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Abstract Background Left ventricular hypertrophy (LVH) is a critical factor in heart failure and cardiovascular event-related mortality. While the prevalence of LVH in diabetic patients is well-documented, its occurrence and risk factors in non-diabetic populations remain largely unexplored. This study addresses this issue by investigating the independent risk factors of LVH in non-diabetic individuals. Methods This cross-sectional study, conducted meticulously, utilized data from a robust and comprehensive source, DATADRYAD, in the Sierra Leone database, collected between October 2019 and October 2021, including LVH and various variables. All variables were described and screened using univariate analysis, Spearman correlation, and principal component analysis (PCA). The lipid profile, including total cholesterols (TC), triglycerides (TG), high-density lipoprotein (HDL-C), non-high-density lipoprotein (Non-HDL-C), and low-density lipoprotein cholesterol (LDL-C), TC/HDL-C ratio, TG/HDL-C ratio, Non-HDL-C /HDL-C ratio and LDL-C/HDL-C ratio, which quartiles were treated as categorical variables, with the lowest quartile serving as the reference category. Three adjusted models were constructed to mitigate the influence of other variables. To ensure the robustness of the model, receiver operating characteristic (ROC) curves were used to calculate the cutoff values by analyzing the ROC curves. A sensitivity analysis was performed to validate the findings further. Results The dataset encompasses information from 2092 individuals. After adjusting for potential factors that could influence the results, we found that TC (OR = 2.773, 95%CI: 1.805–4.26), Non-HDL-C (OR = 2.74, 95%CI: 1.7723–4.236), TC/HDL-C ratio (OR = 2.237, 95%CI: 1.445–3.463), Non-HDL-C/HDL-C ratio (OR = 2.357, 95%CI: 1.548–3.588), TG/HDL-C ratio (OR = 1.513, 95%CI: 1.02–2.245) acts as independent risk factors of LVH. ROC curve analysis revealed the predictive ability of blood lipids for LVH, with Non-HDL-C exhibiting area under the curve (AUC = 0.6109), followed by TC (AUC = 0.6084). Conclusions TC, non-HDL-C, TC/HDL-C ratio, Non-HDL-C/HDL-C ratio, and TG/HDL-C ratio were independent risk factors of LVH in non-diabetic people. Non-HDL-C and TC were found to be essential indicators for predicting the prevalence of LVH.

Abstract Background With the conflict between the promise of ageing in health and longevity and the limited availability of health resources and social support, older adults in China inevitably experience anxieties surrounding health risks. This study aims to investigate how older adults perceive the health risks that come with getting older, explore the degree to which health risks affect older adults, and advocate for active engagement in practices for managing health risks. Methods Using purposive sampling, three districts of Beijing (Xicheng District, Fengtai District, and Daxing District, respectively) were selected for the research. Qualitative semi-structured and in-depth interviews were conducted with 70 community-dwelling older adults who participated in the study. Data were extracted and analyzed based on a thematic framework approach. Results Three main themes were identified: (i) the anxieties of older adults concerning health risks in ageing; (ii) the priorities of older adults for health risk management in ageing; (iii) the expectations of older adults for health risk management in ageing. The primary health concerns among older adults included disease incidence and function decline. It was found that basic health management emerged as a critical need for older adults to mitigate health risks. Moreover, it was observed that healthcare support for older adults from familial, institutional, and governmental levels exhibited varying degrees of inadequacy. Conclusions The primary source of anxieties among older adults regarding health risks predominantly stems from a perceived sense of health deprivation. It is often compounded by persistent barriers to primary care of priorities in managing health risks among older adults. In addition, the expectations of older adults for health risk management emphasize the necessity for integrated care approaches. Therefore, further research should give priority to the prevention and management of health risks, aim to reduce anxieties, provide integrated care to meet the primary needs and expectations of older adults, and ultimately strive toward the overarching goal of promoting health and longevity.

Abstract Background Bawei Chenxiang Wan (BCW) is among the most effective and widely used therapies for coronary heart disease and angina pectoris in Tibet. However, whether it confers protection through a right-ventricle (RV) myocardial metabolic mechanism is unknown. Methods Male Sprague–Dawley rats were orally administrated with BCW, which was injected concurrently with a bolus of Sugen5416, and subjected to hypoxia exposure (SuHx; 5000 m altitude) for 4 weeks. Right ventricular hypertrophy (RVH) in high-altitude heart disease (HAHD) was assessed using Fulton’s index (FI; ratio of RV to left ventricle + septum weights) and heart-weight-to-body-weight ratio (HW/BW). The effect of therapeutic administration of BCW on the RVH hemodynamics was assessed through catheterization (mean right ventricular pressure and mean pulmonary artery pressure (mRVP and mPAP, respectively)). Tissue samples were used to perform histological staining, and confirmatory analyses of mRNA and protein levels were conducted to detect alterations in the mechanisms of RVH in HAHD. The protective mechanism of BCW was further verified via cell culture. Results BCW considerably reduced SuHx-associated RVH, as indicated by macro morphology, HW/BW ratio, FI, mPAP, mRVP, hypertrophy markers, heart function, pathological structure, and myocardial enzymes. Moreover, BCW can alleviate the disorder of glucose and fatty acid metabolism through upregulation of carnitine palmitoyltransferase1ɑ, citrate synthase, and acetyl-CoA and downregulation of glucose transport-4, phosphofructokinase, and pyruvate, which resulted in the reduced levels of free fatty acid and lactic acid and increased aerobic oxidation. This process may be mediated via the regulation of sirtuin 3 (SIRT3)-hypoxia-inducible factor 1α (HIF1α)-pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) signaling pathway. Subsequently, the inhibition of SIRT3 expression by 3-TYP (a selective inhibitor of SIRT3) can reverse substantially the anti-RVH effect of BCW in HAHD, as indicated by hypertrophy marker and serum myocardial enzyme levels. Conclusions BCW prevented SuHx-induced RVH in HAHD via the SIRT3-HIF1ɑ-PDK/PDH signaling pathway to alleviate the disturbance in fatty acid and glucose metabolism. Therefore, BCW can be used as an alternative drug for the treatment of RVH in HAHD.

Vehicle-sharing services are now integrating electric vehicles (EVs) into their sharing systems. Electric vehicle sharing (EVS) is a convenient and cost-effective approach to reducing the use of internal combustion engine vehicles and improving traffic flow. However, the randomness in the charging load transfer eventually affects the reliability of a distribution network that contains microgrids. This study analyzes the spatiotemporal transfer characteristics of the EVS charging load in a distribution network that contains microgrids in different geographical areas. Combined with the improved charging load model, a reliability evaluation model of the charging load transfer is developed based on the Gauss-Markov movement model, which describes the spatiotemporal transfer characteristics of a distribution network with high accuracy. Moreover, the sequential Monte Carlo method for evaluating the reliability of a distribution network that contains microgrids is improved so that considers charging load transfer. Different scenarios, i.e., randomness of charging load transfer, number of EVS, charging locations of the main feeder lines in the microgrid, and the configuration of the wind-photovoltaic-storage power generation capacity are considered in evaluating the impact of charging load transfer on a distribution network that contains microgrids. The results could serve as a basis for integrating EVS into vehicle-sharing networks considering efficient charging load transfer in distribution network that contains microgrids.

Background: This cohort study was conducted to devise an approximation formula for predicting the glomerular filtration rate (GFR) after 1 year using annual medical examination data from the general population. Methods: Consecutive annual medical examination data were obtained for 41,337 inhabitants. Machine learning with the random forest method was used to assess the importance of each clinical parameter in terms of its association with estimated GFR (eGFR) after 1 year. An approximation formula was developed by multiple linear regression analysis based on the four most important clinical parameters. The relationship between the GFR after 1 year approximated by our formula and the eGFR after 1 year was analyzed using Pearson’s correlation coefficient. Results: The following approximation formula was obtained by multiple linear regression analysis: approximate GFR after 1 year (mL/min/1.73 m2) = −0.054 × age + 0.162 × hemoglobin − 0.085 × uric acid + 0.849 × eGFR + 11.5. The approximate GFR after 1 year was significantly and strongly correlated with the eGFR at that time (r = 0.884; p < 0.001). Conclusions: An approximation formula including age, hemoglobin, uric acid, and eGFR may be useful for predicting GFR after 1 year among members of the general population.

