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Abstract Ulcerative colitis (UC) is an idiopathic, chronic inflammatory condition of the colon, characterized by repeated attacks, a lack of effective treatment options, and significant physical and mental health complications for patients. The endoplasmic reticulum (ER) is a vital intracellular organelle in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is induced when the body is exposed to adverse external stimuli. Numerous studies have shown that ERS-induced apoptosis plays a vital role in the pathogenesis of UC. Mogroside V (MV), an active ingredient of Monk fruit, has demonstrated excellent anti-inflammatory and antioxidant effects. In this study, we investigated the therapeutic effects of MV on dextran sulfate sodium (DSS)-induced UC and its potential mechanisms based on ERS. The results showed that MV exerted a protective effect against DSS-induced UC in mice as reflected by reduced DAI scores, increased colon length, reduced histological scores of the colon, and levels of pro-inflammatory cytokines, as well as decreased intestinal permeability. In addition, the expression of ERS pathway including BIP, PERK, eIF2α, ATF4, CHOP, as well as the apoptosis-related protein including Caspase-12, Bcl-2 and Bax, was found to be elevated in UC. However, MV treatment significantly inhibited the UC and reversed the expression of inflammation signaling pathway including ERS and ERS-induced apoptosis. Additionally, the addition of tunicamycin (Tm), an ERS activator, significantly weakened the therapeutic effect of MV on UC in mice. These findings suggest that MV may be a therapeutic agent for the treatment of DSS-induced UC by inhibiting the activation of the ERS-apoptosis pathway, and may provide a novel avenue for the treatment of UC.

Summary: Background: Mapping gut microecological features to serum metabolites (SMs) will help identify functional links between gut microbiome and cardiometabolic health. Methods: This study encompassed 836-1021 adults over 9.7 year in a cohort, assessing metabolic syndrome (MS), carotid atherosclerotic plaque (CAP), and other metadata triennially. We analyzed mid-term microbial metagenomics, targeted fecal and serum metabolomics, host genetics, and serum proteomics. Findings: Gut microbiota and metabolites (GMM) accounted for 15.1% overall variance in 168 SMs, with individual GMM factors explaining 5.65%–10.1%, host genetics 3.23%, and sociodemographic factors 5.95%. Specifically, GMM elucidated 5.5%–49.6% variance in the top 32 GMM-explained SMs. Each 20% increase in the 32 metabolite score (derived from the 32 SMs) correlated with 73% (95% confidence interval [CI]: 53%–95%) and 19% (95% CI: 11%–27%) increases in MS and CAP incidences, respectively. Among the 32 GMM-explained SMs, sebacic acid, indoleacetic acid, and eicosapentaenoic acid were linked to MS or CAP incidence. Serum proteomics revealed certain proteins, particularly the apolipoprotein family, mediated the relationship between GMM-SMs and cardiometabolic risks. Interpretation: This study reveals the significant influence of GMM on SM profiles and illustrates the intricate connections between GMM-explained SMs, serum proteins, and the incidence of MS and CAP, providing insights into the roles of gut dysbiosis in cardiometabolic health via regulating blood metabolites. Funding: This study was jointly supported by the National Natural Science Foundation of China, Key Research and Development Program of Guangzhou, 5010 Program for Clinical Research of Sun Yat-sen University, and the ‘Pioneer' and ‘Leading goose' R&D Program of Zhejiang.

Abstract Early diagnosis and pharmacological treatment of central nervous system (CNS) diseases has been a long-standing challenge for clinical research due to the presence of the blood–brain barrier. Specific proteins and RNAs in brain-derived extracellular vesicles (EVs) usually reflect the corresponding state of brain disease, and therefore, EVs can be used as diagnostic biomarkers for CNS diseases. In addition, EVs can be engineered and fused to target cells for delivery of cargo, demonstrating the great potential of EVs as a nanocarrier platform. We review the progress of EVs as markers and drug carriers in the diagnosis and treatment of neurological diseases. The main areas include visual imaging, biomarker diagnosis and drug loading therapy for different types of CNS diseases. It is hoped that increased knowledge of EVs will facilitate their clinical translation in CNS diseases.

Background: In the management of inflammatory bowel disease, the emergence of drug resistance to monoclonal antibodies has come out as a significant impediment to achieving desired therapeutic outcomes. However, extensive evidence has substantiated that the induction of autophagy holds promise in counteracting the development of drug resistance. In this regard, the utilization of traditional Chinese medicine presents a potential avenue for alleviate drug resistance, specifically through Peilan and Fuling. Consequently, the objective of this study aims to investigate the regulatory effects of p -Cymene and pachymic acid on the autophagy signaling pathway, with the ultimate goal of reducing inflammatory response and alleviating drug resistance. Methods: The RAW 264.7 murine macrophage cell line was subjected to induction using varying concentration gradients of adalimumab in order to establish an adalimumab-resistant cell line. The cell growth curve and viability were assessed using the CCK-8 assay. The expression of cytokines was determined through the implementation of ELISA. The autophagy signaling pathway was evaluated using Western blot analysis. Results: p -Cymene and pachymic acid were found to exert an inhibitory effect on the proliferation of the adalimumab-resistant cell line. Additionally, treatment with p -Cymene and pachymic acid resulted in a decrease in the levels of proinflammatory cytokines, namely TNF-α, IL-1β, and IL-6, while concurrently increasing the level of IL-10. p -Cymene and pachymic acid demonstrated the capacity to suppress the expression of autophagy-related proteins and mRNA including PI3K, AKT, and mTOR. Conclusions: p -Cymene and pachymic acid exhibit the potential to alleviate adalimumab-resistance and ameliorate the inflammatory response, primarily through the activation of the PI3K/AKT/mTOR signaling pathway. These findings suggest that traditional Chinese medicine holds promise as a viable treatment option for mitigating monoclonal antibody resistance in inflammatory bowel disease.

