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Abstract Sorghum ratooning, a time and labor-saving cultivation practice, is increasingly being adopted by farmers in Southwest China as an alternative. Efficient N fertilizer management is critical for economical production of sorghum and the long-term protection of the environment. To investigate the impact of N management on grain yield and nitrogen use efficiencies (NUEs) of ratoon sorghum system, a three-year field experiment was conducted for Jinyunuo3 (a hybrid cultivar) and Guojiaohong1 (an inbred cultivar) using 12 combinations of N rates and splitting ratios. The results showed that increasing N rate and splitting application times led to improvements in various growth parameters such as dry matter weight, crop growth rate (CGR), leaf area index (LAI), and photosynthetic potential (PP). The main, ratoon, and annual yields increased with N rate increase, but there was no significant difference between 225 and 150 kg N ha−1 in the ratoon and annual yields. Splitting the application of N fertilizer enhanced grain yield compared to a single dose application method, especially three-split applications yielded higher than two-split applications. Compared with N rates of 225 and 150 kg ha−1, N rate of 75 kg ha−1 increased apparent recovery rate of applied nitrogen (REN), agronomic efficiency of applied nitrogen (AEN), and partial factor productivity from applied nitrogen (PFPN) in both main season and whole year. But through splitting application methods at high N rates could achieve similar or even higher levels of NUEs compared to all applied as basal fertilizer at low N rates. Therefore, it could be recommended that applying 150 kg N ha−1 with a basal-jointing-heading fertilizer ratio of 2:4:4 represented an efficient N management practice to synchronously obtain high grain yield and NUEs in ratoon sorghum system in Southwest China.

Objective To explore the correlations of genotype and phenotype of myopathic form of carnitine palmitoyltransferase Ⅱ (CPT Ⅱ) deficiency and to improve the clinical understanding of the disease. Methods The clinical data of a case of myopathic form of CPT Ⅱ deficiency were analyzed, including the results of gene detection, diagnosis, treatment, and follow-up. The literature was reviewed to summarize the clinical characteristics, diagnosis, and treatment of CPT Ⅱ deficiency. Results The patient, a 10-month-old girl, was admitted to the hospital with acute enteritis. The blood creatine kinase and myoglobin were significantly increased in the auxiliary examination. Her father had a history of weakness after regular exercise and myoglobinuria. Both the father and the daughter carried the heterozygous pathogenic mutation c.989dupTp. (Ile332fs) in the CPT2 gene, which confirmed the diagnosis of myopathic form of CPT Ⅱ deficiency. After treatment with infection control and supplementation of a large amount of carbohydrates, creatine kinase and myoglobin returned to normal levels. Following discharge, follow-up showed that the patient was in good condition. Conclusion Myopathic form of CPT Ⅱ deficiency is a common disease that affects the lipid metabolism in skeletal muscle and is a common cause of hereditary myoglobinuria. However, its symptoms can be quite subtle and are frequently overlooked in clinical practice. When a patient exhibits repeated increases in creatine kinase as well as exercise intolerance, myoglobinuria, or positive family history, the disease should be taken into consideration.

Abstract To figure out how does SARS-CoV-2 affect sperm parameters and what influencing factors affect the recovery of sperm quality after infection? We conducted a prospective cohort study and initially included 122 men with SARS-CoV-2 infection. The longest time to track semen quality after infection is 112 days and 58 eligible patients were included in our study eventually. We subsequently exploited a linear mixed-effects model to statistically analyze their semen parameters at different time points before and after SARS-CoV-2 infection. Semen parameters were significantly reduced after SARS-CoV-2 infection, including total sperm count (211 [147; 347] to 167 [65.0; 258], P

Abstract Background Previous randomized controlled trials (RCTs) suggested that gut microbiota-based therapies may be effective in treating autoimmune diseases, but a systematic summary is lacking. Methods Pubmed, EMbase, Sinomed, and other databases were searched for RCTs related to the treatment of autoimmune diseases with probiotics from inception to June 2022. RevMan 5.4 software was used for meta-analysis after 2 investigators independently screened literature, extracted data, and assessed the risk of bias of included studies. Results A total of 80 RCTs and 14 types of autoimmune disease [celiac sprue, SLE, and lupus nephritis (LN), RA, juvenile idiopathic arthritis (JIA), spondyloarthritis, psoriasis, fibromyalgia syndrome, MS, systemic sclerosis, type 1 diabetes mellitus (T1DM), oral lichen planus (OLP), Crohn’s disease, ulcerative colitis] were included. The results showed that gut microbiota-based therapies may improve the symptoms and/or inflammatory factor of celiac sprue, SLE and LN, JIA, psoriasis, PSS, MS, systemic sclerosis, Crohn’s disease, and ulcerative colitis. However, gut microbiota-based therapies may not improve the symptoms and/or inflammatory factor of spondyloarthritis and RA. Gut microbiota-based therapies may relieve the pain of fibromyalgia syndrome, but the effect on fibromyalgia impact questionnaire score is not significant. Gut microbiota-based therapies may improve HbA1c in T1DM, but its effect on total insulin requirement does not seem to be significant. These RCTs showed that probiotics did not increase the incidence of adverse events. Conclusions Gut microbiota-based therapies may improve several autoimmune diseases (celiac sprue, SLE and LN, JIA, psoriasis, fibromyalgia syndrome, PSS, MS, T1DM, Crohn’s disease, and ulcerative colitis).

Rheumatoid arthritis (RA) is a prevalent autoimmune disease that involves the overgrowth and inflammation of synovial tissue, leading to the degeneration and impairment of joints. In recent years, numerous studies have shown a close relationship between the hypoxic microenvironment in joints and the occurrence and progression of RA. The main cause of the pathological changes in RA is widely believed to be the abnormal expression of hypoxia-inducible factor-1 (HIF-1) in joints. This paper describes and illustrates the structure and primary functions of HIF-1 and explains the main regulatory methods of HIF-1, including the PHDs/HIF-1/pVHL pathway, factor-inhibiting HIF (FIH), regulation of inflammatory cytokines, and the NF-B pathway. Furthermore, this paper discusses the mechanism of HIF-1 and its impact on inflammation, angiogenesis, and cartilage destruction in greater detail. We summarize previous research findings on the mechanism of HIF-1 and propose new potential treatments for RA based on the pathogenesis of HIF-1 in RA.

Objective To investigate the value of U-wave inversion combined with fragmented QRS (fQRS) on electrocardiogram in predicting the prognosis after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). Methods A total of 123 patients with ACS admitted to The Third People’s Hospital of Henan Province from October 2017 to September 2019 were included. All the patients underwent PCI after electrocardiogram examination, followed by 3 months follow-up. The percentages of U-wave inversion, fQRS, and a poor prognosis were analyzed to determine the predictive value of U-wave inversion combined with fQRS for post-PCI outcome in patients with ACS. Results Among the 123 patients with ACS, the percentages of U-wave inversion, fQRS, and a poor prognosis were 39.84%, 33.33%, and 23.58%, respectively. The patients with a poor outcome showed significantly higher percentages of U-wave inversion and fQRS than those with a good outcome (χ2=20.547,26.080,P

Abstract BET proteins, which influence gene expression and contribute to the development of cancer, are epigenetic interpreters. Thus, BET inhibitors represent a novel form of epigenetic anticancer treatment. Although preliminary clinical trials have shown the anticancer potential of BET inhibitors, it appears that these drugs have limited effectiveness when used alone. Therefore, given the limited monotherapeutic activity of BET inhibitors, their use in combination with other drugs warrants attention, including the meaningful variations in pharmacodynamic activity among chosen drug combinations. In this paper, we review the function of BET proteins, the preclinical justification for BET protein targeting in cancer, recent advances in small-molecule BET inhibitors, and preliminary clinical trial findings. We elucidate BET inhibitor resistance mechanisms, shed light on the associated adverse events, investigate the potential of combining these inhibitors with diverse therapeutic agents, present a comprehensive compilation of synergistic treatments involving BET inhibitors, and provide an outlook on their future prospects as potent antitumor agents. We conclude by suggesting that combining BET inhibitors with other anticancer drugs and innovative next-generation agents holds great potential for advancing the effective targeting of BET proteins as a promising anticancer strategy.