IntroductionCells expressing taste signaling elements in non-gustatory tissues have been described as solitary chemosensory cells (SCCs) or tuft cells. These “taste-like” cells play a critical role in the maintenance of tissue homeostasis. Although the expression of SCC markers and taste signaling constituents has been identified in mouse gingivae, their role in periodontal homeostasis is still unclear. MethodsPublic RNA sequencing datasets were re-analyzed and further validated with RT-PCR/qRT-PCR and immunofluorescent staining to explore the expression of TAS2Rs and downstream signaling constituents in mouse gingival fibroblasts (MGFs). The specific action of salicin on MGFs via Tas2r143 was validated with RNA silence, heterologous expression of taste receptor/Gα-gustducin and calcium imaging. The anti-inflammatory effects of salicin against LPS-induced MGFs were investigated in cell cultures, and were further validated with a ligature-induced periodontitis mouse model using Ga-gustducin-null (Gnat3−/−) mice. ResultsThe expression of Tas2r143, Gnat3, Plcb2, and TrpM5 was detected in MGFs. Moreover, salicin could activate Tas2r143, elicited taste signaling and thus inhibited LPS-induced chemokines expression (CXCL1, CXCL2, and CXCL5) in MGFs. Consistently, salicin-treatment inhibited periodontal bone loss, inflammatory/chemotactic factors expression, and neutrophil infiltration in periodontitis mice, while these effects were abolished in Gnat3−/− mice. DiscussionGingival fibroblasts play a critical role in the maintenance of periodontal homeostasis via “SCC-like” activity. Salicin can activate Tas2r143-mediated bitter taste signaling and thus alleviate periodontitis in mouse, indicating a promising approach to the resolution of periodontal inflammation via stimulating the “SCC-like” function of gingival fibroblasts.

Abstract Background As a chronic mountain sickness(CMS) with the highest incidence and the greatest harm, the pathogenesis of high altitude polycythemia (HAPC) is still not fully understood. Methods 37 HAPC patients and 42 healthy subjects were selected from plateau, and peripheral venous blood samples were collected for transcriptome sequencing on Illumina NovaSeq platform. The sequenced data were analyzed by bioinformatics and phenotypic association analysis. Results The results showed significant differences in multiple clinical indicators including RBC and HGB et al. existed between HAPC and control. Based on the RNA-seq data, 550 genes with significant differential expression were identified in HAPC patients. GO and KEGG pathway enrichment analysis showed that the up-regulated genes were mainly enriched in processes such as erythrocyte differentiation and development and homeostasis of number of cells, while the down-regulated genes were mainly enriched in categories such as immunoglobulin production, classical pathway of complement activation and other biological processes. The coupling analysis of differential expression genes(DEGs) and pathological phenotypes revealed that 91 DEGs were in close correlation with in the phenotype of red blood cell volume distribution (width-CV and width-SD), and they were all up-regulated in HAPC and involved in the process of erythrocyte metabolism. Combined with the functional annotation of DEGs and literature survey, we found that the expression of several potential genes might be responsible for pathogenesis of HAPC. Besides, cell type deconvolution analysis result suggested that the changes in the number of some immune cell types was significantly lower in HAPC patients than control, implying the autoimmune level of HAPC patients was affected to a certain extent. Conclusion This study provides an important data source for understanding the pathogenesis and screening pathogenic genes of HAPC. We found for the first time that there was a significant correlation between HAPC and the pathological phenotype of width-CV and width-SD, wherein the enriched genes were all up-regulated expressed and involved in the process of erythrocyte metabolism. Although the role of these genes needs to be further studied, the candidate genes can provide a starting point for functionally pinning down the underlying mechanism of HAPC.

Abstract SARS‐CoV‐2 viruses are highly transmissible and immune evasive. It is critical to develop broad‐spectrum prophylactic and therapeutic antibodies for potential future pandemics. Here, we used the phage display method to discover nanobodies (Nbs) for neutralizing SARS‐CoV‐2 viruses especially Omicron strains. The leading nanobody (Nb), namely, Nb4, with excellent physicochemical properties, can neutralize Delta and Omicron subtypes, including BA.1, BA.1.1 (BA.1 + R346K), BA.2, BA.5, BQ.1, and XBB.1. The crystal structure of Nb4 in complex with the receptor‐binding domain (RBD) of BA.1 Spike protein reveals that Nb4 interacts with an epitope on the RBD overlapping with the receptor‐binding motif, and thus competes with angiotensin‐converting enzyme 2 (ACE2) binding. Nb4 is expected to be effective for neutralizing most recent Omicron variants, since the epitopes are evolutionarily conserved among them. Indeed, trivalent Nb4 interacts with the XBB1.5 Spike protein with low nM affinity and competes for ACE2 binding. Prophylactic and therapeutic experiments in mice indicated that Nb4 could reduce the Omicron virus loads in the lung. In particular, in prophylactic experiments, intranasal administration of multivalent Nb4 completely protected mice from Omicron infection. Taken together, these results demonstrated that Nb4 could serve as a potent and broad‐spectrum prophylactic and therapeutic Nb for COVID‐19.

Objective: To analyze the efficacy and safety of proprietary Chinese medicines for the treatment of Lupus Nephritis (LN) based on the reticulated meta analysis. The study aim to provide evidence-based evidence for the clinical treatment of LN. Methods: The studies related to the randomized controlled studies (RCTs) on the treatment of LN with oral proprietary Chinese medicines were obtained from China National Knowledge Infrastructure (CNKI), Database for Chinese Technical Periodicals (VIP), SinoMed, Wanfang, PubMed, Web of Science, Embase and Cochrane Library databases since its inception-August 2022. Cochrane tools were used for risk bias assessment, Stata 13.0 and ADDIS 1.16.5 software were used for net evidence analysis.Results.1) 41 RCTs with 3124 L N patients were included, involving 9 types of proprietary Chinese medicines.2) The meta-analysis showed that in terms of efficacy, the top 3 Chinese patent medicine interventions were Xin Gan Bao Capsule (XGB) +western medicines (WM), Huang Kui Capsule (HK) + WM, Kun Xian Capsule (KX) + WM; in terms of reducing adverse event rate, the top 3 Chinese patent medicine interventions were Yi Shen Hua Shi Granules (YSHS) + WM, Jin Shui Bao Capsule (JSB) + WM, HK + WM; in terms of reducing 24 h urine protein, the top 3 Chinese patent medicine interventions were XGB + WM, YSHS + WM, Bai Ling Capsule (BL) + WM; in terms of reducing blood creatinine (Cr), the top 3 Chinese patent medicine interventions were Yi Shen Granules (YS) + WM, JSB + WM, KX + WM; in terms of reducing urea nitrogen (BUN), the top 3 Chinese patent medicine interventions were Shen Kang Capsule (SK) + WM, HK + WM, JSB + WM; in terms of reducing systemic lupus erythematosus disease activity index (SLEDAI) scores, the top 3 Chinese patent medicine interventions were JSB + WM, BL + WM, YSHS + WM; in terms of improving complement C3, the top 3 Chinese patent medicine interventions were HK + WM, XGB + WM, BL + WM; in terms of improving complement C4, the top 3 Chinese patent medicine interventions were KX + WM, YSHS + WM, BL + WM. Conclusion: Xin Gan Bao Capsule has a good efficacy in improving efficiency and the level of complement C3, lowering 24 h urine protein. Jin Shui Bao Capsule and Huang Kui Capsule have a good efficacy in treating LN. However, more multicentre, large sample and high quality RCTs are needed for validation the results.