Summary: Background: The high heterogeneity of tumour and the complexity of tumour microenvironment (TME) greatly impacted the tumour development and the prognosis of cancer in the era of immunotherapy. In this study, we aimed to portray the single cell-characterised landscape of lung adenocarcinoma (LUAD), and develop an integrated signature incorporating both tumour heterogeneity and TME for prognosis stratification. Methods: Single-cell tagged reverse transcription sequencing (STRT-seq) was performed on tumour tissues and matched normal tissues from 14 patients with LUAD for immune landscape depiction and candidate key genes selection for signature construction. Kaplan–Meier survival analyses and in-vitro cell experiments were conducted to confirm the gene functions. The transcriptomic profile of 1949 patients from 11 independent cohorts including nine public datasets and two in-house cohorts were obtained for validation. Findings: We selected 11 key genes closely related to cell-to-cell interaction, tumour development, T cell phenotype transformation, and Ma/Mo cell distribution, including HLA-DPB1, FAM83A, ITGB4, OAS1, FHL2, S100P, FSCN1, SFTPD, SPP1, DBH-AS1, CST3, and established an integrated 11-gene signature, stratifying patients to High-Score or Low-Score group for better or worse prognosis. Moreover, the prognostically-predictive potency of the signature was validated by 11 independent cohorts, and the immunotherapeutic predictive potency was also validated by our in-house cohort treated by immunotherapy. Additionally, the in-vitro cell experiments and drug sensitivity prediction further confirmed the gene function and generalizability of this signature across the entire RNA profile spectrum. Interpretation: This single cell-characterised 11-gene signature might offer insights for prognosis stratification and potential guidance for treatment selection. Funding: Support for the study was provided by National key research and development project (2022YFC2505004, 2022YFC2505000 to Z.W. and J.W.), Beijing Natural Science Foundation (7242114 to J.X.), National Natural Science Foundation of China of China (82102886 to J.X., 81871889 and 82072586 to Z.W.), Beijing Nova Program (20220484119 to J.X.), NSFC general program (82272796 to J.W.), NSFC special program (82241229 to J.W.), CAMS Innovation Fund for Medical Sciences (2021-1-I2M-012, 2022-I2M-1-009 to Z.W. and J.W.), Beijing Natural Science Foundation (7212084 to Z.W.), CAMS Key lab of translational research on lung cancer (2018PT31035 to J.W.), Aiyou Foundation (KY201701 to J.W.). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022003 to J.X.)

Abstract Background The early life stage is critical for the gut microbiota establishment and development. We aimed to investigate the lifelong impact of famine exposure during early life on the adult gut microbial ecosystem and examine the association of famine-induced disturbance in gut microbiota with type 2 diabetes. Methods We profiled the gut microbial composition among 11,513 adults (18–97 years) from three independent cohorts and examined the association of famine exposure during early life with alterations of adult gut microbial diversity and composition. We performed co-abundance network analyses to identify keystone taxa in the three cohorts and constructed an index with the shared keystone taxa across the three cohorts. Among each cohort, we used linear regression to examine the association of famine exposure during early life with the keystone taxa index and assessed the correlation between the keystone taxa index and type 2 diabetes using logistic regression adjusted for potential confounders. We combined the effect estimates from the three cohorts using random-effects meta-analysis. Results Compared with the no-exposed control group (born during 1962–1964), participants who were exposed to the famine during the first 1000 days of life (born in 1959) had consistently lower gut microbial alpha diversity and alterations in the gut microbial community during adulthood across the three cohorts. Compared with the no-exposed control group, participants who were exposed to famine during the first 1000 days of life were associated with consistently lower levels of keystone taxa index in the three cohorts (pooled beta − 0.29, 95% CI − 0.43, − 0.15). Per 1-standard deviation increment in the keystone taxa index was associated with a 13% lower risk of type 2 diabetes (pooled odds ratio 0.87, 95% CI 0.80, 0.93), with consistent results across three individual cohorts. Conclusions These findings reveal a potential role of the gut microbiota in the developmental origins of health and disease (DOHaD) hypothesis, deepening our understanding about the etiology of type 2 diabetes.

Abstract Aimed to explore the relationships between infection localization, bacterial species, and procalcitonin (PCT) and C-reactive protein (CRP) levels in urinary tract infections (UTIs). A retrospective study included 314 UTI hospitalized patients divided into two groups (268 with lower UTI, 46 with upper UTI) in a tertiary care hospital. PCT and CRP were performed. Bacterial isolates were identified using standard microbiological techniques, and statistical analyses were performed to assess associations between infection localization, bacterial species, PCT, and CRP levels. Age and gender showed no significant differences between the lower and upper UTIs. Escherichia coli dominated as the leading UTI pathogen. A positive correlation (r = 0.646, P

Variants (pathogenic) of the LMNA gene are a common cause of familial dilated cardiomyopathy (DCM), which is characterised by early-onset atrioventricular (AV) block, atrial fibrillation and ventricular tachyarrhythmias (VTs), and progressive heart failure. The unstable internal nuclear lamina observed in LMNA-related DCM is a consequence of the disassembly of lamins A and C. This suggests that LMNA variants produce truncated or alternative forms of protein that alter the nuclear structure and the signalling pathway related to cardiac muscle diseases. To date, the pathogenic mechanisms and phenotypes of LMNA-related DCM have been studied using different platforms, such as patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) and transgenic mice. In this review, point variants in the LMNA gene that cause autosomal dominantly inherited forms of LMNA-related DCM are summarised. In addition, potential therapeutic targets based on preclinical studies of LMNA variants using transgenic mice and human iPSC-CMs are discussed. They include mitochondria deficiency, variants in nuclear deformation, chromatin remodelling, altered platelet-derived growth factor and ERK1/2-related pathways, and abnormal calcium handling.