Objective To analyze the mutation site in the ATP-binding cassette subfamily D member 1 gene (ABCD1) in the family of a patient with X-linked adrenoleukodystrophy (X-ALD), and to explore the diagnosis, treatment, and prognosis of X-ALD based on the patient family clinical data and related literature. Methods The clinical data and family information of a patient with X-ALD admitted to the Neurology Department of our hospital in November 2021 were retrospectively analyzed, and relevant literature worldwide was retrieved for review and discussion. Results The main symptoms of the patient were skin blacke-ning, dizziness, headache, general discomfort, fatigue, low blood pressure, loss of appetite, and poor sleep and other symptoms associated with adrenocortical insufficiency, as well as nervous system abnormalities such as lower limb palsy. His parents, brot-her, sister, son of brother, and son of sister had no related clinical manifestations. Magnetic resonance imaging of the brain and spinal cord showed no abnormalities. Genetic testing showed that the proband had a hemizygous mutation in ABCD1 (c.1628C>T), the mother had a heterozygous mutation in ABCD1, and the father had normal ABCD1. Conclusion There are many types of X-ALD with adrenocortical hypofunction or central nervous system abnormal symptoms. In this case, the patient shows the adrenomyeloneuropathy form of X-ALD. A mutation in the exon 6 of ABCD1 (c.1628C>T:p.P543L) is the cause of the disease. Magne-tic resonance imaging may not play a decisive role in the diagnostic of X-ALD.

Abstract Extensive studies have been conducted on the movement of overlying strata when a single coal seam is mined. However, structural characteristics and associated stress field variation of the overlying strata over multiple coal seam mining remain unclear. Here we performed physical modelling experiments analogous to No. 42108 working face of Buertai coal mine, Shendong coalfield, where No. 22 coal seam (2.9 m thickness) was mined first, preceding No. 42 upper coal seam (6.1 m thickness) with an inter-coal-seam distance of 72.8 m. We employed DIC (digital image correlation) measurement and systematically-laid pressure cells to visualize the overlying strata movement and monitor stress field variations over multiple coal seam mining. We found that the stress of the inter-coal-seam strata increased significantly in the late mining stage of No. 22 coal seam due to the strata collapse, and culminated after compaction of the caved blocks. The inter-coal-seam strata stress gradually decreased over mining of No. 42 upper coal seam and arrived at zero after the inter-coal-seam strata collapsed. The mining of No. 42 upper coal seam aggravated the roof settlement of No. 22 coal seam; and the floor stress was noticeably lower than that of No. 22 coal seam due to the pressure-relief caused by the former mining activity. Our physical modelling findings advanced our understanding on structural characteristics and stress evolutions of overlying strata over multiple coal seam mining and offered guidance for prediction and mitigation of strata movement associated disasters in underground coal mining with geomechanical and mining conditions similar to those of Buertai coal mine.

The aim of the study was to investigate the expression levels of ACE2 in ocular glands and to investigate the effect of S protein on them. Male C57BL/6J mice were used for the experiments. The expression levels of ACE2 are highest in the Meibomian glands, followed by the conjunctiva, the cornea, and the lacrimal glands. Co-immunoprecipitation assays confirmed direct binding between ACE2 and S protein in ocular surface epithelia and Meibomian glands. CD45+ cell infiltration was found in the S protein treatment group, which was accompanied by upregulation of inflammation-related cytokines. There was also prominent cell apoptosis in the S protein treatment group. In conclusion, not only the cornea and the conjunctiva, but also the Meibomian glands express ACE2, and S protein could induce ocular surface epithelial cell and Meibomian gland cell inflammation and apoptosis.

Abstract Background The ventral tegmental area (VTA) contains heterogeneous cell populations. The dopaminergic neurons in VTA play a central role in reward and cognition, while CamKIIα-positive neurons, composed mainly of glutamatergic and some dopaminergic neurons, participate in the reward learning and locomotor activity behaviors. The differences in brain-wide functional and structural networks between these two neuronal subtypes were comparatively elucidated. Methods In this study, we applied a method combining Designer Receptors Exclusively Activated by Designer Drugs (DREADD) and fMRI to assess the cell type-specific modulation of whole-brain neural networks. rAAV encoding the cre-dependent hM3D was injected into the right VTA of DAT-cre or CamKIIα-cre transgenic rats. The global brain activities elicited by DREADD stimulation were then detected using BOLD-fMRI. Furthermore, the cre-dependent antegrade transsynaptic viral tracer H129ΔTK-TT was applied to label the outputs of VTA neurons. Results We found that DREADD stimulation of dopaminergic neurons induced significant BOLD signal changes in the VTA and several VTA-related regions including mPFC, Cg and Septum. More regions responded to selective activation of VTA CamKIIα-positive neurons, resulting in increased BOLD signals in VTA, Insula, mPFC, MC_R (Right), Cg, Septum, Hipp, TH_R, PtA_R, and ViC_R. Along with DREADD-BOLD analysis, further neuronal tracing identified multiple cortical (MC, mPFC) and subcortical (Hipp, TH) brain regions that are structurally and functionally connected by VTA dopaminergic and CamKIIα-positive neurons. Conclusions Our study dissects brain-wide structural and functional networks of two neuronal subtypes in VTA and advances our understanding of VTA functions.

Abstract Severe acute mountain sickness (sAMS) can be life-threatening, but little is known about its genetic basis. The study was aimed to explore the genetic susceptibility of sAMS for the purpose of prediction, using microarray data from 112 peripheral blood mononuclear cell (PBMC) samples of 21 subjects, who were exposed to very high altitude (5260 m), low barometric pressure (406 mmHg), and hypobaric hypoxia (VLH) at various timepoints. We found that exposure to VLH activated gene expression in leukocytes, resulting in an inverted CD4/CD8 ratio that interacted with other phenotypic risk factors at the genetic level. A total of 2286 underlying risk genes were input into the support vector machine recursive feature elimination (SVM-RFE) system for machine learning, and a model with satisfactory predictive accuracy and clinical applicability was established for sAMS screening using ten featured genes with significant predictive power. Five featured genes (EPHB3, DIP2B, RHEBL1, GALNT13, and SLC8A2) were identified upstream of hypoxia- and/or inflammation-related pathways mediated by microRNAs as potential biomarkers for sAMS. The established prediction model of sAMS holds promise for clinical application as a genetic screening tool for sAMS.