Abstract Background Currently, population aging has been an obstacle and the spotlight for all countries. Compared with developed countries, problems caused by China’s aging population are more prominent. Beijing, as a typical example, is characterized by advanced age and high disability rate, making this capital city scramble to take control of this severe problem. The main types of care for the disabled elderly are classified as home care, institutional care, and community care. With the obvious shortage of senior care institutions, most disabled elderly people are prone to choose home care. This kind of elderly care model is in line with the traditional Chinese concept and it can save the social cost of the disabled elderly to the greatest extent. However, home care for the disabled elderly is facing bumps from the whole society, such as lack of professional medical care, social support and humanistic care, and the care resources provided by a single subject cannot meet the needs of the disabled elderly. Objective Based on the demands of the disabled elderly and their families, this study aims to explore the current status of home care service, look for what kind of care is more suitable for the disabled elderly, and try to find an appropriate elderly care mechanism which could meet the diverse needs of the disabled elderly. Methods A total of 118 disabled elderly people and their primary caregivers were selected from four districts of Beijing by using multi-stage stratified proportional sampling method. A one-to-one and semi-structured in-depth qualitative interview were conducted in the study to find out the health status of the disabled elderly, the relationship between the disabled elderly and their primary caregivers, and utilization of elderly care resources, etc. The views of the interviewees were analyzed through the thematic framework method. All the methods were carried out in accordance with relevant guidelines and regulations. Results The results showed that the average age of 118 disabled elderly is 81.38 ± 9.82 years; 86 (72.9%) are severe disability; 105 (89.0%)are plagued by chronic diseases; the average duration of disability is 5.63 ± 5.25 years; most of disabled elderly have 2 children, but the primary caregiver are their own partner (42, 35.6%), and there is an uneven sharing of responsibilities among the disabled elderly's offspring in the process of home care. The disabled elderly enjoy medical care services, rehabilitation training, daily health care, psychological and other demands. However, the disabled elderly and their families in Beijing face a significant financial burden, as well as physical and psychological issues. The care services provided by the government, family doctors, family members and social organizations fall far short of satisfying the diverse care needs of the disabled elderly. Conclusions In order to effectively provide home care services for the disabled elderly, it is therefore necessary to establish a coordination mechanism of multiple subjects and give full play to the responsibilities of each subject. This study proposes a strengthening path for the common cooperation of multiple subjects, which taking specific responsibilities and participating in the home care for the disabled elderly: (1) The government should give full play to the top-level leading responsibilities and effectively implement people-oriented measures to the disabled elderly. (2) Family doctors strengthen their responsibilities as health gatekeepers and promote continuous health management of the disabled elderly. (3) Family members assume the main responsibility and provide a full range of basic care services. (4) Social forces promote supplementary responsibilities of public welfare and expand the connotation of personalized care services. (5) The disabled elderly should shoulder appropriate personal responsibility and actively cooperate with other subjects.

Background Alterations in the gut microbiota have been observed in patients with pulmonary hypertension (PH), though whether the roles of the gut microbiota in PH at different altitudes are the same is unknown. This study aims to evaluate the associations of the gut microbiome with PH in highlanders and lowlanders. Methods PH patients and controls were recruited from those who permanently live on the Tibetan plateau (highlanders) or the plains (lowlanders), and underwent transthoracic echocardiography close to their altitude of residence (at 5070 m for highlanders versus6 m for lowlanders). The gut microbiome was profiled using metagenomic shotgun sequencing. Results In total, 13 PH patients (46% highlanders) and 88 controls (70% highlanders) were included. The overall microbial composition was different in PH patients compared to controls (p=0.003). Notably, among lowlanders, a composite microbial score of pro-atherosclerotic trimethylamine-producing species was increased in PH patients compared with that in controls (p=0.028), while among highlanders no such difference was observed (p=0.087). Another composite gut microbial score including eight species of Lactobacillus, which has shown beneficial effects on cardiovascular functions, was higher in highlanders than lowlanders (p

Objective To evaluate the current state of family doctor contract services (FDCS) in Beijing, identify the roles of family doctors who have worked with disabled older adults and investigate the barriers and facilitators faced by family doctors in providing care for them.Design A convergent mixed methods study was carried out from October 2020 to January 2021 to collect and analyse both quantitative and qualitative data. The integration strategies in this study were connecting the results of the quantitative phase to data collection of the qualitative phase.Setting A multi-stage sampling strategy was used to select 15 community health centres (CHCs) in four districts of Beijing. Of the four districts, two were from urban areas and two were from rural areas.Participants The inclusion criteria for participants were (1) family doctors, (2) contracted with disabled older adults, (3) engaged in related work for disabled older adults more than 6 months.Methods A cluster sampling of 283 family doctors was used in the questionnaire. A purposive sample of 30 family doctors from the same CHCs was selected during the same period. Frequency and rank, rank-sum test, Kruskal-Wallis test were conducted in qualitative data analysis, the views of the interviewees were analysed through the thematic framework method.Results Currently, family doctors provided various services to satisfy the health needs of disabled older adults, while the usage of FDCS for disabled older adults is affected by many factors. The differences of the importance of family doctors’ role (p

IntroductionAlthough there is extended research on the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in adult cancer patients (ACP), the immunogenicity to the variants of concern (VOCs) in childhood cancer patients (CCP) and safety profiles are now little known.MethodsA prospective, multi-center cohort study was performed by recruiting children with a solid cancer diagnosis and childhood healthy control (CHC) to receive standard two-dose SARS-CoV-2 vaccines. An independent ACP group was included to match CCP in treatment history. Humoral response to six variants was performed and adverse events were followed up 3 months after vaccination. Responses to variants were compared with ACP and CHC by means of propensity score-matched (PSM) analysis.ResultsThe analysis included 111 CCP (27.2%, median age of 8, quartile 5.5–15 years), 134 CHC (32.8%), and 163 ACP (40.0%), for a total 408 patients. Pathology included carcinoma, neural tumors, sarcoma, and germ cell tumors. Median chemotherapy time was 7 (quartile, 5–11) months. In PSM sample pairs, the humoral response of CCP against variants was significantly decreased, and serology titers (281.8 ± 315.5 U/ml) were reduced, as compared to ACP (p< 0.01 for the rate of neutralization rate against each variant) and CHC (p< 0.01 for the rate of neutralization against each variant) groups. Chemotherapy time and age (Pearson r ≥ 0.8 for all variants) were associated with the humoral response against VOCs of the CHC group. In the CCP group, less than grade II adverse events were observed, including 32 patients with local reactions, and 29 patients had systemic adverse events, including fever (n = 9), rash (n = 20), headache (n = 3), fatigue (n = 11), and myalgia (n = 15). All reactions were well-managed medically.ConclusionsThe humoral response against VOCs after the CoronaVac vaccination in CCP was moderately impaired although the vaccine was safe. Age and chemotherapy time seem to be the primary reason for poor response and low serology levels.

Summary: Background: Cancer-related cognitive decline is a serious problem in long-term survival but no pivotal study has investigated whether checkpoint inhibitors (ICI) may be associated with cognitive adverse events. Methods: This propensity score-matched analysis recruited non-small cell lung cancer (NSCLC) patients prescribed with or without ICI monotherapy from three Chinese tertiary hospitals. Patients were excluded from study who developed brain metastasis or had disorders severely affecting cognitive abilities. Primary outcomes were changes in neuropsychological battery test (NBT) at baseline, 6- and 12-month sessions, and any NBT score changes that exceeded 3∗SD of baseline scores would be marked as objective cognitive adverse events (CoAE). Secondary endpoint was the 20-item Perceived Cognitive Impairment (PCI) sub-scale score change in Functional Assessment of Cancer Therapy-Cognitive Function questionnaire, administered at baseline, 3-, 6-, 9-, 12-, and 15-month follow-up session. Per-protocol ICI and control arms were matched with propensity scores that incorporated baseline variables to compare both NBT and PCI assessment results. Patients participating in PCI assessments were analysed in intention-to-treat analysis. Kaplan–Meier survival curves with log-rank tests were adopted to analyse incidence of perceived cognitive decline events (PCDE). Findings: Between March 12, 2020, and March 28, 2021, 908 participants were enrolled. Compared to control, 3 of 4 subtest of NBT scores in ICI arm showed significant cognitive decline in 6- and 12-month sessions, in which Trail Making Test score change (13.56 ± 11.73) reached threshold of cognitive deficit diagnosis in the 12-month session. In 1:1 matched 292 pairs from 908 patients, PCI score changes in ICI arms were −4.26 ± 8.54 (3rd month), −4.72 ± 11.83 (6th month), −6.16 ± 15.41 (9th month), −6.07 ± 15.71 (12th month), and −7.96 ± 13.97 (15th month). The scores were significantly lower than control arm in 3-, 6-, and 12-session follow-up. The result was validated after adjusting quality of life scores and in intention-to-treat analysis. Mean PCI change exceeded 1/2 SD of baseline PCI score (5.81) in 9-, 12-, and 15-month sessions in ICI arm, but not in control arm. PCDE incidence/prevalence was significantly higher in ICI arm (incidence 26.4% vs. 5.1%, and prevalence 16.2% vs. 1.7%). Immune-related adverse events related to incidence of PCDE after adjusting for baseline variables. Interpretation: ICI monotherapy seemed to relate to higher cognitive decline represented by score changes and incidence/prevalence rates. The decline deteriorated as treatment progressed, and immune-related adverse events seemed to be associated with higher cognitive adverse events incidence in the ICI treatment. Funding: The Fellowship of China Postdoctoral Science Foundation and National Natural Science Foundation of China Youth Science Fund Project.

