whether they engaged in commercial sex with OMCs during the previous month.Main outcome measures Data on sociodemographic characteristics, sexual behaviours, risk perception of HIV/sexually transmitted infection (STI), ever exposure to an HIV prevention service and degree of self-efficacy regarding condom use were collected via a face-to-face questionnaire administered by trained interviewers.Results Of the 2647 participants, 1165 (44.0%) had engaged in commercial sex with OMCs in the previous month. Low-tier FSWs working out of roadside shops, those who had engaged in sex work for longer, those with a larger number of clients, those who had engaged in anal or oral sex during the previous month, those currently using contraception measures, those who had STI symptoms and those who had been exposed to HIV prevention services during the previous 6 months were more likely to engage in commercial sex with OMCs. FSWs with a high level of education; those working out of small venues other than streets, hair salons and roadside shops; those who charged more for commercial sex; those who had sex with young clients during the previous month and those who had seen a doctor during the previous 6 months were less likely to engage in commercial sex with OMCs.Conclusions Low-tier FSWs who engaged in commercial sex with OMCs reported more risky behaviours than those who did not engage in this behaviour. Attention should be paid to these behaviours in future interventions targeting low-tier FSWs.

Background The clinical benefits of antiprogrammed cell death protein 1 (PD-1) therapy are compromised by resistance in immunologically cold tumors. Convergence of immunotherapy and bioengineering is potential to overcome the resistance. Mesoporous silica nanoparticles (MSNs) are considered the most promising inorganic biological nanomaterials for clinical transformation, however, the fundamental influence of MSNs on immunotherapy is unclear. In this study, we aimed to investigate the role of MSNs in tumor resensitization and explore the feasibility of MSNs combined with anti-PD-1 in cancer therapy.Methods Intrinsic and acquired resistant tumors, as well as spontaneous and secondary tumor recurrence models, were used to evaluate the influence of MSNs and the synergistical effect with anti-PD-1 therapy. The roles of CD8+ cytotoxic T-lymphocytes (CTLs) and macrophages were assessed in Rag-1-/- mice, ovalbumin/OT-1 TCR transgenic T-cell system, and other blocking mice models. Mechanistic studies were processed by transcriptomics analysis and conducted in primary cells, in vitro coculture systems, and Toll-like receptor 4 (TLR4) knockout mice.Results Both granular and rod-shaped MSNs efficiently overcame tumor resistance with dependence on diameter and aspect ratio. Only once injection of MSNs in prior to anti-PD-1 markedly improved the treatment efficacy, protective immunity, and prognosis. MSNs per se boosted infiltration of CTLs as the early event (days 2–3); and synergistically with anti-PD-1 therapy, MSNs rapidly established a T cell-inflamed microenvironment with abundant high-activated (interferon-γ/tumor necrosis factor-α/Perforin/GranzymeB) and low-exhausted (PD-1/lymphocyte-activation gene 3 (LAG-3)/T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)) CTLs. Chemokines Ccl5/Cxcl9/Cxcl10, which were produced predominantly by macrophages, promoted MSNs-induced CTLs infiltration. MSNs led to high Ccl5/Cxcl9/Cxcl10 production in vitro and in mice through regulating TLR4-NFκB axis. Blocking TLR4-NFκB axis in macrophages or CTLs infiltration abrogated MSNs-induced resensitization to anti-PD-1 therapy.Conclusions MSNs efficiently and rapidly inflame immunologically cold tumors and resensitize them to anti-PD-1 therapy through TLR4-NFκB-Ccl5/Cxcl9/Cxcl10 axis. MSNs-based theranostic agents can serve as sensitizers for patients with resistant tumors to improve immunotherapy.