Abstract. Background:. Preliminary studies have indicated that Shexiang Baoxin Pill (MUSKARDIA) has a coronary artery dilation effect and increases the coronary blood flow, relieving the symptoms of angina. This study aimed to evaluate the benefit of MUSKARDIA on patients with stable coronary artery disease (CAD) and diabetes mellitus (DM). Methods:. This was a subgroup analysis of a multicenter, randomized, placebo-controlled phase IV trial. CAD patients with a medical history of DM or baseline fasting blood glucose (FBG) ≥7.0 mmol/L were grouped according to the treatment (standard therapy plus MUSKARDIA or placebo). The primary outcome was major adverse cardiovascular events (MACEs), which was the composite outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. The secondary outcome was the composite outcome of all-cause death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina or heart failure, and coronary angioplasty. Results:. MACEs occurred in 2.6% (9/340) and 4.8% (18/376) of patients in the MUSKARDIA and placebo groups, respectively (P = 0.192). Secondary composite outcome was significantly less frequent with MUSKARDIA than with placebo (15.3% [52/340] vs. 22.6% [85/376], P = 0.017). Risk of MACEs (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.31–1.57) was comparable between two groups. In patients with uncontrolled DM (≥4 measurements of FBG ≥7 mmol/L in five times of follow-up), the risk of secondary outcome was significantly lower with MUSKARDIA (5/83, 6.0%) than with placebo (15/91, 16.5%) (HR = 0.35, 95%CI: 0.13–0.95). Conclusion:. As an add-on to standard therapy, MUSKARDIA shows a trend of reduced MACEs in patients with stable CAD and DM. Furthermore, MUSKARDIA may reduce the frequency of all-cause death, hospitalization, and coronary angioplasty in this population, especially in those with uncontrolled DM. Trial Registration:. ChiCTR.org.cn, ChiCTR-TRC-12003513

Abstract Mitochondria determine the physiological status of most eukaryotes. Mitochondrial dynamics plays an important role in maintaining mitochondrial homeostasis, and the disorder in mitochondrial dynamics could affect cellular energy metabolism leading to tumorigenesis. In recent years, disrupted mitochondrial dynamics has been found to influence the biological behaviors of gastrointestinal cancer with the potential to be a novel target for its individualized therapy. This review systematically introduced the role of mitochondrial dynamics in maintaining mitochondrial homeostasis, and further elaborated the effects of disrupted mitochondrial dynamics on the cellular biological behaviors of gastrointestinal cancer as well as its association with cancer progression. We aim to provide clues for elucidating the etiology and pathogenesis of gastrointestinal cancer from the perspective of mitochondrial homeostasis and disorder.

Abstract Recurrence, metastasis, and drug resistance are still big challenges in breast cancer therapy. Internal and external stresses have been proven to substantially facilitate breast cancer progression through molecular and systemic mechanisms. For example, endoplasmic reticulum stress (ERS) results in activation of the unfolded protein response (UPR), which are considered an important cellular stress response. More and more reports indicate its key role in protein homeostasis and other diverse functions involved in the process of breast cancer progression. Therefore, therapies targeting the activation of ERS and its downstream signaling pathways are potentially helpful and novel tools to counteract and fight breast cancer. However, recent advances in our understanding of ERS are focused on characterizing and modulating ERS between healthy and disease states, and so little attention has been paid to studying the role and clinical application of targeting ERS in a certain cancer. In this review, we summarize the function and main mechanisms of ERS in different molecular types of breast cancer, and focus on the development of agents targeting ERS to provide new treatment strategies for breast cancer. Video Abstract

Objective To investigate the expression and its significance of miR-21 and B-cell lymphoma-2(Bcl-2) protein in skin lesions of Xinjiang Uygur patients with psoriasis vulgaris. Methods The expressions of miR-21 were measured with real-time fluorescent quantitative PCR in the 15 psoriatic vulgaris lesions and beside-lesional tissue as well as 15 normal skin samples collected from patients in People's Hospital of Xinjiang Uygur Autonomous Region from 2013 to 2019. The expressions of Bcl-2 were measured with immunohistochemical method in the 51 Uygur patients with psoriasis vulgaris and 29 Uygur normal control. The positive mainly as brown or tan particles in cytoplasm. miR-21 mimics and inhibitors were transient transfected into HaCaT cells. The expression of Bcl-2 protein in transfected cells was detected by Western blot. Results With real-time fluorescent quantitative PCR, the expression of miR-21 was higher in lesions of psoriasis vulgaris than in the beside-lesional tissue(P＜0.01) and normal skin tissue(P＜0.05). Immunohistochemical results showed that the positive expression of Bcl-2 protein was located in the cytoplasm and membrane. The expression rate of psoriasis vulgaris was 35.29%, which was lower than that of normal skin tissue(93.10%)(P＜0.01).The expression of Bcl-2 protein in HaCaT cells transfected with miR-21 mimic and miR-21 inhibitor was detected. With overexpressing miR-21, the expression of Bcl-2 was decreased. With inhibiting miR-21 expression, the Bcl-2 expression was increased(P＜0.01). Conclusions Abnormal expression of miR-21 and Bcl-2 protein in the skin of Xinjiang Uygur patients with psoriasis vulgaris may be involved in the potential mechanism.

Objective: Examine effect of sleep duration on children's risk of overweight and obesity; and study associations between activities in the last hour before bedtime and sleep outcomes (sleep duration, sleep quality, and sleep onset latency). Methods: Children's data were recruited using a questionnaire survey from a nationally representative sample of children (n = 10 279) in China in 2013‒2016. Mixed-effects models were used to test associations among variables stratified by sex. Results: Sleep duration was positively associated with BMI in boys (β = 0.04, P = 0.021). Girls with short sleep durations (< 8 h/d) tended to have higher BMI values than those with normal sleep durations (8‒9 h/d) (β = 0.12, P = 0.063). The top three activities were playing electronic devices (Factor 1), doing homework, and reading (combined as Factor 2). Factors 1 and 2 were both significantly associated with sleep duration (β = 0.17, P < 0.001; β = −0.26, P < 0.001, respectively). Conclusion: Sleep duration seems to affect BMI in Chinese children. Using electronic devices and reading before bedtime influenced sleep duration. Good bedtime habits and sleep duration can help weight management in children.

Sunflower is an important oilseed crop across the world. It is considered as a moderately drought tolerant plant, however, its yield is still negatively affected by drought stress. Improving drought tolerance is of the outmost important for breeding. Although several studies have documented the relationship between the sunflower phenotype and genotype under drought stress, but relatively few studies have simultaneously investigated the molecular mechanisms of drought tolerance in the sunflower at different growth stages. In this study, we conducted quantitative trait locus (QTL) analysis for different sunflower traits during the germination and seedling stages. Eighteen phenotypic traits were evaluated under well-watered and drought stress conditions. We determined that the germination rate, germination potential, germination index, and root-to-shoot ratio can be used as effective indexes for drought tolerance selection and breeding. A total of 33 QTLs were identified on eight chromosomes (PVE: 0.016%–10.712% with LOD: 2.017–7.439). Within the confidence interval of the QTL, we identified 60 putative drought-related genes. Four genes located on chromosome 13 may function in both germination and seedling stages for drought response. Genes LOC110898128, LOC110898092, LOC110898071, and LOC110898072 were annotated as aquaporin SIP1-2-like, cytochrome P450 94C1, GABA transporter 1-like, and GABA transporter 1-like isoform X2, respectively. These genes will be used for further functional validation. This study provides insight into the molecular mechanisms of the sunflower’s in response to drought stress. At the same time, it lays a foundation for sunflower drought tolerance breeding and genetic improvement.

With the widespread application of low-dose computed tomography (LDCT) technology, pulmonary nodules have aroused more attention. Significant alteration in plasma metabolite levels, mainly amino acid and lipid, have been observed in patients of PNs. However, evidence on the association between central carbon metabolism and PNs are largely unknown. The aim of this study was to investigate the underlying association of PNs and plasma central carbon metabolites. We measured the levels of 16 plasma central carbon metabolites in 1954 participants who gained LDCT screening in MALSC cohort. The inverse probability weighting (IPW) technique was used to control for bias due to self-selection for LDCT in the assessed high-risk population. The least absolute shrinkage and selection operator (LASSO) penalized regression was used to deal with the problem of multicollinearity among metabolites and the combined association of central carbon metabolites with PNs was estimated by using quantile g-computation (QgC) models. A quartile increase in 3-hydroxybutyric acid, gluconic acid, succinic acid and hippuric acid was positively associated with the PNs risk, whereas a quartile increase in 2-oxadipic acid and fumaric acid was negatively associated with the risk of PNs in multiple-metabolite models. A positive but insignificant joint associations of the mixture of 16 metabolites with PNs was observed by using QgC models analyses. Further studies are warranted to clarify the association between circulating metabolites and PNs and the biological mechanisms.