ContextSevere acute respiratory syndrome-coronavirus 2 (COVID-19) vaccines may incur changes in thyroid functions followed by mood changes, and patients with Hashimoto thyroiditis (HT) were suggested to bear a higher risk.ObjectivesWe primarily aim to find whether COVID-19 vaccination could induce potential subsequent thyroid function and mood changes. The secondary aim was to find inflammatory biomarkers associated with risk.MethodsThe retrospective, multi-center study recruited patients with HT receiving COVID-19–inactivated vaccines. C-reactive proteins (CRPs), thyroid-stimulating hormones (TSHs), and mood changes were studied before and after vaccination during a follow-up of a 6-month period. Independent association was investigated between incidence of mood state, thyroid functions, and inflammatory markers. Propensity score–matched comparisons between the vaccine and control groups were carried out to investigate the difference.ResultsFinal analysis included 2,765 patients with HT in the vaccine group and 1,288 patients in the control group. In the matched analysis, TSH increase and mood change incidence were both significantly higher in the vaccine group (11.9% versus 6.1% for TSH increase and 12.7% versus 8.4% for mood change incidence). An increase in CRP was associated with mood change (p< 0.01 by the Kaplan–Meier method) and severity (r = 0.75) after vaccination. Baseline CRP, TSH, and antibodies of thyroid peroxidase (anti-TPO) were found to predict incidence of mood changes.ConclusionCOVID-19 vaccination seemed to induce increased levels and incidence of TSH surge followed by mood changes in patients with HT. Higher levels of pre-vaccine serum TSH, CRP, and anti-TPO values were associated with higher incidence in the early post-vaccine phase.

Periodontitis is a chronic inflammatory condition triggered by oral bacteria. A sustained inflammatory state in periodontitis could eventually destroy the alveolar bone. The key objective of periodontal therapy is to terminate the inflammatory process and reconstruct the periodontal tissues. The traditional Guided tissue regeneration (GTR) procedure has unstable results due to multiple factors such as the inflammatory environment, the immune response caused by the implant, and the operator’s technique. Low-intensity pulsed ultrasound (LIPUS), as acoustic energy, transmits the mechanical signals to the target tissue to provide non-invasive physical stimulation. LIPUS has positive effects in promoting bone regeneration, soft-tissue regeneration, inflammation inhibition, and neuromodulation. LIPUS can maintain and regenerate alveolar bone during an inflammatory state by suppressing the expression of inflammatory factors. LIPUS also affects the cellular behavior of periodontal ligament cells (PDLCs), thereby protecting the regenerative potential of bone tissue in an inflammatory state. However, the underlying mechanisms of the LIPUS therapy are still yet to be summarized. The goal of this review is to outline the potential cellular and molecular mechanisms of periodontitis-related LIPUS therapy, as well as to explain how LIPUS manages to transmit mechanical stimulation into the signaling pathway to achieve inflammatory control and periodontal bone regeneration.

With the rapid growth of the solar photovoltaic (PV) market, many distributed PV power projects are introduced to the market. Selecting a rational project investment portfolio is a complex and challenging task for energy enterprises as both financial and non-financial factors of projects are needed to be considered under limited information and resources. This study presents a two-stage hybrid multi-attribute decision-making and integer programming model for distributed PV project portfolio selection. In Stage I, a multiple attribute group decision-making method based on mathematical programming is used to evaluate the non-financial value of projects under incomplete preference information. Compensative weighted averaging operators with an adjustable parameter are utilized to capture the subjective attitudinal character of an expert in the aggregation process. Then, a rank acceptability index is developed to measure each project’s group support degree in non-financial dimension. In Stage II, a bi-objective integer programming model is constructed to optimize project portfolios, which considers both financial and non-financial values of projects under resource, carbon emission and other strategic constraints. The applicability and effectivity of the proposed approach are demonstrated by a case study of a distributed PV project portfolio selection.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting people’s health worldwide. Exploring the potential biomarkers and dynamic networks during NAFLD progression is urgently important. Material and methods Differentially expressed genes (DEGs) in obesity, NAFL and NASH were screened from GSE126848 and GSE130970, respectively. Gene set enrichment analysis of DEGs was conducted to reveal the Gene Ontology (GO) biological process in each period. Dynamic molecular networks were constructed by DyNet to illustrate the common and distinct progression of health- or obesity-derived NAFLD. The dynamic co-expression modular analysis was carried out by CEMiTool to elucidate the key modulators, networks, and enriched pathways during NAFLD. Results A total of 453 DEGs were filtered from obesity, NAFL and NASH periods. Function annotation showed that health-NAFLD sequence was mainly associated with dysfunction of metabolic syndrome pathways, while obesity-NAFLD sequence exhibited dysregulation of Cell cycle and Cellular senescence pathways. Nine nodes including COL3A1, CXCL9, CYCS, CXCL10, THY1, COL1A2, SAA1, CDKN1A, and JUN in the dynamic networks were commonly identified in health- and obesity-derived NAFLD. Moreover, CYCS, whose role is unknown in NAFLD, possessed the highest correlation with NAFLD activity score, lobular inflammation grade, and the cytological ballooning grade. Dynamic co-expression modular analysis showed that module 4 was activated in NAFL and NASH, while module 3 was inhibited at NAFLD stages. Module 3 was negatively correlated with CXCL10, and module 4 was positively correlated with COL1A2 and THY1. Conclusion Dynamic network analysis and dynamic gene co-expression modular analysis identified a nine-gene signature as the potential key regulator in NAFLD progression, which provided comprehensive regulatory mechanisms underlying NAFLD progression.

Tibetan, one of the largest indigenous populations living in the high-altitude region of the Tibetan Plateau (TP), has developed a suite of physiological adaptation strategies to cope with the extreme highland environment in TP. Here, we reported genome-wide SNP data from 48 Kham-speaking Nagqu Tibetans and analyzed it with published data from 1,067 individuals in 167 modern and ancient populations to characterize the detailed Tibetan subgroup history and population substructure. Overall, the patterns of allele sharing and haplotype sharing suggested (1) the relatively genetic homogeny between the studied Nagqu Tibetans and ancient Nepalese as well as present-day core Tibetans from Lhasa, Nagqu, and Shigatse; and (2) the close relationship between our studied Kham-speaking Nagqu Tibetans and Kham-speaking Chamdo Tibetans. The fitted qpAdm models showed that the studied Nagqu Tibetans could be fitted as having the main ancestry from late Neolithic upper Yellow River millet farmers and deeply diverged lineages from Southern East Asians (represented by Upper Paleolithic Guangxi_Longlin and Laos_Hoabinhian), and a non-neglectable western Steppe herder-related ancestry (∼3%). We further scanned the candidate genomic regions of natural selection for our newly generated Nagqu Tibetans and the published core Tibetans via FST, iHS, and XP-EHH tests. The genes overlapping with these regions were associated with essential human biological functions such as immune response, enzyme activity, signal transduction, skin development, and energy metabolism. Together, our results shed light on the admixture and evolutionary history of Nagqu Tibetan populations.

The electrochemical properties of as-cast Zr56Cu19Ni11Al9Nb5 metallic glass and samples annealed at different temperatures were investigated using potentiodynamic polarization tests and electrochemical impedance spectroscopy (EIS) in phosphate buffer saline (PBS) solution. It was shown that passivation occurred for the as-cast sample and the samples annealed at 623–823 K, indicating good corrosion resistance. At higher annealing temperature, the corrosion resistance first increased, and then decreased. The sample annealed at 823 K exhibited the best corrosion resistance, with high spontaneous corrosion potential Ecorr at −0.045 VSCE, small corrosion current density icorr at 1.549 × 10−5 A·cm−2, high pitting potential Epit at 0.165 VSCE, the largest arc radius, and the largest sum of Rf and Rct at 5909 Ω·cm2. For the sample annealed at 923 K, passivation did not occur, with low Ecorr at −0.075 VSCE, large icorr at 1.879 × 10−5 A·cm−2, the smallest arc radius, and the smallest sum of Rf and Rct at 2173 Ω·cm2, which suggested the worst corrosion resistance. Proper annealing temperature led to improved corrosion resistance due to structural relaxation and better stability of the passivation film, however, if the annealing temperature was too high, the corrosion resistance deteriorated due to the chemical inhomogeneity between the crystals and the amorphous matrix. Optical microscopy and scanning electron microscopy (SEM) examinations indicated that localized corrosion occurred. Results of energy dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) illustrated that the main corrosion products were ZrO2, CuO, Cu2O, Ni(OH)2, Al2O3, and Nb2O5.