Herbal medicine is popularly used among patients who suffer from allergic rhinitis. This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of single medicinal plants in the management of allergic rhinitis. We searched MEDLINE, CENTRAL, and Web of Science for randomised controlled trials which evaluated the use of single medicinal plant for allergic rhinitis among adults and children. Twenty-nine randomised controlled trials (n = 1879) were eligible while 27 (n = 1769) contributed data for meta-analyses. Most studies (studies = 20) compared medicinal plants against placebo and Petasites hybridus was most frequently investigated (studies = 5). Very-low-to-low-certainty evidence suggests that compared to placebo, single medicinal plants may improve overall total nasal symptoms (SMD -0.31, 95% CI -0.59 to -0.02; participants = 249; studies = 5; I2 = 21%) especially nasal congestion and sneezing; and rhinoconjunctivitis quality of life (RQLQ) scores (MD -0.46, 95% CI -0.84 to -0.07; participants = 148; studies = 3; I2 = 0%). Moderate-certainty evidence show no clear differences between single medicinal plants and antihistamine in overall symptoms (Total nasal symptoms: SMD -0.14, 95% CI -0.46 to 0.18; participants = 149; studies = 2; I2 = 0%). As adjunctive therapy, moderate-certainty evidence shows that medicinal plants improved SNOT-22 scores when given as intranasal treatment (MD -7.47, 95% CI -10.75 to -4.18; participants = 124; studies = 2; I2 = 21%). Risk of bias domains were low or not clearly reported in most studies while heterogeneity was substantial in most pooled outcomes. Route of administration and age were identified to be plausible source of heterogeneity for certain outcomes. Medicinal plants appear to be well tolerated up to 8 weeks of use. Clear beneficial evidence of medicinal plants for allergic rhinitis is still lacking. There is a need for improved reporting of herbal trials to allow for critical assessment of the effects of each individual medicinal plant preparation in well-designed future clinical studies.

Purpose: Adhesion between calcium oxalate crystals and renal tubular epithelial cells is a vital cause of renal stone formation; however, the drugs that inhibit crystal adhesion and the mechanism of inhibition have yet to be explored. Methods: The cell injury model was constructed using nano-COM crystals, and changes in oxidative stress levels, endoplasmic reticulum (ER) stress levels, downstream p38 MAPK protein expression, apoptosis, adhesion protein osteopontin expression, and cell–crystal adhesion were examined in the presence of Laminarin polysaccharide (DLP) and sulfated DLP (SDLP) under protected and unprotected conditions. Results: Both DLP and SDLP inhibited nano-COM damage to human kidney proximal tubular epithelial cell (HK-2), increased cell viability, decreased ROS levels, reduced the opening of mitochondrial membrane permeability transition pore, markedly reduced ER Ca2+ ion concentration and adhesion molecule OPN expression, down-regulated the expression of ER stress signature proteins including CHOP, Caspase 12, and p38 MAPK, and decreased the apoptosis rate of cells. SDLP has a better protective effect on cells than DLP. Conclusions: SDLP protects HK-2 cells from nano-COM crystal-induced apoptosis by reducing oxidative and ER stress levels and their downstream factors, thereby reducing crystal–cell adhesion interactions and the risks of kidney stone formation.

Abstract Manganese dioxide nanoparticles (MnO2-NPs) have a wide range of applications in biomedicine. Given this widespread usage, it is worth noting that MnO2-NPs are definitely toxic, especially to the brain. However, the damage caused by MnO2-NPs to the choroid plexus (CP) and to the brain after crossing CP epithelial cells has not been elucidated. Therefore, this study aims to investigate these effects and elucidate potential underlying mechanisms through transcriptomics analysis. To achieve this objective, eighteen SD rats were randomly divided into three groups: the control group (control), low-dose exposure group (low-dose) and high-dose exposure group (high-dose). Animals in the two treated groups were administered with two concentrations of MnO2-NPs (200 mg kg−1 BW and 400 mg kg−1 BW) using a noninvasive intratracheal injection method once a week for three months. Finally, the neural behavior of all the animals was tested using a hot plate tester, open-field test and Y-type electric maze. The morphological characteristics of the CP and hippocampus were observed by H&E stain, and the transcriptome of CP tissues was analysed by transcriptome sequencing. The representative differentially expressed genes were quantified by qRT-PCR. We found that treatment with MnO2-NPs could induce learning capacity and memory faculty decline and destroy the structure of hippocampal and CP cells in rats. High doses of MnO2-NPs had a more obvious destructive capacity. For transcriptomic analysis, we found that there were significant differences in the numbers and types of differential genes in CP between the low- and high-dose groups compared to the control. Through GO terms and KEGG analysis, high-dose MnO2-NPs significantly affected the expression of transporters, ion channel proteins, and ribosomal proteins. There were 17 common differentially expressed genes. Most of them were transporter and binding genes on the cell membrane, and some of them had kinase activity. Three genes, Brinp, Synpr and Crmp1, were selected for qRT-PCR to confirm their expression differences among the three groups. In conclusion, high-dose MnO2-NPs exposure induced abnormal neurobehaviour, impaired memory function, destroyed the structure of the CP and changed its transcriptome in rats. The most significant DEGs in the CP were within the transport system.

Abstract Background Despite advances in treatment, patients with refractory colorectal cancer (CRC) still have poor long-term survival, so there is a need for more effective therapeutic options. Methods To evaluate the HDAC8 inhibition efficacy as a CRC treatment, we examined the effects of various HDAC8 inhibitors (HDAC8i), including BMX (NBM-T-L-BMX-OS01) in combination with temozolomide (TMZ) or other standard CRC drugs on p53 mutated HT29 cells, as well as wild-type p53 HCT116 and RKO cells. Results We showed that HDAC8i with TMZ cotreatment resulted in HT29 arrest in the S and G2/M phase, whereas HCT116 and RKO arrest in the G0/G1 phase was accompanied by high sub-G1. Subsequently, this combination approach upregulated p53-mediated MGMT inhibition, leading to apoptosis. Furthermore, we observed the cotreatment also enabled triggering of cell senescence and decreased expression of stem cell biomarkers. Mechanistically, we found down-expression levels of β-catenin, cyclin D1 and c-Myc via GSK3β/β-catenin signaling. Intriguingly, autophagy also contributes to cell death under the opposite status of β-catenin/p62 axis, suggesting that there exists a negative feedback regulation between Wnt/β-catenin and autophagy. Consistently, the Gene Set Enrichment Analysis (GSEA) indicated both apoptotic and autophagy biomarkers in HT29 and RKO were upregulated after treating with BMX. Conclusions BMX may act as a HDAC8 eraser and in combination with reframed-TMZ generates a remarkable synergic effect, providing a novel therapeutic target for various CRCs. Video Abstract