Abstract Mutational signatures are characteristic patterns of mutations generated by exogenous mutagens or by endogenous mutational processes. Mutational signatures are important for research into DNA damage and repair, aging, cancer biology, genetic toxicology, and epidemiology. Unsupervised learning can infer mutational signatures from the somatic mutations in large numbers of tumors, and separating correlated signatures is a notable challenge for this task. To investigate which methods can best meet this challenge, we assessed 18 computational methods for inferring mutational signatures on 20 synthetic data sets that incorporated varying degrees of correlated activity of two common mutational signatures. Performance varied widely, and four methods noticeably outperformed the others: hdp (based on hierarchical Dirichlet processes), SigProExtractor (based on multiple non-negative matrix factorizations over resampled data), TCSM (based on an approach used in document topic analysis), and mutSpec.NMF (also based on non-negative matrix factorization). The results underscored the complexities of mutational signature extraction, including the importance and difficulty of determining the correct number of signatures and the importance of hyperparameters. Our findings indicate directions for improvement of the software and show a need for care when interpreting results from any of these methods, including the need for assessing sensitivity of the results to input parameters.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. Methods The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (N cases = 20,806, N controls = 59,804) with ‘omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray N total = 942, protein N total = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). Results SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10−6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10−3, adjusted R 2 = 0.042, B effect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all

Intrauterine adhesion (IUA) is a common gynecological disease with limited therapeutic options. Dulaglutide is a long-acting glucagon-like peptide-1 (GLP-1) analog with some anti-fibrotic and anti-inflammatory properties; however, its action on IUA remains uncertain. The purpose of the experiments in this study was to explore the effect of dulaglutide on IUA and to elucidate its mechanism to provide new ideas for the clinical treatment of IUA. An IUA mouse model was established via mechanical curettage and inflammation induction; mice received subcutaneous injection with three doses of dulaglutide once a day for two weeks (treatment) or equal amounts of sterile ddH2O (control), and sham-operated mice were treated similarly to the control mice. Mice were sacrificed, and uterine tissues were subjected to hematoxylin and eosin (H&E) and Masson’s trichrome staining for histomorphological and pathological analyses and real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting (WB) for gene and protein expression analyses. Dulaglutide improved the shape of the uterine cavity, increased endometrial thickness and the number of glands, and significantly reduced the area of collagen fiber deposition in the endometrium. It significantly reduced collagen type I A 1 (COL1A1), interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), C-C motif chemokine ligand 2 (CCL2), F4/80 (macrophage), vimentin and transforming growth factor-beta (TGF-β) mRNA levels and COL1A1, IL-1β, IL-6, TNF-α, F4/80, vimentin, E-cadherin, TGF-β, and p-Smad2 protein expression levels. This study demonstrates that dulaglutide reduces inflammatory responses by inhibiting M1 macrophage polarization and inflammatory factor release and may ameliorate fibrosis by inhibiting epithelial–mesenchymal transition (EMT) via TGF-β/Smad2 signaling.

Abstract It’s a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86–19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82–20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06–15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r 2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

Objectives This study aims to examine the association of work-related basic need satisfaction (W-BNS) with doctors’ work engagement and explore the mediating role of work motivation and job satisfaction between the two variables.Design This was a cross-sectional study.Setting The study was conducted in four public grade A tertiary hospitals in China.Participants A total of 1000 doctors were invited to participate; 849 doctors completed questionnaires validly.Primary and secondary outcome measures Questionnaires were administered online and offline to collect data, consisting of six parts: social demographic characteristics, work-related characteristics, and scales related to W-BNS, work motivation, job satisfaction and work engagement. One-way analysis of variance, Pearson correlation analysis were performed using SPSS, and mediation analysis was carried out via PROCESS macro.Results Our research showed that W-BNS, work motivation, job satisfaction and work engagement were positively correlated. Work engagement was significantly predicted by W-BNS (β＝0.15, p

Objective Hypertension predicts the development of diabetes. However, there are still lacking high-quality studies on the correlation between mean arterial pressure (MAP) and incident diabetes. We aimed to explore the relationship between MAP and diabetes in Chinese adults.Design This is a secondary retrospective cohort study and the data were downloaded from the ‘DATADRYAD’ database (www.Datadryad.org).Participants The study included 210 418 adults without diabetes at baseline between 2010 and 2016 across 32 sites and 11 cities in China.Setting The target-independent and dependent variables were MAP measured at baseline and diabetes occurred during follow-up. Cox proportional hazards regression was used to explore the relationship between MAP and diabetes.Primary outcome measures The outcome was incident diabetes, which was defined as fasting blood glucose ≥7.00 mmol/L and/or self-reported diabetes during follow-up. Patients were censored either at the time of the diagnosis or at the last visit, whichever comes first.Results 3927 participants developed diabetes during a 5-year follow-up. After adjusting covariates, MAP positively correlated with diabetes (HR=1.008, 95% CI 1.005 to 1.011, p

Objective: To explore the related factors of enlarged perivascular spaces (EPVS) and lacunes in the patients with hypertension, and to provide a basis for the prevention and treatment of cerebral small vessel disease. Methods: A total of 1 070 patients with essential hypertension without stroke history were enrolled, and the data was analyzed retrospectively. All patients received MRI scanning and ambulatory blood pressure monitoring. According to MRI images, they were divided into normal control, EPVS and lacunes groups, respectively. Univariate and multivariate logistic regression were performed among three groups to determine the factors related to EPVS and lacunes. Results: The indexes including age, gender, smoking, diabetes history, antiplatelet drugs, statins, hypertension duration, nocturnal blood pressure dip degree, mean systolic blood pressure, cholesterol, triglyceride, high-density lipoprotein, low density lipoprotein, urea nitrogen, creatinine, homocysteine and carotid plaque were significantly different among EPVS, lacunes and controls groups. Mean high systolic blood pressure and age were independent risk factors for EPVS, while the dipping degree of blood pressure, antiplatelet medicines and statins were independent protective factors for it. High mean systolic blood pressure, old age, smoking, and diabetes were independent risk factors for lacunes, while the dipping degree of nocturnal blood pressure, antiplatelet medicines and statins were independent protective factors for lacunes. Conclusions: For the patients with hypertension, the increase of mean systolic blood pressure and the decrease of nocturnal blood pressure dipping are the risk factors for EPVS and lacunes. Besides controlling mean systolic blood pressure level, the patients with hypertension should also receive chronotherapy to restore the normal nocturnal blood pressure dipping through changing the time of taking medicine.

Abstract The COVID-19 pandemic poses a global threat to public health and economy. The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines. In this study, we identified that EK1 and cholesterol-coupled derivative of EK1, EK1C4, as pan-CoV fusion inhibitors, exhibit potent antiviral activity against SARS-CoV-2 infection in both lung- and intestine-derived cell lines (Calu-3 and Caco2, respectively). They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7 (Alpha) and B.1.1.248 (Gamma) as well as those with mutations in S protein, including N417T, E484K, N501Y, and D614G, which are common in South African and Brazilian variants. Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity. Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues. EK1 showed good safety profiles in various animal models, supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.