Obesity-related diseases are always the major health problems that concern the whole world. Serial studies have reported that obesity development is closely related to the out-of-control leptin encoded by the obesity gene (ob). The latest report declaimed “Less Is More,” a model explaining that partial leptin reduction triggers leptin sensitization and contributes to obesity control. Here, we came up with a novel concept, in vivo protein interference (iPRTi), an interesting protein knock-down strategy for in vivo partial leptin reduction. First, the specific immune response against leptin induced by the oral administration of ob recombinant yeast was confirmed. Subsequentally, leptin resistance was observed in diet-induced obese mice, and oral administration with ob recombinant yeast declined the circulating leptin and reduced significantly the body weight gain. To further investigate whether the iPRTi strategy is capable of obesity management, the diet-induced obese mice were administrated with ob recombinant yeast. All the indexes examined including the circulating leptin, triglyceride, and total cholesterol, as well as food intake and weight gain, demonstrated a positive effect of the iPRTi strategy on obesity control. In short, this study provides a novel strategy for the potential application of recombinant yeast for the therapy of obese individuals with leptin resistance.

Background: The incidence of gallstones in the Tibetan population is increasing rapidly. Previous studies indicated that genetic variation located in the cholesterol metabolism pathway may be associated with the incidence of gallstones.Methods: By recruiting 132 Tibetan gallstone patients and 52 normal Tibetan controls, we performed next-generation sequencing for 508 genes in the cholesterol metabolism pathway. Additionally, by integrating the sequence data of 41 normal Tibetan subjects in the public database, we finally obtained 93 normal Tibetan controls. Single nucleotide polymorphisms (SNPs) calling were performed by using the GATK pipeline. The quality control criteria for SNPs were: missing rate 0.01; and p value >0.001 in the Hardy-Weinberg Equilibrium (HWE) test. To eliminate the influence of population heterogeneity, Principal Component Analysis (PCA) was carried out by using the smartpca software. Association analyses were performed by Plink software. Multiple tests were adjusted by the false discovery rate (FDR) method.Results: A total of 2,401 SNPs were obtained by analyzing 508 genes, and 2,011 SNPs left after quality control. After adjusting the eigen vectors, we found that 10 SNPs (SNV05997, rs80145081, rs80005560, rs79074685, rs748546375, rs201880593, rs142559357, rs750769471, rs869789 and rs4072341) were significantly associated with gallstone. Subsequently, by comparing the case group with our control group and the public database control group separately, we further found that the SNP rs869789 was consistently significantly associated with gallstone (p = 9.04 × 10–3 in cases vs. our controls and 5.73 × 10–3 in cases vs. public controls, respectively).Conclusion: By systematically analyzed SNPs in the cholesterol metabolism pathway, we identified one polymorphic locus rs869789 significantly associated with the pathogenesis of gallstone in the Tibetan population. This study will provide clue for further mechanism study of gallstone in the Tibetan population.

ABSTRACT The Argonaute proteins are present in all three domains of life, which are archaea, bacteria, and eukarya. Unlike the eukaryotic Argonaute proteins, which use small RNA guides to target mRNAs, some prokaryotic Argonaute proteins (pAgos) use a small DNA guide to interfere with DNA and/or RNA targets. However, the mechanisms of pAgo natural function remain unknown. Here, we investigate the mechanism by which pAgo from Natronobacterium gregoryi (NgAgo) targets plasmid and bacteriophage T7 DNA using a heterologous Escherichia coli-based model system. We show that NgAgo expressed from a plasmid linearizes its expression vector. Cotransformation assays demonstrate that NgAgo requires an RNA in trans that is transcribed from the bacteriophage T7 promoter to activate cleavage of a cotransformed plasmid, reminiscent of the trans-RNA function in CRISPR/Cas9. We propose a mechanism to explain how NgAgo eliminates invading foreign DNA and bacteriophage. By leveraging this discovery, we show that NgAgo can be programmed to target a plasmid or a chromosome locus. IMPORTANCE We revealed the mechanism that explains how the NgAgo eliminates the invading foreign DNA and bacteriophage in bacterial cells at 37°C, and by leveraging this discovery, NgAgo can be programmed to target a plasmid or a chromosome locus.

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 has emerged as a critical regulator of cellular processes. We took a chemical biology approach to gain further insights into its function. We developed C17, a potent small-molecule DYRK2 inhibitor, through multiple rounds of structure-based optimization guided by several co-crystallized structures. C17 displayed an effect on DYRK2 at a single-digit nanomolar IC50 and showed outstanding selectivity for the human kinome containing 467 other human kinases. Using C17 as a chemical probe, we further performed quantitative phosphoproteomic assays and identified several novel DYRK2 targets, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and stromal interaction molecule 1 (STIM1). DYRK2 phosphorylated 4E-BP1 at multiple sites, and the combined treatment of C17 with AKT and MEK inhibitors showed synergistic 4E-BP1 phosphorylation suppression. The phosphorylation of STIM1 by DYRK2 substantially increased the interaction of STIM1 with the ORAI1 channel, and C17 impeded the store-operated calcium entry process. These studies collectively further expand our understanding of DYRK2 and provide a valuable tool to pinpoint its biological function.

Abstract Human oral microbes play a vital role maintaining host metabolic homeostasis. The Qinghai-Tibet Plateau is mainly characterized by a high altitude, dry, cold, and hypoxic environment. The oral microbiota is subject to selective pressure from the plateau environment, which affects oral health. Only a few studies have focused on the characteristics of oral microbiota in high-altitude humans. We collected saliva samples from 167 Tibetans at four altitudes (2800 to 4500 m) in Tibet to explore the relationship between the high altitude environment and oral microbiota. We conducted a two (high- and ultra-high-altitude) group analysis based on altitude, and adopted the 16S rRNA strategy for high-throughput sequencing. The results show that the alpha diversity of the oral microbiota decreased with altitude, whereas beta diversity increased with altitude. A LEfSe analysis revealed that the oral microbial biomarker of the high-altitude group ( 4000 m) was Prevotella. The relative abundance of Prevotella increased with altitude, whereas the relative abundance of Streptococcus decreased with altitude. A network analysis showed that the microbial network structure was more compact and complex, and the interaction between the bacterial genera was more intense in the high altitude group. Gene function prediction results showed that the amino acid and vitamin metabolic pathways were upregulated in the ultra-high-altitude group. These result show that altitude is an important factor affecting the diversity and community structure of the human oral microbiota.

Background Diet, environment, and genomic context have a significant impact on humans’ intestinal microbiota. Moreover, migration may be accompanied by changes in human eating habits and living environment, which could, in turn, affect the intestinal microbiota. Located in southwestern China, Tibet has an average altitude of 4,000 meters and is known as the world’s roof. Xianyang is situated in the plains of central China, with an average altitude of about 400 meters. Methods To understand the association between intestinal microbiota and population migration, we collected the fecal samples from 30 Tibetan women on the first day (as TI1st), six months (as TI2nd), and ten months (as TI3rd) following migration from Tibet to Xianyang. Fecal samples were collected from 29 individuals (belonging to the Han women) as a control. The dietary information of the Tibetan women and the Han women was gathered. We performed a 16S rRNA gene survey of the collected fecal samples using Illumina MiSeq sequencing. Results Following the migration, the alpha and beta diversity of Tibetan women’s intestinal microbiota appeared unaffected. Linear discriminant analysis effect size (LEfSe) analysis showed that Klebsiella, Blautia, and Veillonella are potential biomarkers at TI1st, while Proteobacteria and Enterobacteriaceae were common in TI3rd. Finally, functional prediction by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) found no significant up-regulation or down-regulation gene pathway in the intestinal microbiota of Tibetan women after migration. The present study reveals that the higher stability in Tibetan women’s intestinal microbiota was less affected by the environment and diet, indicating that Tibetan women’s intestinal microbiota is relatively stable. The main limitations of the study were the small sample size and all volunteers were women.