Abstract Background Language deficits frequently occur during the prodromal stages of Alzheimer’s disease (AD). However, the characteristics of linguistic impairment and its underlying mechanism(s) remain to be explored for the early diagnosis of AD. Methods The percentage of silence duration (PSD) of 324 subjects was analyzed, including patients with AD, amnestic mild cognitive impairment (aMCI), and normal controls (NC) recruited from the China multi-center cohort, and the diagnostic efficiency was replicated from the Pitt center cohort. Furthermore, the specific language network involved in the fragmented speech was analyzed using task-based functional magnetic resonance. Results In the China cohort, PSD increased significantly in aMCI and AD patients. The area under the curve of the receiver operating characteristic curves is 0.74, 0.84, and 0.80 in the classification of NC/aMCI, NC/AD, and NC/aMCI+AD. In the Pitt center cohort, PSD was verified as a reliable diagnosis biomarker to differentiate mild AD patients from NC. Next, in response to fluency tasks, clusters in the bilateral inferior frontal gyrus, precentral gyrus, left inferior temporal gyrus, and inferior parietal lobule deactivated markedly in the aMCI/AD group (cluster-level P

Abstract Dialysis adequacy is a known risk factor for mortality in maintenance hemodialysis (MHD) patients. However, the optimal dialysis dose remains controversial. Therefore, we aimed to explore the relationship between dialysis dose and all-cause and cardiovascular disease (CVD) mortality among MHD. We examined the associations of dialysis dose with mortality in a cohort (n = 558) of MHD patients from 31 December 2015 to 31 December 2020. Dialysis adequacy was assessed using baseline Single-pool Kt/Vurea (spKt/V), which was categorized into three groups, and the lowest dose group was used as the reference category. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. A total of 214 patients died (64.5% for CVD). Compared with the low-dose group, high-dose group could reduce the risk of all-cause mortality by 33% (HR = 0.67, 95% CI: 0.47–0.98). Of note, when stratification by age, high-dose group was associated with both lower all-cause (HR = 0.46, 95% CI: 0.26–0.81) and CVD mortality (HR = 0.42, 95% CI: 0.20–0.88) among patients with age below 65 years. When stratification by dialysis age, high-dose group was associated with decreased risk of CVD mortality (HR = 0.43, 95% CI: 0.20–0.91) among patients with dialysis age over 60 months. spKt/V is a simple index of hemodialysis dose used in clinical practice and a useful modifiable factor in predicting the risk of death, especially in MHD patients under 65 years old or dialysis age more than 60 months.

Abstract Ferroptosis is a form of regulated cell death triggered by the iron‐dependent peroxidation of phospholipids. Interactions of iron and lipid metabolism factors jointly promote ferroptosis. Ferroptosis has been demonstrated to be involved in the development of various diseases, such as tumors and degenerative diseases (e.g., aortic dissection), and targeting ferroptosis is expected to be an effective strategy for the treatment of these diseases. Recent studies have shown that the regulation of ferroptosis is affected by multiple mechanisms, including genetics, epigenetics, posttranscriptional modifications, and protein posttranslational modifications. Epigenetic changes have garnered considerable attention due to their importance in regulating biological processes and potential druggability. There have been many studies on the epigenetic regulation of ferroptosis, including histone modifications (e.g., histone acetylation and methylation), DNA methylation, and noncoding RNAs (e.g., miRNAs, circRNAs, and lncRNAs). In this review, we summarize recent advances in research on the epigenetic mechanisms involved in ferroptosis, with a description of RNA N6‐methyladenosine (m6A) methylation included, and the importance of epigenetic regulation in biological processes and ferroptosis‐related diseases, which provides reference for the clinical application of epigenetic regulators in the treatment of related diseases by targeting ferroptosis.

Backgrounds Early detection might help in reducing the burden and promoting the survival rate of gastric cancers. Herein, we tried to explore the diagnostic value of insulin-like growth factor binding protein 7 (IGFBP7) in gastric cancers. Methods In this study, we first analyzed the expression levels and prognostic value of IGFBP7 mRNA in gastric cancers from The Cancer Genome Atlas (TCGA) database. Then, we recruited 169 gastric cancer patients and 100 normal controls as training cohort, and 55 gastric cancer patients and 55 normal controls as independent validation cohort. Enzyme-linked immunosorbent assay was applied to test the serum levels of IGFBP7. The receiver operating characteristic curve (ROC) and the area under the curve (AUC) were applied to evaluation the diagnostic value. Results TCGA showed that IGFBP7 mRNA was dysregulated and associated with prognosis in gastric cancer patients. Then, we examined the expression of serum IGFBP7 and found that serum IGFBP7 expressed lower in gastric cancer patients than normal controls both in training and independent validation cohorts (p < 0.0001). In training cohort, with the cutoff value of 1.515 ng/ml, the AUC for distinguishing gastric cancer patients was 0.774 (95% CI [0.713–0.836]) with sensitivity of 36.7% (95% CI [29.5–44.5]) and specificity of 90.0% (95% CI [82.0–94.8]). As for early-stage EJA, the AUC was 0.773 (95% CI [0.701–0.845]) with the sensitivity of 33.3% (95% CI [14.4–58.8]). In independent validation cohort, with the same cutoff value, the AUC reached to 0.758 (95% CI [0.664–0.852]). Similarly, for early-stage gastric cancer diagnosis in the independent validation cohort, the AUC value was 0.778 (95% CI [0.673–0.882]). Conclusions This study indicated that serum IGFBP7 might act as a potential early diagnostic marker for gastric cancers.