Case presentation Here we report a case of refractory EOC in a patient who had relapsed after multiline chemotherapy. The patient received autologous T cells that contained sequences encoding single-chain variable fragments specific for MSLN and full-length antibody for PD-1 (αPD-1). The modified T cells were called αPD-1-mesoCAR-T cells. After infusion, the copy number and PD-1 antibody secretion of the CAR-T cells were increased in the blood. By application of multimodality tumor tracking, MRI of the liver showed shrinkage of metastatic nodules from average diameter of 71.3–39.1 mm at month 2. The patient achieved partial response and survived more than 17 months. IL-6 levels in the patient fluctuated from the baseline to 2–4-folds after treatment, but side effects were mild with only grade 1 hypertension and fatigue.Conclusion αPD-1-mesoCAR-T cell therapy combined with apatinib demonstrates a potential therapeutic effect on advanced refractory ovarian cancer.Trial registration number NCT03615313.

Background Burn-out among doctors threatens their own health, and that of their patients. To identify risk factors of the doctor burn-out is vital to improving their health and increasing the quality of healthcare services. This study aims to explore the relationship between work-family conflict (WFC) and burn-out among Chinese doctors and the mediating role of coping styles in this relationship.Methods A cross-sectional survey was conducted in China, with a questionnaire packet which consisted of the Chinese Maslach Burnout Inventory (CMBI), WFC Scale and the Simplified Coping Style Questionnaire (SCSQ). A total of 2530 doctors participated in the survey. Correlation analysis was performed to explore the relationship between CMBI, WFC and SCSQ scores. A linear regression model was set to determine the mediating role of coping styles on the relationship between WFC and burn-out.Results Doctors who had higher scores on work interfering with family conflict, reported more emotional exhaustion (r=0.514, P

Objective: To explore the association between three-dimensional (3D) cardiac magnetic resonance (CMR) feature tracking (FT) right ventricular peak global longitudinal strain (RVpGLS) and major adverse cardiovascular events (MACEs) in patients with stage C or D heart failure (HF) with non-ischaemic dilated cardiomyopathy (NIDCM) but without atrial fibrillation (AF).Methods: Patients with dilated cardiomyopathy were enrolled in this prospective cohort study. Comprehensive clinical and biochemical analysis and CMR imaging were performed. All patients were followed up for MACEs.Results: A total of 192 patients (age 53±14 years) were eligible for this study. A combination of cardiovascular death and cardiac transplantation occurred in 18 subjects during the median follow-up of 567 (311, 920) days. Brain natriuretic peptide, creatinine, left ventricular (LV) end-diastolic volume, LV end-systolic volume, right ventricular (RV) end-diastolic volume and RVpGLS from CMR were associated with the outcomes. The multivariate Cox regression model adjusting for traditional risk factors and CMR variables detected a significant association between RVpGLS and MACEs in patients with stage C or D HF with NIDCM without AF. Kaplan-Meier analysis based on RVpGLS cut-off value revealed that patients with RVpGLS <-8.5% showed more favourable clinical outcomes than those with RVpGLS ≥-8.5% (p=0.0037). Subanalysis found that this association remained unchanged.Conclusions: RVpGLS-derived from 3D CMR FT is associated with a significant prognostic impact in patients with NIDCM with stage C or D HF and without AF. [ABSTRACT FROM AUTHOR]

Objectives: Osteophytes are highly prevalent in osteoarthritis (OA) and are associated with pain and functional disability. These pathological outgrowths of cartilage and bone typically form at the junction of articular cartilage, periosteum and synovium. The aim of this study was to identify the cells forming osteophytes in OA.Methods: Fluorescent genetic cell-labelling and tracing mouse models were induced with tamoxifen to switch on reporter expression, as appropriate, followed by surgery to induce destabilisation of the medial meniscus. Contributions of fluorescently labelled cells to osteophytes after 2 or 8 weeks, and their molecular identity, were analysed by histology, immunofluorescence staining and RNA in situ hybridisation. Pdgfrα-H2BGFP mice and Pdgfrα-CreER mice crossed with multicolour Confetti reporter mice were used for identification and clonal tracing of mesenchymal progenitors. Mice carrying Col2-CreER, Nes-CreER, LepR-Cre, Grem1-CreER, Gdf5-Cre, Sox9-CreER or Prg4-CreER were crossed with tdTomato reporter mice to lineage-trace chondrocytes and stem/progenitor cell subpopulations.Results: Articular chondrocytes, or skeletal stem cells identified by Nes, LepR or Grem1 expression, did not give rise to osteophytes. Instead, osteophytes derived from Pdgfrα-expressing stem/progenitor cells in periosteum and synovium that are descendants from the Gdf5-expressing embryonic joint interzone. Further, we show that Sox9-expressing progenitors in periosteum supplied hybrid skeletal cells to the early osteophyte, while Prg4-expressing progenitors from synovial lining contributed to cartilage capping the osteophyte, but not to bone.Conclusion: Our findings reveal distinct periosteal and synovial skeletal progenitors that cooperate to form osteophytes in OA. These cell populations could be targeted in disease modification for treatment of OA. [ABSTRACT FROM AUTHOR]