The human oral microbiota plays a vital role in maintaining metabolic homeostasis. To explore the relationship between Helicobacter pylori (Hp) and reflux esophagitis, we collected 86 saliva samples from reflux esophagitis patients (RE group) and 106 saliva samples from healthy people (C group) for a high-throughput sequencing comparison. No difference in alpha diversity was detected between the RE and the C groups, but beta diversity of the RE group was higher than the C group. Bacteroidetes was more abundant in the RE group, whereas Firmicutes was more abundant in the C group. The linear discriminant analysis effect size analysis demonstrated that the biomarkers of the RE group were Prevotella, Veillonella, Leptotrichia, and Actinomyces, and the biomarkers of the C group were Lautropia, Gemella, Rothia, and Streptococcus. The oral microbial network structure of the C group was more complex than that of the RE group. Second, to explore the effect of Hp on the oral microbiota of RE patients, we performed the 14C-urea breath test on 45 of the 86 RE patients. We compared the oral microbiota of 33 Hp-infected reflux esophagitis patients (REHpp group) and 12 non-Hp-infected reflux esophagitis patients (REHpn group). No difference in alpha diversity was observed between the REHpn and REHpp groups, and beta diversity of the REHpp group was significantly lower than that of the REHpn group. The biomarkers in the REHpp group were Veillonella, Haemophilus, Selenomonas, Megasphaera, Oribacterium, Butyrivibrio, and Campylobacter; and the biomarker in the REHpn group was Stomatobaculum. Megasphaera was positively correlated with Veillonella in the microbial network of the REHpp group. The main finding of this study is that RE disturbs the human oral microbiota, such as increased beta diversity. Hp infection may inhibit this disorderly trend.

Effective maize and weed detection plays an important role in farmland management, which helps to improve yield and save herbicide resources. Due to their convenience and high resolution, Unmanned Aerial Vehicles (UAVs) are widely used in weed detection. However, there are some challenging problems in weed detection: (i) the cost of labeling is high, the image contains many plants, and annotation of the image is time-consuming and labor-intensive; (ii) the number of maize is much larger than the number of weed in the field, and this imbalance of samples leads to decreased recognition accuracy; and (iii) maize and weed have similar colors, textures, and shapes, which are difficult to identify when an UAV flies at a comparatively high altitude. To solve these problems, we propose a new weed detection framework in this paper. First, to balance the samples and reduce the cost of labeling, a lightweight model YOLOv4-Tiny was exploited to detect and mask the maize rows so that it was only necessary to label weeds on the masked image. Second, the improved YOLOv4 was used as a weed detection model. We introduced the Meta-ACON activation function, added the Convolutional Block Attention Module (CBAM), and replaced the Non-Maximum Suppression (NMS) with Soft Non-Maximum Suppression (Soft-NMS). Moreover, the distributions and counts of weeds were analyzed, which was useful for variable herbicide spraying. The results showed that the total number of labels for 1000 images decrease by half, from 33,572 to 17,126. The improved YOLOv4 had a mean average precision (mAP) of 86.89%.

Bawei Chenxiang Wan (BCW), a well-known traditional Chinese Tibetan medicine formula, is effective for the treatment of acute and chronic cardiovascular diseases. In the present study, we investigated the effect of BCW in cardiac hypertrophy and underlying mechanisms. The dose of 0.2, 0.4, and 0.8 g/kg BCW treated cardiac hypertrophy in SD rat model induced by isoprenaline (ISO). Our results showed that BCW (0.4 g/kg) could repress cardiac hypertrophy, indicated by macro morphology, heart weight to body weight ratio (HW/BW), left ventricle heart weight to body weight ratio (LVW/BW), hypertrophy markers, heart function, pathological structure, cross-sectional area (CSA) of myocardial cells, and the myocardial enzymes. Furthermore, we declared the mechanism of BCW anti-hypertrophy effect was associated with activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/peroxisome proliferator–activated receptor-α (PPAR-α) signals, which regulate carnitine palmitoyltransferase1β (CPT-1β) and glucose transport-4 (GLUT-4) to ameliorate glycolipid metabolism. Moreover, BCW also elevated mitochondrial DNA-encoded genes of NADH dehydrogenase subunit 1(ND1), cytochrome b (Cytb), and mitochondrially encoded cytochrome coxidase I (mt-co1) expression, which was associated with mitochondria function and oxidative phosphorylation. Subsequently, knocking down AMPK by siRNA significantly can reverse the anti-hypertrophy effect of BCW indicated by hypertrophy markers and cell surface of cardiomyocytes. In conclusion, BCW prevents ISO-induced cardiomyocyte hypertrophy by activating AMPK/PPAR-α to alleviate the disturbance in energy metabolism. Therefore, BCW can be used as an alternative drug for the treatment of cardiac hypertrophy.

Objectives To develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.Design A nationally representative retrospective study.Setting Representative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.Participants Representative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.Primary outcome measures In-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).Results A total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as ‘reference model’, was 0.08% (10th and 90th percentiles: −1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.Conclusions The models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.

The goal of the present study was to determine the efficacy of osimertinib (AZD9291), a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor for the treatment of aggressive EGFR-mutant non-small cell lung cancer (NSCLC), compared to cisplatinum (CDDP) + pemetrexed (PEM). The NSCLC cell line PC-9 expressing green fluorescence protein (PC-9-GFP) was implanted in the brain of nude mice and was treated with CDDP + PEM or AZD9291. Tumors were observed by non-invasive fluorescence imaging. AZD9291 treatment caused tumor regression in contrast to CDDP + PEM which had only a slight inhibitory effect. These results suggest that AZD9291 is a promising clinical option for NSCLC patients with brain metastasis.

Undifferentiated/unclassified soft-tissue sarcomas (USTS) is recalcitrant neoplasms that is usually treated with doxorubicin (DOX)-containing regimens as first-line therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a nanotechnology-based drug and is widely used in pancreatic cancer in combination with gemcitabine (GEM). The major goal of the present study was to determine the efficacy of nab-PTX in combination with GEM, compared to conventional drugs such as docetaxel (DOC), GEM combined with DOC, or first-line drug DOX on a USTS not-otherwise specified (USTS/NOS) from a striated muscle implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. USTS PDOX models were randomized into six groups: untreated control; DOX; DOC; nab-PTX; GEM combined with DOC; and GEM combined with nab-PTX. Tumor size and body weight were measured. Tumor growth was inhibited to the greatest extent by GEM combined with nab-PTX. Tumors treated with GEM combined with nab-PTX had the most necrosis. Body weight of the treated mice was not significantly different from the untreated controls. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the combination of GEM and nab-PTX for recalcitrant soft-tissue sarcomas. These results suggest that combination of GEM and nab-PTX could be a promising therapeutic strategy for USTS.

Strain coupling with ferromagnetism and ferroelectricity plays an important role in the development of multiferroic metal-organic frameworks (MOFs) with strong magnetoelectric coupling, but the underlying mechanisms have not been well understood. Strain coupling and dynamic relaxation in multiferroic MOF with perovskite structure [(CH3)2NH2][Mn(HCOO)3] were investigated using X-ray diffraction (XRD), Raman spectroscopy, Infra-red (IR) spectroscopy, differential scanning calorimetry (DSC), magnetic measurements and dynamic mechanical analysis (DMA). DSC results showed peaks at 183 K and 190 K at the rate of 5 K/min during cooling and heating processes, respectively. Magnetic measurements showed magnetic transition at ∼8.5 K at the heating rate of 2 K/min. Temperature and frequency dependences of elastic properties studied by DMA at frequencies of 0.5 Hz–10 Hz between 140 K and 300 K at heating rate of 2 K/min indicated that the minimum in storage modulus and the maximum in loss modulus and loss factor occurred near 190 K. The peak height of loss modulus and loss factor decreased at higher frequency, and the peak temperature was independent of frequency, showing the features of first-order phase transition. Near 190 K, paraelectric to ferroelectric phase transition triggered by disorder–order transition of alkylammonium cations located in the framework cavities occurred accompanied by the structural phase transition from rhombohedral space group R3-c to monoclinic space group Cc. The elastic anomalies and large energy loss near 190 K were associated with the coupling of the local strain with the freezing of dimethylammonium cation and the freezing of twin walls. Keywords: Metal-organic framework (MOF), Phase transition, Dynamic mechanical analysis (DMA), Elastic modulus, Energy loss