Objectives To evaluate the association between anxiety, depression and resilience with overall health and functioning in axial spondyloarthritis (axSpA).Design Cross-sectional evaluation of baseline data from a prospective cohort study, with recruitment from January 2018 to March 2021.Setting Outpatient clinic in a tertiary hospital in Singapore.Participants Patients aged 21 years and above who were diagnosed with axSpA.Outcome measures The Hospital Anxiety and Depression Scale (HADS) was used for assessing anxiety and depression, 10-item Connor Davidson Resilience Scale (CD-RISC-10) for resilience, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for disease activity, Bath Ankylosing Spondylitis Functional Index (BASFI) for functional limitation and Assessment of SpondyloArthritis International Society Health Index (ASAS HI) for overall health and functioning. Univariable and multivariable linear regression analyses were performed to assess the association between anxiety, depression and resilience with health and functioning.Results We included 296 patients in this study. The median (IQR) score for HADS-Anxiety was 5.0 (2.0–8.0), with 13.5% and 13.9% having borderline abnormal and abnormal anxiety, respectively. The median (IQR) score for HADS-Depression was 3.0 (1.0–7.0), with 12.8% and 8.4% having borderline abnormal and abnormal depression, respectively. The median (IQR) CD-RISC-10 score was 29.0 (23.0–32.0) while the median (IQR) ASAS HI score was 4.0 (2.0–7.0). Apart from BASDAI, BASFI and disease duration, anxiety and depression were associated with overall health and functioning (β: 0.12, 95% CI 0.03, 0.20; β: 0.20, 95% CI 0.09, 0.31) in the multivariable linear regression. Level of resilience was not associated with health and functioning.Conclusion Anxiety and depression, but not resilience, were associated with poorer health and functioning. Clinicians could consider routinely screening for anxiety and depression in their patients, especially in patients with more severe symptoms.

Abstract Background Proper home medication management plays a role in improving medication adherence, preserving drug efficacy and ensuring safe medication practices, which is crucial to establish positive treatment outcomes. However, no published studies are available on home medication management among psychiatric patients. The study aimed to identify home medication management problems among psychiatric patients in Malaysia and to examine the associations of inappropriate medication storage and lack of a medication administration schedule with sociodemographic factors, disease insight, number of medications and type of home care pharmacy services (HCPS). Methods This multicentre cross-sectional study was conducted among psychiatric patients using HCPS in six government hospitals in western Malaysia. Data were extracted from the HCPS form used for each visit as per the protocol published by the Pharmaceutical Services Division, Ministry of Health Malaysia. A minimum sample size of 169 was needed. Proportional random sampling was applied. The associations of inappropriate medication storage and lack of medication administration schedule with study parameters were analysed using multiple logistic regressions. Results A total of 205 home visits were conducted with 229 home medication management problems identified; inappropriate medication storage and lack of medication administration schedule topped the list. Inappropriate medication storage was significantly associated with low income [AOR = 4.34 (95% CI 1.17:15.98), p = 0.027], alcohol consumption [AOR = 14.26 (95% CI 1.82:111.38), p = 0.011], poor insight [AOR = 2.34 (95% CI 1.08:5.06), p = 0.030] and part-time HCPS [AOR = 2.60 (95% CI 1.20:5.67), p = 0.016]. Lack of administration schedule was significantly associated with low income [AOR = 6.90 (95% CI 1.46:32.48), p = 0.014], smoking [AOR = 2.43 (95% CI 1.20:4.92), p = 0.013], poor insight [AOR = 5.32 (95% CI 2.45:11.56), p

The quantification of hepatitis B virus(HBV) core antibody (anti-HBc) is related to host immunity and can be detected in the serum of patients with current or past infections. The antibody against core antigen of HBV plays an important role in the inflammation pathogenesis of liver,evaluation of epidemiology history and of treatment strategy. Chronic HBV infection is closely related to active transcription and persistence of covalently closed circular DNA(cccDNA) in the liver. The result of quantitative anti-HBc antibody examination shows a good correlation with cccDNA level so it is a potential index for comprehensive evaluation of HBV infectious diseases.

Abstract Recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects. Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient’s own blood cells. We sought to induce donor-specific hypo-responsiveness of SOT recipients by infusing ECP-treated donor leukocytes prior to transplant. To this end, we utilized major histocompatibility complex mismatched rodent models of allogeneic cardiac, liver, and kidney transplantation to test this novel strategy. Leukocytes isolated from donor-matched spleens for ECP treatment (ECP-DL) were infused into transplant recipients seven days prior to SOT. Pre-transplant infusion of ECP-DL without additional IS was associated with prolonged graft survival in all models. This innovative approach promoted the production of tolerogenic dendritic cells and regulatory T-cells with subsequent inhibition of T-cell priming and differentiation, along with a significant reduction of donor-specific T-cells in the spleen and grafts of treated animals. This new application of donor-type ECP-treated leukocytes provides insight into the mechanisms behind ECP-induced immunoregulation and holds significant promise in the prevention of graft rejection and reduction in need of global immune suppressive therapy in patients following SOT.