Abstract. Background:. The Shexiang Baoxin Pill (MUSKARDIA) has been used for treating coronary artery disease (CAD) and angina for more than 30 years in China. Nevertheless, methodologically sound trials on the use of MUSKARDIA in CAD patients are scarce. The aim of the study is to determine the effects of MUSKARDIA as an add-on to optimal medical therapy (OMT) in patients with stable CAD. Methods:. A total of 2674 participants with stable CAD from 97 hospitals in China were randomized 1:1 to a MUSKARDIA or placebo group for 24 months. Both groups received OMT according to local tertiary hospital protocols. The primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary outcomes included all-cause mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina or heart failure, peripheral revascularization, angina stability and angina frequency. Results:. In all, 99.7% of the patients were treated with aspirin and 93.0% with statin. After 2 years of treatment, the occurrence of MACEs was reduced by 26.9% in the MUSKARDIA group (MUSKARDIA: 1.9% vs. placebo: 2.6%; odds ratio = 0.80; 95% confidence interval: 0.45–1.07; P = 0.2869). Angina frequency was significantly reduced in the MUSKARDIA group at 18 months (P = 0.0362). Other secondary endpoints were similar between the two groups. The rates of adverse events were also similar between the two groups (MUSKARDIA: 17.7% vs. placebo: 17.4%, P = 0.8785). Conclusions:. As an add-on to OMT, MUSKARDIA is safe and significantly reduces angina frequency in patients with stable CAD. Moreover, the use of MUSKARDIA is associated with a trend toward reduced MACEs in patients with stable CAD. The results suggest that MUSKARDIA can be used to manage patients with CAD. Trial registration. chictr.org.cn, No. ChiCTR-TRC-12003513

Abstract Identifying individuals at high risk for incident diabetes could help achieve targeted delivery of interventional programs. We aimed to develop a personalized diabetes prediction nomogram for the 3-year risk of diabetes among Chinese adults. This retrospective cohort study was among 32,312 participants without diabetes at baseline. All participants were randomly stratified into training cohort (n = 16,219) and validation cohort (n = 16,093). The least absolute shrinkage and selection operator model was used to construct a nomogram and draw a formula for diabetes probability. 500 bootstraps performed the receiver operating characteristic (ROC) curve and decision curve analysis resamples to assess the nomogram's determination and clinical use, respectively. 155 and 141 participants developed diabetes in the training and validation cohort, respectively. The area under curve (AUC) of the nomogram was 0.9125 (95% CI, 0.8887–0.9364) and 0.9030 (95% CI, 0.8747–0.9313) for the training and validation cohort, respectively. We used 12,545 Japanese participants for external validation, its AUC was 0.8488 (95% CI, 0.8126–0.8850). The internal and external validation showed our nomogram had excellent prediction performance. In conclusion, we developed and validated a personalized prediction nomogram for 3-year risk of incident diabetes among Chinese adults, identifying individuals at high risk of developing diabetes.

Objective: Gamma knife radiosurgery (GKRS) has served as an adjunctive treatment in Cushing’s disease (CD) for decades and has become a vital part of therapy in the management of CD. Biological effective dose (BED) is a radiobiological parameter with time correction, considering the cellular deoxyribonucleic acid repairment. We aimed to investigate the safety and efficacy of GKRS for CD and evaluate the association of BED and treatment outcome. Methods: A cohort study of 31 patients with CD received GKRS in West China Hospital between June 2010 and December 2021. Endocrine remission was defined as normalization of 24 h urinary free cortisol (UFC) or serum cortisol ≤ 50 nmol/L after a 1 mg dexamethasone suppression test. Result: The mean age was 38.6 years old, and females accounted for 77.4%. GKRS was the initial treatment for 21 patients (67.7%), and 32.3% of patients underwent GKRS after surgery due to residual disease and recurrence. The mean endocrine follow-up duration was 22 months. The median marginal dose was 28.0 Gy, and the median BED was 221.5 Gy2.47. Fourteen patients (45.1%) experienced control of hypercortisolism in the absence of pharmacological treatment, and the median duration to remission was 20.0 months. The cumulative rates of endocrine remission at 1, 2, and 3 years after GKRS were 18.9%, 55.3%, and 72.21%, respectively. The total complication rate was 25.8%, and the mean duration from GKRS to hypopituitary was 17.5 months. The new hypopituitary rate at 1, 2, and 3 years were 7.1%, 30.3%, and 48.4%, respectively. A high BED level (BED > 205 Gy2.47) was associated with better endocrine remission than a low BED level (BED ≤ 205 Gy2.47), while no significant differences were found between the BED level and hypopituitarism. Conclusions: GKRS was a second-line therapeutic option for CD with satisfactory safety and efficacy. BED should be considered during GKRS treatment planning, and optimization of BED is a potentially impactful avenue toward improving the efficacy of GKRS.

Background: In acute myocardial infarction (AMI), acute hepatic injury is an independent risk factor for prognosis and is associated with complex coagulation dynamics. This study aims to determine the interaction between acute hepatic injury and coagulation dysfunction on outcomes in AMI patients. Methods: The Medical Information Mart for Intensive Care (MIMIC-III) database was used to identify AMI patients who underwent liver function testing within 24 h of admission. After ruling out previous hepatic injury, patients were divided into the hepatic injury group and the nonhepatic injury group based on whether the alanine transaminase (ALT) level at admission was >3 times the upper limit of normal (ULN). The primary outcome was intensive care unit (ICU) mortality. Results: Among 703 AMI patients (67.994% male, median age 65.139 years (55.757–76.859)), acute hepatic injury occurred in 15.220% (n = 107). Compared with the nonhepatic injury group, patients with hepatic injury had a higher Elixhauser comorbidity index (ECI) score (12 (6–18) vs. 7 (1–12), p < 0.001) and more severe coagulation dysfunction (85.047% vs. 68.960%, p < 0.001). In addition, acute hepatic injury was associated with increased in-hospital mortality (odds ratio (OR) = 3.906; 95% CI: 2.053–7.433; p < 0.001), ICU mortality (OR = 4.866; 95% CI: 2.489–9.514; p < 0.001), 28-day mortality (OR = 4.129; 95% CI: 2.215–7.695; p < 0.001) and 90-day mortality (OR = 3.407; 95% CI: 1.883–6.165; p < 0.001) only in patients with coagulation disorder but not with normal coagulation. Unlike patients with coagulation disorder and normal liver, patients with both coagulation disorder and acute hepatic injury had greater odds of ICU mortality (OR = 8.565; 95% CI: 3.467–21.160; p < 0.001) than those with normal coagulation. Conclusions: The effects of acute hepatic injury on prognosis are likely to be modulated by early coagulation disorder in AMI patients.

Andrographolide (Andro), the major constituent of Andrographis paniculata Nees (Acanthaceae), is was known to reduces inflammatory reaction. In the current study, the ability of Andro to reduce pain sensation in a rat post-operative wound model was explored. The hind paws of 18 Sprague-Dawley rats (SD) bearing post-operative wounds received the following three treatments: Saline, Andro via direct injection into the paw (Andro-injected) and Tablet containing Andro + poly (lactic-co-glycolic acid) (PLGA) (Andro-tablet). Von Frey tests assessed mechanical allodynia at 1, 3, 5 h and 1-, 2-, 3-, 4-, and 5-days post-operation. Behavioral analyses were performed to measure reaction threshold and reaction frequencies. Immunoreactivity of p-ERK and GluR1 was examined in the dorsal horn of the spinal cord. Histopathological and immunostaining studies were conducted on paw epidermis to observe the gross morphology and angiogenesis. The threshold for inducing allodynia increased and the reaction frequency reduced in the Andro-injected group compared to the saline-group, at 3 h post-surgery and the effect lasted between 3–4 days. The threshold for inducing pain and reaction frequency for the Andro-tablet group did not differ from the saline-treated group. The levels of p-ERK and GluR1 in the dorsal horn were reduced after Andro treatment. No significant difference in wound healing index was observed between saline and Andro-injected groups, but CD-31 staining showed less angiogenesis in the Andro-injected group. Andro significantly reduced mechanical allodynia compared to saline treatment, both in shorter and longer time frames. Furthermore, Andro influenced the expression of p-ERK and GluR1 in the dorsal horn, and the angiogenesis process in the wound healing area.