Introduction Childhood-onset schizophrenia with obsessive-compulsive symptoms (COSO) and without obsessive-compulsive symptoms (COS) share considerable overlap in clinical features and genetic risk factors. However, the extent of brain functional abnormalities in COSO and COS is poorly understood. Material and methods A total of 51 first-episode childhood schizophrenic patients and 30 healthy age- and sex-matched controls were recruited. We used the Yale-Brown Obsessive Compulsive Scale to divide patients into COSO (n = 21) and COS (n = 30) groups. Resting-state functional magnetic resonance imaging images were obtained using a gradient-echo echo-planar imaging sequence. Voxel-based analysis of amplitude of low-frequency fluctuation (ALFF) maps between the two groups was performed. Results The COS group showed significantly increased ALFF in the right caudate body, middle temporal gyrus and inferior parietal lobule (p < 0.05), while showing decreased ALFF in the left cerebellum posterior lobe (p < 0.05). The COSO group showed significantly increased ALFF in the left and right frontal lobe, cerebellum posterior lobe and precuneus (p < 0.05). When comparing the two groups, COSO showed significantly higher ALFF in the left cerebellum posterior lobe, frontal lobe, supramarginal gyrus, precuneus, right inferior frontal gyrus and medial frontal gyrus (p < 0.05). Interestingly, significantly lower ALFF was found in the right fusiform gyrus, corpus callosum and inferior parietal lobule in the group of patients with obsessive-compulsive symptoms (p < 0.05). Conclusions Our findings increase the understanding of the pathophysiology of schizophrenia and may provide imaging evidence for early diagnosis of COSO or COS.

The widespread use of cyclophosphamide (CP) in medical treatment had caused ubiquitous contamination in the environment. To data, many studies have been carried out on the toxic effect of CP. However, among these toxic effects of CP, which are the most sensitive remains unclear. Present study aimed to investigate the toxicity of CP on mice and evaluate the sensitivity of physiological-biochemical parameters upon exposure of mice to CP. Results showed that as compared with the control group, CP caused significant reduction in body weight (p leukocyte density > ALT in kidney > spleen coefficient; while among the stimulated parameters, the sensitivity was ranked as MDA (liver) > Cr (kidney) > ALT (liver). Overall, the most sensitive parameters to CP toxicity may be associated with growth, immune system and the normal function of liver and kidney.

Periodontal disease is a chronic infectious disease associated with a variety of bacteria, which can cause damage to the periodontal support structure and affect a variety of systemic system diseases such as cancer, cardiovascular disease, diabetes, rheumatoid arthritis, non-alcoholic fatty liver, and Alzheimer’s disease. Porphyromonas gingivalis (P. gingivalis) is the most important pathogenic bacteria for periodontal disease. It can produce outer membrane vesicles (OMVs) and release them into the environment, playing an important role in its pathogenesis. This article focuses on P. gingivalis OMVs, reviews its production and regulation, virulence components, mode of action and related diseases, with a view to providing new ideas for the prevention and treatment of diseases related to P. gingivalis infections.

Background Most countries worldwide, especially low- and middle-income countries (LMICs), are facing an increasing prevalence of fast-food consumption and multiple burdens of malnutrition among young adolescents. Objective To compare the prevalence of fast-food consumption among young adolescents in LMICs. Methods We used data from the most recent Global School-Based Student Health Survey (2009–2015), which had been collected using a standardized questionnaire. The weighted prevalence and 95% confidential intervals of fast-food consumption were calculated overall and in subgroups stratified by age, sex, and nutritional status. The pooled overall and regional estimates were obtained using a random-effects model. Heterogeneity was assessed using the I2 statistic. The associated risk factors for fast-food consumption were explored using logistic regression analysis. Results Our study comprised 153,496 young adolescents (46.90% boys) from 54 LMICs. Overall, approximately 55.2% (51.3–59.1%) of the adolescents consumed fast food at least 1 day per week, and 10.3% (8.3–12.4%) did so 4–7 days per week. The prevalence of fast-food consumption 4–7 days per week was lowest in the Americas (8.3%; 6.7–9.9%) and highest in Southeast Asia (17.7%; 2.3–33.2%). At a country level, the prevalence was lowest in Pakistan (1.5%; 1.0–2.0%) and highest in Thailand (43.3%; 40.4–46.1%). Furthermore, in subgroups stratified by nutritional status, the prevalence was lowest in the obesity group (6.6%; 4.5–8.7%). Factors such as age, sex, BMI, food insecurity, fruit consumption, vegetable consumption, soft-drink consumption, smoking, physical activity level, and sedentary behavior level were found to be correlated with fast-food consumption. Conclusions The identified high prevalence of fast-food consumption among young adolescents in LMICs indicates the urgent need to prioritize the implementation of healthy-diet promotion programs to improve adolescent health in these countries.

The damping system characterizes the spatial distribution of structural energy dissipation. Identifying a damping system is the premise for determining the dynamic analysis method. Concepts of nonlinear processes and non-classical damping systems are often confused without theoretical primary and experimental verification. This paper proposes an identification method of damping systems based on motion states at the interface by analyzing the correlation between the damping system and dynamic characteristics. The relationship between the change of damping system type and relative motion states at the interface is studied by investigating multiple material properties through shaking table model tests of a large-scale soil-structure interaction (SSI) system. The results show that a nonlinear system can demonstrate the characteristics of the classical damping system as soon as there is no mutation of motion states at the interface of the system. The identification method of damping system based on motion states at the interface can reflect the change of dynamical characteristics of the system under linear and nonlinear processes.

Residential whole-decoration is an important initiative for housing industrialization in China. Selecting the most suitable component supplier for housing development is of great significance for both property developers and buyers in the implementation of such a strategy. To address such a problem, this study uses hesitant fuzzy linguistic term sets to express the inaccurate judgments of individuals and then introduces a novel probability aggregation approach based on interval rough boundaries to enable a realistic presentation of the collective evaluations of a group. Then, we propose a hybrid multi-expert multiple criteria decision-making model by integrating the Best Worst Method (BWM) and Combined Compromise Solution (CoCoSo) method based on the interval rough boundaries. A case study about the supplier selection for housing development is carried out, which demonstrates the feasibility and applicability of our proposed hybrid model. A comparison study is also performed to further validate the robustness of the model.

Estimation of distribution functions has many real-world applications. We study kernel estimation of a distribution function when the density function has compact support. We show that, for densities taking value zero at the endpoints of the support, the kernel distribution estimator does not need boundary correction. Otherwise, boundary correction is necessary. In this paper, we propose a boundary distribution kernel estimator which is free of boundary problem and provides non-negative and non-decreasing distribution estimates between zero and one. Extensive simulation results show that boundary distribution kernel estimator provides better distribution estimates than the existing boundary correction methods. For practical application of the proposed methods, a data-dependent method for choosing the bandwidth is also proposed.

OBJECTIVE:To investigate that whether an association between marital status and the female breast cancer risk exists. METHODS:The MEDLINE, EMBASE and PsycINFO databases were searched from their inception to July 2019. The Newcastle-Ottawa Scale was used to rate the methodological quality of included studies. Study data were pooled using random-effects meta-analyses to compare the breast cancer risk between unmarried, widowed, divorced or lifelong single women and married women. This study is registered with PROSPERO (number CRD42018112368). RESULTS:Forty-nine publications were included in the meta-analysis. Compared with married women, unmarried and lifelong single women had an elevated risk of breast cancer, and the pooled ORs of case-control studies were 1.20 (95% CI: 1.07 to 1.35) and 1.24 (95% CI: 1.05 to 1.45), respectively. In the subgroup analyses under these two comparisons, hospital-based estimates and multivariate-adjusted estimates demonstrated a strong association, while population-based estimates and age-adjusted estimates produced nonsignificant results. The pooled OR of cohort studies examining the effect of being a lifelong single woman was 1.10 (95% CI: 1.04 to 1.16). Heterogeneity was moderate to substantial across case-control studies (I2: 46% to 82%), which may be partially explained by differences in geographic regions, publication years and control types. Possible publication bias was indicated by the funnel plot and Egger's test (P = 0.03). CONCLUSIONS:Marital status may correlate with the risk of developing female breast cancer. However, suboptimal selection of controls, insufficient exploration of confounding effects, inadequate ascertainment of marital status, and possible publication bias may have limited the quality of the available evidence. Overall, conclusions that marital status is an independent risk factor for breast cancer could not be drawn, and further prospective rigorous cohort studies are warranted.