Abstract Androgenesis is an important chromosome set manipulation technique used in sex control in aquaculture. Haploid embryos exhibit haploid syndrome with body abnormalities and even die during early embryonic development. In this study, we used whole genome bisulfite sequencing (WGBS) to investigate the genome-wide DNA methylation profiles in haploid females (1n-X) and males (1n-Y), and diploid females (2n-XX) and males (2n-XY) of tiger pufferfish (Takifugu rubripes), an economically important fish in China. A total of 96.32 Gb clean data was produced. Differentially methylated regions (DMRs) were found between haploids and diploids, which may be related to abnormal development and early embryonic death in haploids. There were 3,641 hyper-methylated differentially methylated genes (DMGs) and 2,179 hypo-methylated DMGs in haploid vs. diploid comparisons in both females and males. These DMGs were mainly related to genomic stability maintenance and cell cycle regulation. slf1, actr8, gas2, and pbrm1 genes were selected to validate the methylation sequencing. After combining the methylation data with the corresponding transcriptome data, we identified several genes, including guca2a, myoc, fezf2, rprml, telo2, s100a1, and marveld1, which exhibited differential expression levels modulated by DNA methylation. In conclusion, our study revealed different methylation and expression profiles between haploid and diploid T. rubripes for the first time. Several DMGs were identified between different ploidy levels, which may be related to haploid syndrome formation. The results expand the understanding of the effects of ploidy on the early development of teleosts and provide knowledge about target genes and networks to improve the survival rate of haploids.

Abstract Background The Debriefing Experience Scale (DES) is a tool that is used to explore nursing students’ subjective experiences during a debriefing and to help determine best debriefing practices. A Chinese version of the scale has not been found; its development can enhance learning in simulation activites in Chinese healthcare education programs. Methods A simplified Chinese version of the DES was developed and tested using 34 Chinese undergraduate (second year) nursing students. They participated in six simulation scenarios and debriefings. Eight experts were consulted to determine the content validity of the scale. Critical ratio method, Cronbach’s alpha, intraclass correlation coefficient, correlation coefficient and factor analysis were used in testing the psychometric properties of the scale. Results Analysis of 200 scales showed that the simplified Chinese version of the DES had good potential in discriminatiing Chinese nursing students’ experiences of debriefing. Conclusions The simplified Chinese DES was effective in evaluating the experience of debriefing. A larger sample size and multicenter research is needed to confirm these findings.

Abstract Acute myocardial infarction (AMI) is one of the main causes of death in the world, and the incidence of AMI is increasing in the young population. Drug-coated balloon (DCB) has become an effective concept for the treatment of in-stent restenosis, small vessel disease, bifurcation lesions, high blood risk conditions, and even de novo large vessel disease. To ensure whether DCB can play an alternative role in AMI, we conducted a comprehensive meta‐analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of DCB in the treatment of AMI. Electronic databases were searched for RCTs that compared DCB with stent for AMI. The primary outcome was major adverse cardiac events (MACEs), the secondary outcome was late lumen loss (LLL). RevMan 5.3 software and RStudio software were used for data analysis. Five RCTs involving 528 patients with 6–12 months of follow-up were included. There was no significant difference in the incidence of MACEs between DCB group and stent group (RR, 0.85; 95% CI 0.42 to 1.74; P = 0.66). Lower LLL was shown in DCB group (WMD, − 0.29; 95% CI − 0.46 to − 0.12; P

BackgroundConcussion is a common condition that can lead to a constellation of symptoms that affect quality of life, social integration, and return to work. There are several evidence-based behavioral and psychological interventions that have been found to improve postconcussion symptom burden. However, these are not routinely delivered, and individuals receive limited support during their concussion recovery. ObjectiveThis study aimed to develop and test the feasibility of a digital health intervention using a systematic evidence-, theory-, and person-based approach. MethodsThis was a mixed methodology study involving a scoping review (n=21), behavioral analysis, and logic model to inform the intervention design and content. During development, the intervention was optimized with feedback from individuals who had experienced concussions (n=12) and health care professionals (n=11). The intervention was then offered to patients presenting to the emergency department with a concussion (n=50). Participants used the intervention freely and input symptom data as part of the program. A number of outcome measures were obtained, including participant engagement with the intervention, postconcussion symptom burden, and attitudes toward the intervention. A selection of participants (n=15) took part in in-depth qualitative interviews to understand their attitudes toward the intervention and how to improve it. ResultsEngagement with the intervention functionality was 90% (45/50) for the symptom diary, 62% (31/50) for sleep time setting, 56% (28/50) for the alcohol tracker, 48% (24/50) for exercise day setting, 34% (17/50) for the thought diary, and 32% (16/50) for the goal setter. Metrics indicated high levels of early engagement that trailed off throughout the course of the intervention, with an average daily completion rate of the symptom diary of 28.23% (494/1750). A quarter of the study participants (13/50, 26%) were classified as high engagers who interacted with all the functionalities within the intervention. Quantitative and qualitative feedback indicated a high level of usability and positive perception of the intervention. Daily symptom diaries (n=494) demonstrated a wide variation in individual participant symptom burden but a decline in average burden over time. For participants with Rivermead scores on completion of HeadOn, there was a strong positive correlation (r=0.86; P

Objective To explore the effect of prednisone acetate on renal function, renal inflammatory response and AMP-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) signaling pathway in diabetic nephropathy (DN) rats. Methods Twelve rats were randomly selected as the control group, and the remaining rats were given high-sugar and high-fat diet supplemented with intraperitoneal injection of streptozotocin (STZ) to construct a DN rat model. The successful model rats were randomly divided into model group, prednisone acetate low (6.25 mg/kg), high (12.5 mg/kg) dose groups, prednisone acetate + CC group (prednisone acetate 12.5 mg/kg+AMPK inhibitor compound C 0.2 mg/kg), with 12 animals in each group. Each group was given corresponding treatment, once a day for 4 weeks. The general state of rats was observed, and the fasting blood glucose (FBG), 24-hour urine microalbumin (U-mAlb), blood creatinine (SCr), blood urea nitrogen (BUN), serum interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were detected; the pathological changes of renal tissue were observed with hematoxylin eosin (HE) staining and periodate schiff (PAS) staining; The expression of proteins related to the renal tissue AMPK/SIRT1 signaling pathway was detected with Western blot. Results Prednisone acetate can improve the general state of DN rats, reduce FBG, 24 h U-mAlb, serum SCr, BUN, IL-1β, IL-6 and TNF-α levels, and renal tissue acetylation nuclear factor-κB p65 (ac-NF-κB p65)/NF-κB p65 and monocyte chemotactic protein-1 (MCP-1) protein expression (P＜0.05), increase phosphorylated AMPK(p-AMPK)/AMPK and SIRT1 protein expression (P＜0.05), improve kidney disease; compound C could significantly weaken the protective effect of prednisone acetate on DN rats. Conclusions Prednisone acetate can reduce renal inflammatory response and protect renal function in DN rats. Its mechanism may be related to the activation of AMPK/SIRT1 pathway to inhibit the activation of NF-κB.