Background The microbial decomposition of soil organic carbon (SOC) is a major source of carbon loss, especially in ecologically fragile regions (e.g., the Tibetan Plateau), which are also affected by global warming and anthropogenic activities (e.g., fertilization). The inherent differences between bacteria and fungi indicate that they are likely to play distinct roles in the above processes. However, there still have been no reports on that, which is restricting our knowledge about the mechanisms underlying SOC decomposition. Methods A long-term nitrogen (N) and phosphorus (P) addition field experiment was conducted to assess their effects on soil microbial, fungal, and bacterial respiration (RM, RF, and RB, respectively) and temperature sensitivity (Q10; at 15 °C, 25 °C, and 35 °C) using cycloheximide and streptomycin to inhibit the growth of fungi and bacteria. Results We found that N suppressed RM and RF at all temperatures, but RB was only suppressed at 15 °C, regardless of the addition of P. The addition of N significantly decreased the ratio of RF/RM at 35 °C, and the combined NP treatment increased the Q10 of RB but not that of RF. Results of the redundancy analysis showed that variations in soil respiration were linked with NO3−-N formation, while the variations in Q10 were linked with SOC complexity. Long-term N addition suppressed RM by the formation of NO3−-N, and this was mediated by fungi rather than bacteria. The contribution of fungi toward SOC decomposition was weakened by N addition and increasing temperatures. Combined NP addition increased the Q10 of RB due to increased SOC complexity. The present study emphasizes the importance of fungi and the soil environment in SOC decomposition. It also highlights that the role of bacteria and SOC quality will be important in the future due to global warming and increasing N deposition.

Drought is one of the most serious abiotic stress factors limiting crop yields. Although sunflower is considered a moderate drought-tolerant plant, drought stress still has a negative impact on sunflower yield as cultivation expands into arid regions. The extent of drought stress is varieties and time-dependent, however, the molecular response mechanisms of drought tolerance in sunflower with different varieties are still unclear. Here, we performed comparative physiological and transcriptome analyses on two sunflower inbred lines with different drought tolerance at the seedling stage. The analysis of nine physiological and biochemical indicators showed that the leaf surface area, leaf relative water content, and cell membrane integrity of drought tolerance inbred line were higher than those of drought-sensitive inbred line under drought stress, indicating that DT had stronger drought resistance. Transcriptome analyses identified 24,234 differentially expressed genes (DEGs). Gene ontology (GO) analysis showed the up-regulated genes were mainly enriched in gibberellin metabolism and rRNA processing, while the down-regulated genes were mainly enriched in cell-wall, photosynthesis, and terpene metabolism. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis showed genes related to GABAergic synapse, ribosome biogenesis were up-regulated, while genes related with amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, photosynthesis were down-regulated. Mapman analysis revealed differences in plant hormone-signaling genes over time and between samples. A total of 1,311 unique putative transcription factors (TFs) were identified from all DEGs by iTAK, among which the high abundance of transcription factor families include bHLH, AP2/ERF, MYB, C2H2, etc. Weighted gene co-expression network analysis (WGCNA) revealed a total of 2,251 genes belonging to two modules(blue 4, lightslateblue), respectively, which were significantly associated with six traits. GO and KEGG enrichment analysis of these genes was performed, followed by visualization with Cytoscape software, and the top 20 Hub genes were screened using the CytoHubba plugin.

Objective To investigate the clinical features, endoscope diagnosis, and treatment of cases of colorectal foreign bodies. Methods A retrospective analysis of colorectal foreign body cases admitted to the Digestive Endoscope Center from June 2005 to September 2018 were completed. The information of gender, age, source and location of foreign bodies, complications, and methods of removal was collected so that characteristics and management experience were summarized. Results A total of 14 cases of colorectal foreign bodies were included, among which there were 10 males (71%) with an average age of 49 years old (21-80 years old). The origin of foreign body included iatrogenic (5 cases), oral (3 cases), anal (5 cases) and one case of unknown reason. As to the position of foreign bodies, iatrogenic and oral foreign bodies might distribute in the whole colon, while anal foreign bodies located in sigmoid-rectum mainly. In total 6 cases suffered from foreign body-related complications, including mucosal injury (1 case), intestinal wall injury (2 cases), intestinal obstruction (2 cases) and liver abscess (1 case). We attempted to remove foreign bodies under endoscopy in 12 cases, with success in 11 cases; the instruments used were foreign body forceps (7 cases) and snares (5 cases). The main reason of failure was big size of foreign bodies. Conclusions The distribution of colorectal foreign bodies is related to its origin; colorectal foreign bodies may cause colonic mucosal injury, intestinal obstruction or intestinal perforation, and even severe peritoneal infection; when attempting to remove colorectal foreign body under endoscope, foreign body forceps and snares can be used. After the foreign body's removal, it is necessary to be alert of the colon perforation.

Abstract Background The role of body fat distribution in uric acid metabolism is still ambiguity. We aimed to investigate the independent contribution of visceral adipose measured by visceral adiposity index and lipid accumulation product and liver fat assessed by fatty liver index to the risk of hyperuricemia. Methods We conducted a cross-sectional study involving 1284 participants aged ≥ 40 years old recruited from communities in Zhonglou district, Changzhou. Each participant completed a standard questionnaire, and provided blood samples for biochemical measurements. Visceral adiposity index, fatty liver index and lipid accumulation product were calculated by simple anthropometric and functional parameters. Hyperuricemia was defined as serum uric acid ≥ 420 μmol/l for males and ≥ 360 μmol/l for females. Results The prevalence of hyperuricemia was 15.9% and gradually increased across tertiles of adiposity-based indices. The visceral adipose-based measurements (visceral adiposity index, fatty liver index, lipid accumulation product) had better power to discriminate hyperuricemia than body mass index (BMI), waist circumference and neck circumference, and visceral adiposity index exhibited the highest power, with the area under the receiver operating characteristics curve (AUROC) of 0.662 (0.636–0.688). Multivariate logistic regression found 1.49-fold, 2.21-fold and 2.12-fold increased risk of hyperuricemia with 1-unit increment of visceral adiposity index, fatty liver index, and lipid accumulation product, respectively. Compared to tertile 1, the odds ratios of hyperuricemia for the second tertile and the third tertile of visceral adiposity index were 1.57 (1.00–2.50) and 3.11 (1.96–4.94), those of fatty liver index were 1.64 (1.05–2.68) and 3.58 (1.94–6.01), and those of lipid accumulation product were 1.93 (1.19–3.15) and 3.53 (2.05–6.09), respectively. However, no significant associations of BMI, waist circumference and neck circumference with hyperuricemia were observed. Conclusions Visceral adipose accumulation increased the risk of hyperuricemia, independently of BMI, waist circumference and neck circumference, among middle-aged and elderly Chinese adults.