Objectives: Increasing data about COVID-19 have been acquired from the general population. We aim to further evaluate the clinical characteristics of COVID-19 in patients with systemic autoimmune diseases (AIDs).Methods: We included all confirmed inpatients with COVID-19 and systemic AIDs in Wuhan Tongji Hospital from 29 January to 8 March 2020. We retrospectively collected and analysed information on epidemiology of 1255 inpatients and additional clinical characteristics of patients with systemic AIDs. Outcomes were followed up until 16 April 2020.Results: Of the 1255 patients with COVID-19, the median age was 64.0 years and 53.1% were male. More than half (63.0%) had chronic comorbidities. The proportions of elderly, male and patients with comorbidities were significantly higher in intensive care unit (ICU) than in the general ward (p<0.001). 17 (0.61%) patients with systemic AIDs were further screened and analysed from 2804 inpatients. The median age was 64.0 years and 82.4% were female. All patients were living in Wuhan and two family clusters were found. 1 (5.9%) patient was admitted to ICU and one died. 10 (62.5%) of 16 patients changed or stopped their anti-AIDs treatments during hospitalisation, and 5 of them felt that the disease had worsened after the quarantine.Conclusions: Older males with chronic comorbidities are more vulnerable to severe COVID-19. The lower proportion of COVID-19 in patients with systemic AIDs needs more high-quality human clinical trials and in-depth mechanism researches. Of note, the withdrawal of anti-AIDs treatments during hospitalisation can lead to flares of diseases. [ABSTRACT FROM AUTHOR]

Objective: We sought to explore the prevalence and immediate clinical implications of acute myocardial injury in a cohort of patients with COVID-19 in a region of China where medical resources are less stressed than in Wuhan (the epicentre of the pandemic).Methods: We prospectively assessed the medical records, laboratory results, chest CT images and use of medication in a cohort of patients presenting to two designated covid-19 treatment centres in Sichuan, China. Outcomes of interest included death, admission to an intensive care unit (ICU), need for mechanical ventilation, treatment with vasoactive agents and classification of disease severity. Acute myocardial injury was defined by a value of high-sensitivity troponin T (hs-TnT) greater than the normal upper limit.Results: A total of 101 cases were enrolled from January to 10 March 2020 (average age 49 years, IQR 34-62 years). Acute myocardial injury was present in 15.8% of patients, nearly half of whom had a hs-TnT value fivefold greater than the normal upper limit. Patients with acute myocardial injury were older, with a higher prevalence of pre-existing cardiovascular disease and more likely to require ICU admission (62.5% vs 24.7%, p=0.003), mechanical ventilation (43.5% vs 4.7%, p<0.001) and treatment with vasoactive agents (31.2% vs 0%, p<0.001). Log hs-TnT was associated with disease severity (OR 6.63, 95% CI 2.24 to 19.65), and all of the three deaths occurred in patients with acute myocardial injury.Conclusion: Acute myocardial injury is common in patients with COVID-19 and is associated with adverse prognosis. [ABSTRACT FROM AUTHOR]