Background: An accurate measurement of the glomerular filtration rate (GFR) is essential for detecting renal insufficiency in living kidney donors. Iohexol is a “near-ideal” exogenous filtration marker for GFR measurements that has attracted increasing interest in clinical practice because it is non-toxic, non-radioactive, readily available, and easy to measure. In this study, we aimed to set up a laboratory test to conveniently assess the plasma clearance of iohexol in living kidney donors. Methods: A workflow was established in the institution’s infusion clinic to administer iohexol and to collect three timed blood samples from renal transplant donors. Iohexol was thereafter measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS). The serum proteins were precipitated and the supernatant containing iohexol was diluted prior to the LC-MS/MS analysis. The LC-MS/MS method was developed on a Thermo Vanquish UHPLC coupled with a TSQ Endura triple quadruple mass spectrometer with a total run time of 2.5 min. The analytical performance of the method was assessed. Results: The LC-MS/MS method demonstrated a good analytical performance. To calculate the iohexol clearance rate and the GFR, automated data integration and a result calculation were accomplished by using a custom Python script. Automated result reporting was achieved using a laboratory informatics system (LIS) vendor’s direct media interface. Conclusions: We developed and implemented a laboratory test to assess the plasma clearance of iohexol. A workflow was established in the hospital to reliably measure the GFR in living kidney donors, with a potential to be further expanded into other areas where an accurate GFR measurement is needed.

Abstract Mesenchymal progenitors differentiate into several tissues including bone, cartilage, and adipose. Targeting these cells in vivo is challenging, making mesenchymal progenitor cell lines valuable tools to study tissue development. Mesenchymal stem cells (MSCs) can be isolated from humans and animals; however, obtaining homogenous, responsive cells in a reproducible fashion is challenging. As such, we developed two mesenchymal progenitor cell (MPC) lines, MPC1 and MPC2, generated from bone marrow of male C57BL/6 mice. These cells were immortalized using the temperature sensitive large T-antigen, allowing for thermal control of proliferation and differentiation. Both MPC1 and MPC2 cells are capable of osteogenic, adipogenic, and chondrogenic differentiation. Under osteogenic conditions, both lines formed mineralized nodules, and stained for alizarin red and alkaline phosphatase, while expressing osteogenic genes including Sost, Fgf23, and Dmp1. Sost and Dmp1 mRNA levels were drastically reduced with addition of parathyroid hormone, thus recapitulating in vivo responses. MPC cells secreted intact (iFGF23) and C-terminal (cFGF23) forms of the endocrine hormone FGF23, which was upregulated by 1,25 dihydroxy vitamin D (1,25D). Both lines also rapidly entered the adipogenic lineage, expressing adipose markers after 4 days in adipogenic media. MPC cells were also capable of chondrogenic differentiation, displaying increased expression of cartilaginous genes including aggrecan, Sox9, and Comp. With the ability to differentiate into multiple mesenchymal lineages and mimic in vivo responses of key regulatory genes/proteins, MPC cells are a valuable model to study factors that regulate mesenchymal lineage allocation as well as the mechanisms that dictate transcription, protein modification, and secretion of these factors.

Background: One Health is an integrated concept of health that aims to optimize the health of humans, animals, plants, and the environment. Identifying research gaps and specific expertise areas is important for understanding the role of One Health in practice. This information on One Health could be used to promote collaboration and research, inspire innovative ideas, and accelerate the translation of evidence-based practices into policies. Methods: We searched the Scopus database for publications related to One Health between 2012 and 2021 to extract bibliometric information and investigate the possibility of establishing a dedicated expertise database. We matched scholarly information using SciVal to exclude duplicate information and identify scholars’ affiliations, countries, and academic profiles. Individual academic contributions to One Health were evaluated according to their citations, publication impact, publication type, and author contributions. Results: A total of 8,313 publications on One Health over a ten-year period were identified, with the number of publications increasing over time. The largest number of publications came from the United States and the United Kingdom. These countries also had the highest number of experts and a high level of international collaboration. We identified 500 scholars from 53 countries and 313 affiliations with a median Hirsch Index of 20 who could be included in a One Health expert database. These scientists had a median of six publications on One Health, with topics mostly focusing on dengue and antimicrobial resistance. Conclusion: A One Health information database could be used as a third-party reference for scholars, a source to track the ongoing academic progress, and support for active scholars in this field of research.

Abstract Background Colorectal cancer (CRC) is a major cancer type whose mechanism of metastasis remains elusive. Methods In this study, we characterised the evolutionary pattern of metastatic CRC (mCRC) by analysing bulk and single-cell exome sequencing data of primary and metastatic tumours from 7 CRC patients with liver metastases. Here, 7 CRC patients were analysed by bulk whole-exome sequencing (WES); 4 of these were also analysed using single-cell sequencing. Results Despite low genomic divergence between paired primary and metastatic cancers in the bulk data, single-cell WES (scWES) data revealed rare mutations and defined two separate cell populations, indicative of the diverse evolutionary trajectories between primary and metastatic tumour cells. We further identified 24 metastatic cell-specific-mutated genes and validated their functions in cell migration capacity. Conclusions In summary, scWES revealed rare mutations that failed to be detected by bulk WES. These rare mutations better define the distinct genomic profiles of primary and metastatic tumour cell clones.