(1) Background: Laparoscopic sleeve gastrectomy (LSG) is widely performed in bariatric surgery. However, the prevalence and risk factors of gastroesophageal reflux disease (GERD) symptoms after LSG remain unclear to date. This study aimed to identify risk factors of GERD after LSG. (2) Methods: We conducted a retrospective study at Linkou Chang Gung Memorial Hospital and reviewed 296 patients who underwent LSG from 2016 to 2019. A total of 143 patients who underwent preoperative esophagogastroduodenoscopy and completed the 12-month postoperative follow-up were enrolled. Patients’ demographic data, comorbidities, and postoperative weight loss results were recorded for analysis. The GerdQ questionnaire was used to assess GERD after LSG. (3) Results: There were eight surgical complications (5.6%) among the 143 studied patients (median age, 36 years; 56 (39.2%) men; median body weight 105.5 kg; median body mass index [BMI], 38.5 kg/m2). Twenty-three patients (16.1%) developed de novo GERD symptoms. GERD was significantly associated with older age (p = 0.022) and lower BMI (2, p = 0.028). In multiple logistic regression analysis, age and BMI were significantly associated with GERD. (4) Conclusions: LSG is a safe and effective weight loss surgery. In our study, it led to 16.1% of de novo GERD symptoms, which were significantly related to older age and lower BMI (2).

Introduction Perianal fistulising Crohn’s disease (pfCD) can be somewhat treatment refractory. Higher infliximab trough levels (TLIs) may improve fistula healing rates; however, it remains unclear whether escalating infliximab therapy to meet higher TLI targets using proactive, or routine, therapeutic drug monitoring (TDM) improves outcomes. This randomised controlled trial aimed to assess whether infliximab therapy targeting higher TLIs guided by proactive TDM improves outcomes compared with standard therapy.Methods and analysis Patients with active pfCD will be randomised 1:1 to either the proactive TDM arm or standard dosing arm and followed up for 54 weeks. Patients in the proactive TDM arm will have infliximab dosing optimised to target higher TLIs. The targets will be TLI ≥ 25 µg/mL at week 2, ≥ 20 µg/mL at week 6 and ≥ 10 µg/mL during maintenance therapy. The primary objective will be fistula healing at week 32. Secondary objectives will include fistula healing, fistula closure, radiological fistula healing, patient-reported outcomes and economic costs up to 54 weeks. Patients in the standard dosing arm will receive conventional infliximab dosing not guided by TLIs (5 mg/kg at weeks 0, 2 and 6, and 5 mg/kg 8 weekly thereafter). Patients aged 18–80 years with pfCD with single or multiple externally draining complex perianal fistulas who are relatively naïve to infliximab treatment will be included. Patients with diverting ileostomies or colostomies and pregnant or breast feeding will be excluded. Fifty-eight patients per arm will be required to detect a 25% difference in the primary outcome measure, with 138 patients needed to account for an estimated 6.1% primary non-response rate and 10% dropout rate.Ethics and dissemination Results will be presented in peer-reviewed journals and international conferences. Ethics approval has been granted by the South Western Sydney Local Health District Human Research Ethics Committee in Australia.Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN12621000023853); Pre-results.

Neuropsychiatric systemic lupus erythematosus (NPSLE) has a broad spectrum of subtypes with diverse severities and prognoses. Ischemic and inflammatory mechanisms, including autoantibodies and cytokine-mediated pathological processes, are key components of the pathogenesis of NPSLE. Additional brain-intrinsic elements (such as the brain barrier and resident microglia) are also important facilitators of NPSLE. An improving understanding of NPSLE may provide further options for managing this disease. The attenuation of neuropsychiatric disease in mouse models demonstrates the potential for novel targeted therapies. Conventional therapeutic algorithms include symptomatic, anti-thrombotic, and immunosuppressive agents that are only supported by observational cohort studies, therefore performing controlled clinical trials to guide further management is essential and urgent. In this review, we aimed to present the latest pathogenetic mechanisms of NPSLE and discuss the progress in its management.

Abstract Background Major challenges in understanding the functional consequences of genetic risk factors for human disease are which tissues and cell types are affected and the limited availability of suitable tissue. The aim of this study was to evaluate tissue-specific genotype-epigenetic characteristics in DNA samples from both endometrium and blood collected from women at different stages of the menstrual cycle and relate results to genetic risk factors for reproductive traits and diseases. Results We analysed DNA methylation (DNAm) data from endometrium and blood samples from 66 European women. Methylation profiles were compared between stages of the menstrual cycle, and changes in methylation overlaid with changes in transcription and genotypes. We observed large changes in methylation (27,262 DNAm probes) across the menstrual cycle in endometrium that were not observed in blood. Individual genotype data was tested for association with methylation at 443,016 and 443,101 DNAm probes in endometrium and blood respectively to identify methylation quantitative trait loci (mQTLs). A total of 4546 sentinel cis-mQTLs (P

Background Polycystic ovary syndrome (PCOS) is a common gynecological disease that is often accompanied by some metabolic abnormality such as insulin resistance and dyslipidemia. As a non-pharmacological therapy, acupuncture is widely used for the treatment of PCOS, but the effectiveness for insulin resistance and lipid metabolic disorder remains controversial. Objectives To assess the effectiveness and safety of acupuncture for insulin resistance and lipid metabolic disorder of women with PCOS. Search methods Eight databases will be searched from inception to June 2021, three clinical trial registration platforms will be searched for relevant trials. Selection criteria Randomized controlled trials (RCTs) of acupuncture therapy for insulin resistance and lipid metabolic of PCOS will be included. Data collection and analysis Study screening, data collection, and analysis will be performed by two or more reviewers independently. We will calculate mean difference (MD), standard mean difference (SMD) with 95% confidence intervals (CIs). Data synthesis will be performed with RevMan V.5.3 software and with Stata V.15.0 software when necessary. PROSPERO registration number CRD42020177846

The 4SPRR-SPR parallel robot, which has considerable potential for application in the field of machining, is a novel closed-loop mechanism with a high rigid-weight ratio. Kinematics and workspace analyses of the 4SPRR-SPR parallel robot are key requirements for its application in machining. In this study, the inverse kinematics of the 4SPRR-SPR parallel robot is analyzed using a geometric method based on the mechanism arrangement of the robot. The forward kinematics model is derived by training the vector-quantified temporal associative memory (VQTAM) network, which originates from a self-organizing map (SOM). Furthermore, an improved algorithm is obtained by combining the locally linear embedding (LLE) and VQTAM methods. A boundary extraction algorithm for the workspace analysis of the parallel robot is proposed. The performance of the boundary extraction algorithm is analyzed and compared with that of a global search algorithm; the result indicates that the novel algorithm has the same computational accuracy in addition to higher efficiency. The workspace of the 4SPRR-SPR parallel robot is analyzed using the boundary extraction algorithm. Finally, the 3D model of the 4SPRR-SPR parallel robot is simulated using the ADAMS software to verify the reliability of the proposed algorithms. The simulation results demonstrate the effectiveness of the methods proposed in this study. In addition, the robot kinematics and workspace analysis methods described herein can be extended to other serial and parallel robots. This research provides a theoretical framework for trajectory planning of mechanisms, workspace optimization of robots, and robotic control.

Introduction The catheter is the only intravascular portion of an implanted port and plays a crucial role in catheter related complications. Both polyurethane and silicone are biocompatible materials which are utilized for catheter manufacturing, but their correlation to complications remains controversial. The aim of this study was to try to analyze the relationship between catheter materials and complications. Materials and methods A total of 3144 patients who underwent intravenous port implantation between March 2012 and December 2018 at Chang Gung Memorial Hospital, Linkou, Taiwan were recruited. Of these, 1226 patients received silicone catheter port implantation and 1679 received polyurethane catheter ports. Case matching was done prior to analysis and catheter related complications and cumulative complication incidence for each group were compared. Results Intergroup differences were identified in entry vessel (p = 0.0441), operation year (p < 0.0001), operation method (p = 0.0095), functional period (p < 0.0001), patient follow up status (p < 0.0001), operating time for vessel cutdown (p < 0.0001) and wire assisted approach (p = 0.0008). Stratified by specific entry vessel, no statistical difference was found in complication rate or incidence between the silicone and polyurethane groups. We further compared the cumulative complication incidence of the silicone and polyurethane groups, and also found no statistical difference (p = 0.4451). Conclusion As long as external stress forces generated by surrounding structures and focused on potential weak points are avoided, both silicone and polyurethane materials provide sufficient structural stability to serve as reliable vascular access for patients.