Background: The advents of novel immunotherapies have revolutionized the treatment of cancer. Adoptive cellular therapies using chimeric antigen receptor T (CAR-T) cells have achieved remarkable clinical responses in B cell leukemia and lymphoma but the effect on solid tumors including lung cancer is limited. Here we present data on the therapeutic potential of allogeneic CD3+CD4-CD8- double negative T (DNT) cells as a new cellular therapy for the treatment of lung cancer and underlying mechanisms. Methods: DNTs were enriched and expanded ex vivo from healthy donors and phenotyped by flow cytometry. Functionally, their cytotoxicity was determined against primary and established non-small-cell lung cancer (NSCLC) cell lines in vitro or through in vivo adoptive transfer into xenograft models. Mechanistic analysis was performed using blocking antibodies against various cell surface and soluble markers. Furthermore, the role of IL-15 on DNT function was determined. Results: We demonstrated that ex vivo expanded DNTs can effectively lyse various human NSCLC cells in vitro and inhibit tumor growth in xenograft models. Expanded DNTs have a cytotoxic phenotype, as they express NKp30, NKG2D, DNAM-1, membrane TRAIL (mTRAIL), perforin and granzyme B, and secrete IFNγ and soluble TRAIL (sTRAIL). DNTmediated cytotoxicity was dependent on a combination of tumor-expressed ligands for NKG2D, DNAM-1, NKp30 and/or receptors for TRAIL, which differ among different NSCLC cell lines. Furthermore, stimulation of DNTs with IL-15 increased expression of effector molecules on DNTs, their TRAIL production and cytotoxicity against NSCLC in vitro and in vivo. Conclusion: Healthy donor-derived DNTs can target NSCLC in vitro and in vivo. DNTs recognize tumors via innate receptors which can be up-regulated by IL-15. DNTs have the potential to be used as a novel adoptive cell therapy for lung cancer either alone or in combination with IL-15. [ABSTRACT FROM AUTHOR]

Introduction Osteoporotic fracture is one of the most common causes of disability and a major contributor to medical care costs in many regions of the world. The polymorphisms of genes related to vitamin D metabolism and transportation are associated with variation in bone mineral density and the risk of osteoporosis. Methods and analysis The China Community-based Cohort of Osteoporosis study is an observational, longitudinal, multicentre, prospective cohort study for middle-aged and older permanent residents of China, which has been ongoing in six cities since 2016. Female residents aged 45–80 years old and male residents aged 50–80 years old are identified through permanent resident lists. All the enrolled participants will complete questionnaires on their personal characteristics and histories. The bone mineral density of their lumbar vertebrae and left hip will be measured and serum bone metabolism parameters assessed. Polymorphisms of genes related to vitamin D metabolism and transportation will be detected, and their relationship with the risk of osteoporosis, and osteoporotic fracture, will be analysed. About 18 000 residents will be involved in the study. Ethics and dissemination The study was approved by Institutional Ethics Board of Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine (2016LCSY065). Results will be published in peer-reviewed journals. The results of this study are expected to improve the understanding of the association between polymorphisms of genes related to vitamin D metabolism and transportation and the risk of osteoporosis and osteoporotic fracture among middle-aged and older residents of China. [ABSTRACT FROM AUTHOR]