Background A limited amount of research has demonstrated beneficial effects of caffeine and theanine supplementation for enhancement of mental performance. The purpose of this investigation was to determine whether the acute ingestion of a supplement containing caffeine, theanine and tyrosine improves mental and physical performance in athletes. Methods Twenty current or former male collegiate athletes (age: 20.5 ± 1.4 y; height: 1.82 ± 0.08 m; weight: 83.9 ± 12.6 kg; body fat: 13.8 ± 5.6%) completed this randomized, double-blind, placebo-controlled crossover trial. After familiarization, each participant completed two identical testing sessions with provision of a proprietary dietary supplement (SUP) containing caffeine theanine and tyrosine or a placebo (PL). Within each testing session, participants completed assessments of mental and physical performance before and after provision of SUP or PL, as well as after two rounds of exercise. Assessments were performed using a performance testing device (Makoto Arena) that evaluated multiple aspects of mental and physical performance in response to auditory and visual stimuli. Testing was performed both with the body in a static position and during dynamic movement. General linear models were used to evaluate the effects of SUP and PL on performance. Results Changes in movement accuracy during performance assessment were greater following SUP ingestion as compared to PL for both static and dynamic testing (SUP: + 0.4 to 7.5%; PL: − 1.4 to 1.4% on average; p 0.05). Discussion The present results indicate that a combination of a low-dose of caffeine with theanine and tyrosine may improve athletes’ movement accuracy surrounding bouts of exhaustive exercise without altering subjective variables. Based on this finding, supplementation with caffeine, theanine and tyrosine could potentially hold ergogenic value for athletes in sports requiring rapid and accurate movements. Trial registration NCT03019523. Registered 24 January 2017.

Abstract Background Treatment for drug-sensitive tuberculosis (TB) is taken for at least 6 months and problems with adherence are common. Therefore, there is substantial interest in the possible use of eHealth interventions to support patients to take their treatment. Electronic medication monitors have been shown to improve adherence to TB medication, but the impact on clinical outcomes is unknown. We aim to evaluate the impact of a medication monitor-based treatment strategy for drug-sensitive TB patients on a composite poor outcome measured over 18 months from start of TB treatment. Methods/design We will conduct an open, pragmatic, cluster randomised superiority trial, with 24 counties/districts in three provinces in China, randomised 1:1 to implement the intervention or standard of care. Adults (aged ≥ 18 years) with a new episode of GeneXpert-positive and rifampicin-sensitive pulmonary TB, who plan to be in the study area for the next 18 months, and will receive daily fixed-dose combination tablets for 6 months of treatment are eligible. The intervention is centred around a medication monitor that holds a 1-month supply of medication and has three key functions: as an audio and visual reminder for patients to take their daily medication; reminds patients of upcoming monthly visit; and records date and time whenever the box is opened. At the monthly follow-up visit, the doctor downloads these data to generate a graphical display of the last month’s adherence record for discussion with the patient and potentially to switch the patient to more intensive management. The primary outcome is a composite poor outcome measured over 18 months from start of TB treatment, defined as either of poor outcome at the end of treatment (death, treatment failure, or loss to follow-up) or subsequent recurrence (culture positive for TB at 12 or 18 months or re-starting TB treatment in the follow-up period). An economic evaluation will also be conducted as part of this study. Discussion This trial will assess whether a medication monitor-based treatment strategy can improve clinical outcomes for TB patients. Several trials of other eHealth interventions for TB treatment are ongoing and are summarised in this paper. This trial will provide an important part of the emerging evidence base for the potential of eHealth to improve TB treatment outcomes. Trial registration This trial was registered with Current Controlled Trials (identifier: ISRCTN35812455). Registered on May 19, 2016.

Abstract Background High-altitude polycythemia (HAPC) is a chronic high-altitude disease that can lead to an increase in the production of red blood cells in the people who live in the plateau, a hypoxia environment, for a long time. The most frequent symptoms of HAPC include headache, dizziness, breathlessness, sleep disorders, and dilation of veins. Although chronic hypoxia is the main cause of HAPC, the fundamental pathophysiologic process and related molecular mechanisms responsible for its development remain largely unclear yet. Aim/methods This study aimed to explore the related hereditary factors of HAPC in the Chinese Han and Tibetan populations. A total of 140 patients (70 Han and 70 Tibetan) with HAPC and 60 healthy control subjects (30 Han and 30 Tibetan) were recruited for a case-control association study. To explore the genetic basis of HAPC, we investigated the association between HAPC and both phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit delta gene (PIK3CD) and collagen type IV α3 chain gene (COL4A3) in Chinese Han and Tibetan populations. Results/conclusion Using the unconditional logistic regression analysis and the false discovery rate (FDR) calculation, we found that eight SNPs in PIK3CD and one SNP in COL4A3 were associated with HAPC in the Tibetan population. However, in the Han population, we did not find any significant association. Our study suggested that polymorphisms in the PIK3CD and COL4A3 were correlated with susceptibility to HAPC in the Tibetan population.

Base on the practical of MSTN-specific yeast-based protein vaccine in mice as described previously, this research was designed for developing a better DNA vaccine (a cascade of shIL21-MSTN yeast-based DNA vaccine) than solely MSTN yeast-based DNA vaccine to block the endogenous MSTN in the murine model. We first constructed the target vectors, including CMV-driven MSTN expression vector and a combined shIL21-MSTN vector which containing MSTN expression cassette and shIL21 (short hairpin RNA-IL21) expression cassette. After necessary validation, recombinant yeast vaccines harboring different vectors were well prepared. Subsequently, after 2-month administration, the MSTN-specific immune response was detected with western blots. The commercial ELISA assays indicated that the production of IL21 and IL6 were decreased compared with control groups. More importantly, the MSTN-specific antibody titer was much higher in the shIL21-MSTN group than MSTN group, which was consistent with the western blots result. The most important finding was significant body mass increased after oral administration of these yeast-based DNA vaccines, in which the shIL21-MSTN vaccine is slightly higher than the sole MSTN vaccine in mice. In this study, we confirmed the role of different MSTN-specific yeast-based DNA vaccines on increasing body mass in mice, to provide a good inspiration for livestock breeding through the new type of immunoregulatory method. On the other hand, we also detected the possible modulating role of shIL21 on the dendritic cell-mediated immune function which needs more practical application and deeper exploration.

MicroRNAs (miRNAs) are endogenously expressed small noncoding RNAs and play critical roles in the regulation of post-transcriptional gene expression. Our previous study uncovered that chi-miR-487b-3p is widespread in different goat tissues, which is significantly higher in muscle, especially in lamb. Here, we demonstrate the role of chi-miR-487b-3p as a myogenic miRNA that regulates skeletal muscle development. chi-miR-487b-3p overexpression was demonstrated to significantly inhibit goat myoblast proliferation and differentiation, whereas chi-miR-487b-3p inhibition resulted in the opposite effects. Next, chi-miR-487b-3p was predicted to target the 3′UTR of insulin receptor substrate 1 (IRS1) gene by Target-Scan and miRDB. The results of dual-luciferase assay, RT-qPCR, and western blot all confirmed that IRS1 might be a direct target of chi-miR-487b-3p as its expression was negatively regulated by chi-miR-487b-3p. siRNA silencing of IRS1 further demonstrated significant inhibition on goat myoblast proliferation and differentiation, confirming the effect of IRS1 downregulation by chi-miR-487b-3p in myogenesis. In addition, chi-miR-487b-3p knockout goat myoblast clones were generated using CRISPR/Cas9 technology, and we further illustrated that chi-miR-487b-3p regulates goat myoblast growth through the PI3K/Akt signaling pathway by targeting IRS1. Collectively, our work demonstrated that chi-miR-487b-3p is a potent inhibitor of skeletal myogenesis and provided new insights into the mechanisms of miRNA on the regulation of goat growth.