Background: Sequestration and cytoadherence of Plasmodium falciparum-infected erythrocytes (IE) to microvascular endothelium alters endothelial barrier function and plays a role in the pathogenesis of severe malaria. Binding of IE is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1) and the PfEMP1 variants that binds to endothelial protein C receptor (EPCR) have, in particular, been associated with the dysregulation of the coagulation/inflammation pathways in endothelial cells. This has prompted speculation about the role of protease-activated receptor-1 (PAR1) activation and signalling in causing endothelial activation and loss of barrier function in cerebral malaria. Methods: We used a co-culture of primary human brain microvascular endothelial cells (HBMEC) with P. falciparum material, recombinant PfEMP1 or lysates from IE, and measured barrier function by trans endothelial electrical resistance (TEER). A selection of PAR1 inhibitors was tested for their ability to reverse the P. falciparum and thrombin induced decrease in barrier function. Results: An initial screen in the presence of recombinant PfEMP1 identified a few inhibitors that were able to reduce the rapid thrombin-induced barrier disruption even when activated protein C (aPC) was unable to do so. However, PAR1 inhibitors did not rescue the barrier dysfunction after co-culture with IE lysate. Conclusions: The selected PAR1 inhibitors were able to reverse the disruption of barrier function by thrombin but did not reverse the IE lysate induced disruption of barrier function, implicating a different PAR1-independent mechanism. These findings have implications for the design of adjunct therapies to reduce brain swelling in cerebral malaria.

Evidence suggests the existence of association between a large panel of modifiable biomarkers representing inflammation, coagulation, paraoxonase, and endothelial activation pathways and carotid atherosclerosis. Thus, this study investigated whether CRP, FGA, FGB, FGG, PON1, and EDNRA gene variants affected plasma hs-CRP, fibrinogen levels, and thickness of carotid intima media thickness (IMT). Nineteen single-nucleotide polymorphisms of CRP, FGA, FGB, FGG, PON1, and EDNRA genes were examined in 480 participants from 160 families. Carotid IMT was measured by ultrasound. Generalized linear models with generalized estimating equation were utilized to consider the dependence of subjects within families. In the recessive model, homozygotes for the minor alleles of rs1800789, rs1800790 and rs4220 SNPs in FGB gene indicated a reduced risk of IMT (Exp. β = 0.89, 0.89, 0.88), which remained significant after adjustment for confounding factors. Significant interaction effects between CRP SNP rs1130864 and rs3093059 and gender for IMT were observed with a significant association in men only. Men carrying minor-minor genotype of CRP SNP rs1130864 and rs3093059 had 0.70- and 0.78-fold lower IMT than men carrying minor-major/major-major genotype. We also observed that the interaction of CRP SNP rs1130864 and rs3093059 with obesity on IMT, hs-CRP and fibrinogen levels. These results support the hypothesis that inflammatory genes are involved in atherosclerosis, most likely via complex gene-gender and gene-obesity interactions.

This study assessed the interactions among IGF-1, AKT2, FOXO1, and FOXO3 variations and the interactions of gene and physical activity on handgrip strength, arm muscle mass-adjusted handgrip (armGrip), gait speed (GS), timed up and go (TUG), and leg press strength (LPS). Nine single nucleotide polymorphisms (SNPs) containing three IGF-1 SNPs (rs6214, rs5742692, and rs35767), two AKT2 SNPs (rs892119 and rs35817154), two FOXO1 SNPs (rs17446593 and rs10507486), and two FOXO3 SNPs (rs9480865 and rs2153960) were genotyped in 472 unrelated elders with a mean age of 73.8 years. We observed significant interactions of IGF-1 SNP rs6214 and rs35767 with regular physical activity on TUG and GS; and AKT2 SNP rs892119 and FOXO3 SNP rs9480865 with regular physical activity on armGrip. Genotype GG of IGF-1 rs6214 and rs35767 in individuals without regular physical activity had poor performance in TUG and GS, as well as GG of AKT2 rs892119 decreased armGrip in individuals without regular physical activity. After FDR adjustment, no significant gene-gene interactions were found. A sedentary lifestyle may increase the risk of impairing physical performance and regular physical activity is a remedy for sarcopenia, even a little regular physical activity can overcome carrying some risk alleles in this pathway.

Background The major landscape in the hilly-gully region of the Loess Plateau is greatly affected by vegetation rehabilitation on abandoned cropland. Although many studies have shown that the rehabilitation have greatly improved soil conditions and protected them from erosion, these effectiveness were not always in consensus possibly due to the land type of vegetation or to the rehabilitation time. To close this gap, we conducted a long term experiment as follows. Methods In this study, we analysed four land types of vegetation rehabilitation (shrub land, woodland, naturally revegetated grassland, and orchard land) with different rehabilitation times and investigated the mechanical composition and erodibility of the soil. Areas of slope croplandand natural forest were selected as controls. Results The results showed that soil depth, rehabilitation time and rehabilitation land type had strong impacts on soil mechanical composition, micro-aggregation and erodibility. Following rehabilitation, naturally revegetated grassland and shrub land had lower fractal dimensions of particle size distribution (fractal dimensions of PSD), fractal dimensions of micro-aggregation, and erodibility (K factor) than did cropland. Compared to the positive effects of rehabilitation mainly happened in the topsoil layer at other rehabilitation land type, that of woodland happened in the deeper soil layer. Besides, the indispensable rehabilitation time for the significant improvement of soil condition was shorter at naturally revegetated grassland than that at shrub land and woodland. Discussion Although rehabilitation time was more influential than was rehabilitation land type or soil depth, the differences among the rehabilitation land types showed that naturally revegetated grassland with native plants is the most time-saving rehabilitation vegetation for the Loess Plateau in the conversion from slope cropland. The success of rehabilitation in this forestry practice was mainly contributed by the suited species of rehabilitation land type to the local climate and soil. Based on the differences of rehabilitation effectiveness resulting from land type, we should be cautious to choose land types for the rehabilitation of soil conditions in the Loess Plateau.

Abstract Chronic lymphocytic thyroiditis (CLT) is a common autoimmune disorder. The possible pathogenic role and mechanism of dibutyl phthalate (DBP) in CLT is still controversial. Experiments were conducted after 35-days of oral exposure to the three concentrations of DBP or saline, and three immunizations with thyroglobulin (TG). Healthy female Wistar rats were randomly divided into ten exposure groups (n = 8 each): (A) saline control, (B) 0.5 mg/kg/d DBP, (C) 5 mg/kg/d DBP, (D) 50 mg/kg/d DBP, (E) TG-immunized group, (F) TG- combined with 0.5 mg/kg/d DBP, (G) TG- combined with 5 mg/kg/d DBP, (H) TG- combined with 50 mg/kg/d DBP, (I) TG- combined with 50 mg/kg/d DBP plus 100 mg/kg/d vitamin C; (J) 100 mg/kg/d vitamin C. We showed that oral exposure DBP can aggravate CLT in rats. This deterioration was concomitant with increased thyroid auto antibodies, Th1/Th2 imbalance and Th17 immune response, activated pro-inflammatory and apoptosis pathways, and increased thyroid dysfunction in rats. Our results also suggested that DBP could promote oxidative damage. The study also found that vitamin C reduced the levels of oxidative stress and alleviated CLT. In short, the study showed that DBP exacerbated CLT through oxidative stress.