Objectives To investigate the relationship between right-to-left shunt and migraine to account for the unexplained high prevalence of migraine in patients with epilepsy. Design This is a cross-sectional study. The diagnosis and interview process of patients with migraine was based on the International Classification of Headache Disorders-3 beta in patients with epilepsy. Participants underwent transthoracic echocardiography (TTE) with contrast medium to identify right-to-left shunt. The highest number of microbubbles were recorded in the left atrium before the complete microbubble outflow of the right atrium. A moderate-to-large shunt was defined as the presence of 10 or more microbubbles. Setting A single-centre, cross-sectional study in China, 2015-2017. Participants Patients with epilepsy. Primary and secondary outcome measures The primary outcome measures were the prevalence of migraine, the prevalence of right-to-left shunt in patients with migraine and those without migraine, and the prevalence of migraine in different degrees of shunting. Results Three hundred thirty-nine participants with epilepsy who completed TTE were included in the analysis. The overall prevalence of migraine was 23.0%. One-third of the migraineurs had mild right-to-left shunt and onefifth of the migraineurs had moderate-to-large right-to-left shunt. Patients with mild shunt did not have a higher prevalence of migraine than those without shunt (26.3% vs 18.1%, p=0.102); however, a higher prevalence of migraine was found in patients with moderate-to-large shunt (39.0% vs 18.1%, OR=2.90, 95% CI=1.41 to 5.98, p=0.003). Patients with migraine and patients without migraine had similar prevalence of mild shunt; however, patients with migraine had more moderate-to-large shunt (20.5% vs 9.6%, p=0.002). Right-to-left shunt and female were factors predicting migraine prevalence. Conclusions One-fifth of migraineurs were correlated with moderate-to-large right-to-left shunt which could be an underlying cause of migraine in epilepsy. [ABSTRACT FROM AUTHOR]

Background: Burn-out among doctors threatens their own health, and that of their patients. To identify risk factors of the doctor burn-out is vital to improving their health and increasing the quality of healthcare services. This study aims to explore the relationship between workfamily conflict (WFC) and burn-out among Chinese doctors and the mediating role of coping styles in this relationship. Methods: A cross-sectional survey was conducted in China, with a questionnaire packet which consisted of the Chinese Maslach Burnout Inventory (CMBI), WFC Scale and the Simplified Coping Style Questionnaire (SCSQ). A total of 2530 doctors participated in the survey. Correlation analysis was performed to explore the relationship between CMBI, WFC and SCSQ scores. A linear regression model was set to determine the mediating role of coping styles on the relationship between WFC and burn-out. Results: Doctors who had higher scores on work interfering with family conflict, reported more emotional exhaustion (r=0.514, P<0.001) and had a sense of accomplishment (r=-0.149, P<0.001). Simultaneously, family interfering with work (FIW) was positively associated with all dimensions of burn-out (r=0.213, 0.504, 0.088, respectively, P<0.001). Coping styles had partial, complete and even mediating effects on the relationship between WFC and burn-out among Chinese doctors. Conclusions: WFC was correlated with burn-out, and coping style was a mediator in this relationship among Chinese doctors. Coping style was a positive resource against burnout. [ABSTRACT FROM AUTHOR]

Objectives Men who have sex with men (MSM) are a marginalised population at high risk for a variety of mental health problems that may mutually facilitate HIV transmission. We assessed factors associated with depressive symptoms among MSM, which can provide some guidance for future mental health interventions with the MSM population for prevention of HIV infection and transmission. Methods A cross-sectional study was conducted in Wenzhou city, China using respondent-driven sampling (RDS) between December 2013 and June 2014. A faceto- face questionnaire survey was employed to collect information about mental and psychosocial health conditions and sexual behaviour characteristics among MSM. Bivariate and multivariable logistic regression analyses were used to identify factors associated with major depressive symptoms. Results Of the 454 participants in the study, prevalence of major depressive symptoms was 34.6%. During the past 6 months, 85% had anal sex with men, and rate of consistent condom use during anal intercourse was 45.1%. Of the respondents, 16.1% reported suicidal ideation, 62.6% had a history of smoking and 41.4% had a history of drinking alcohol, of which 46.3% reported that they were once drunk. Drug use was reported in 3.7% of the sample. Adult sexual violence from same-sex partners was 7.9%, and 5.1% reported childhood sexual abuse. ARDS-weighted multivariable analysis showed that major depressive symptoms among MSM were associated with inconsistent condom use during anal sex with men, multiple oral male sexual partners, suicidal ideation, adult sexual violence from male partners and being once drunk in the past year. Conclusion We found high levels of depressive symptoms, unprotected sex and suicidal ideation among MSM. Comprehensive intervention strategies that combine psychological, behavioural and social aspects are needed to address the mental health issues of MSM, with special attention given to suicidality and high-risk behaviours in mental health and HIV prevention interventions. [ABSTRACT FROM AUTHOR]

Objectives Many clinical studies have indicated that obstructive sleep apnoea (OSA), the most common chronic sleep disorder, may affect neurocognitive function, and that treatment for continuous positive airway pressure (CPAP) has some neurocognitive protective effects against the adverse effects of OSA. However, the effects of CPAP treatment on neurocognitive architecture and function remain unclear. Therefore, this multicentre trial was designed to investigate whether and when neurocognitive architecture and function in patients with OSA can be improved by CPAP treatment and to explore the role of gut microbiota in improving neurocognitive function during treatment. Methods/design This study will be a multicentre, randomised, controlled trial with allocation concealment and assessor blinding. A total of 148 eligible patients with moderate to severe OSA will be enrolled from five sleep centres and randomised to receive CPAP with best supportive care (BSC) intervention or BSC intervention alone. Cognitive function, structure and function of brain regions, gut microbiota, metabolites, biochemical variables, electrocardiography, echocardiography, pulmonary function and arterial stiffness will be assessed at baseline before randomisation and at 3, 6 and 12 months. Ethics and dissemination This study has been approved by the Medical Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (approval number 2015-79). The results from this study will be published in peer-reviewed journals and at relevant conferences. [ABSTRACT FROM AUTHOR]

Objective: To use a computational approach to investigate the cellular and extracellular matrix changes that occur with age in the knee joints of mice.Methods: Knee joints from an inbred C57/BL1/6 (ICRFa) mouse colony were harvested at 3-30 months of age. Sections were stained with H&E, Safranin-O, Picro-sirius red and antibodies to matrix metalloproteinase-13 (MMP-13), nitrotyrosine, LC-3B, Bcl-2, and cleaved type II collagen used for immunohistochemistry. Based on this and other data from the literature, a computer simulation model was built using the Systems Biology Markup Language using an iterative approach of data analysis and modelling. Individual parameters were subsequently altered to assess their effect on the model.Results: A progressive loss of cartilage matrix occurred with age. Nitrotyrosine, MMP-13 and activin receptor-like kinase-1 (ALK1) staining in cartilage increased with age with a concomitant decrease in LC-3B and Bcl-2. Stochastic simulations from the computational model showed a good agreement with these data, once transforming growth factor-β signalling via ALK1/ALK5 receptors was included. Oxidative stress and the interleukin 1 pathway were identified as key factors in driving the cartilage breakdown associated with ageing.Conclusions: A progressive loss of cartilage matrix and cellularity occurs with age. This is accompanied with increased levels of oxidative stress, apoptosis and MMP-13 and a decrease in chondrocyte autophagy. These changes explain the marked predisposition of joints to develop osteoarthritis with age. Computational modelling provides useful insights into the underlying mechanisms involved in age-related changes in musculoskeletal tissues. [ABSTRACT FROM AUTHOR]

Introduction: Traditional Chinese medicine (TCM) has accumulated some experience in curing stable angina pectoris (SAP) and efficacy has been demonstrated. Chinese patent medicines, known as modern dosage forms of TCM, can attain the desired effect in clinical application only with the guidance of TCM syndrome theory. However, due to their use by a large number of persons with little knowledge of TCM theories and practices, their efficacy and reputation have been seriously affected. Method and analysis: Two common syndrome types of SAP in TCM, 'qi deficiency and blood stasis' and 'qi stagnation and blood stasis', will be studied in 144 subjects from four TCM hospitals in Tianjin in China using a partial crossover design. The two syndromes will be broken down into six symptom combinations; patients will select a combination of the most distressing to them, and then will be randomised into two groups. Each group, on the basis of routine medication, will be administered one kind of Chinese patent drug: Qishenyiqi Dripping Pills or Compound Danshen Dripping Pills. The treatment characteristics of the two medicines will be evaluated with the COME-PIO method developed by our research team. [ABSTRACT FROM AUTHOR]