Abstract Background Poor communication skills can potentially compromise patient care. However, as communication skills training (CST) programs are not seen as a priority to many clinical departments, there is a discernible absence of a standardised, recommended framework for these programs to be built upon. This systematic scoping review (SSR) aims to gather prevailing data on existing CSTs to identify key factors in teaching and assessing communication skills in the postgraduate medical setting. Methods Independent searches across seven bibliographic databases (PubMed, PsycINFO, EMBASE, ERIC, CINAHL, Scopus and Google Scholar) were carried out. Krishna’s Systematic Evidence-Based Approach (SEBA) was used to guide concurrent thematic and content analysis of the data. The themes and categories identified were compared and combined where possible in keeping with this approach and then compared with the tabulated summaries of the included articles. Results Twenty-five thousand eight hundred ninety-four abstracts were identified, and 151 articles were included and analysed. The Split Approach revealed similar categories and themes: curriculum design, teaching methods, curriculum content, assessment methods, integration into curriculum, and facilitators and barriers to CST. Amidst a wide variety of curricula designs, efforts to develop the requisite knowledge, skills and attitudes set out by the ACGME current teaching and assessment methods in CST maybe categorised into didactic and interactive methods and assessed along Kirkpatrick’s Four Levels of Learning Evaluation. Conclusions A major flaw in existing CSTs is a lack of curriculum structure, focus and standardisation. Based upon the findings and current design principles identified in this SSR in SEBA, we forward a stepwise approach to designing CST programs. These involve 1) defining goals and learning objectives, 2) identifying target population and ideal characteristics, 3) determining curriculum structure, 4) ensuring adequate resources and mitigating barriers, 5) determining curriculum content, and 6) assessing learners and adopting quality improvement processes.

This study aimed to examine changes in electrolytes and acid-base status in primary and secondary hypokalaemic periodic paralysis (HypoPP), which will help early differential diagnosis of HypoPP. A total of 64 HypoPP patients were enrolled and relevant data from clinical records was collected. Overall, 64 patients (mean age 28.2±7.3 years) of which 58(91%) were males, with 39, 11 and 14 patients, respectively, diagnosed as primary HypoPP, thyrotoxic HypoPP, and other secondary HypoPPs at discharge, were assessed. Those with HypoPP secondary to conditions other than hyperthyroidism were more likely to develop acid-base imbalance (p

Background: This systematic review and network meta-analysis aimed to assess comparative efficacy and safety of interventions to treat symptomatic, biopsy-proven oral lichen planus (OLP). Methods: Search was conducted for trials published in Medline, Embase and Cochrane Central Register of Controlled Trials. Network meta-analysis was performed on data from randomized controlled trials that assessed efficacy and safety of interventions used in the treatment of OLP. Agents were ranked according to their effectiveness in treatment of OLP based on outcomes using surface under the cumulative ranking [SUCRA]. Results: In total, 37 articles were included in the quantitative analysis. Purslane was clinically significant and ranked first in improving clinical symptoms [RR = 4.53; 95% CI: 1.45, 14.11], followed by aloe vera [RR = 1.53; 95% CI: 1.05, 2.24], topical calcineurin [RR = 1.38; 95% CI: 1.06, 1.81] and topical corticosteroid [RR = 1.35 95% CI: 1.05, 1.73]. Topical calcineurin demonstrated the highest incidence of adverse effects [RR, 3.25 [95% CI: 1.19, 8.86. Topical corticosteroids were significant in achieving clinical improvement of OLP with RR1.37 [95% CI: 1.03, 1.81]. PDT [MD = −5.91 [95% CI: −8.15, –3.68] and showed statistically significant improvement in the clinical score for OLP. Conclusions: Purslane, aloe vera and photodynamic therapy appear promising in treatment of OLP. More high-quality trials are recommended for strengthening the evidence. Although topical calcineurin is significantly efficacious in the treatment of OLP, significant adverse effects are a concern for clinical use. Based on the current evidence, topical corticosteroids are recommended for treatment of OLP owing to their predictable safety and efficacy.

Abstract. Background:. Vitamin D deficiency has been reported to be associated with diabetic microvascular complications, but previous studies have only focused on the relationship between vitamin D and specific complications. Therefore, we aimed to explore the relationship between vitamin D level and diabetic microvascular complications in general, including diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN). Methods:. This was a cross-sectional study of 815 patients with type 2 diabetes mellitus (T2DM). Clinical information and laboratory results were collected from the medical records. The relationship between vitamin D and the three diabetic microvascular complications was investigated. Results:. The serum 25-hydroxyvitamin D (25 [OH] D) level of patients with DPN and/or DN was significantly lower than that of T2DM patients without any microvascular complications (P

Low temperature germination (LTG) is a key agronomic trait in rice (Oryza sativa L.). However, the genetic basis of natural variation for LTG is largely unknown. Here, a genome-wide association study (GWAS) was performed using 276 accessions from the 3,000 Rice Genomes (3K-RG) project with 497 k single nucleotide polymorphisms (SNPs) to uncover potential genes for LTG in rice. In total, 37 quantitative trait loci (QTLs) from the 6th day (D6) to the 10th day (D10) were detected in the full population, overlapping with 12 previously reported QTLs for LTG. One novel QTL, namely qLTG1-2, was found stably on D7 in both 2019 and 2020. Based on two germination-specific transcriptome datasets, 13 seed-expressed genes were isolated within a 200 kb interval of qLTG1-2. Combining with haplotype analysis, a functional uncharacterized gene, LOC_Os01g23580, and a seed germination-associated gene, LOC_Os01g23620 (OsSar1a), as promising candidate genes, both of which were significantly differentially expressed between high and low LTG accessions. Collectively, the candidate genes with favorable alleles may be useful for the future characterization of the LTG mechanism and the improvement of the LTG trait in rice breeding.

Abstract Glutathione (GSH) is a useful biomarker in the development, diagnosis and treatment of cancer. However, most of the reported GSH biosensors are expensive, time-consuming and often require complex sample treatment, which limit its biological applications. Herein, a nanobiosensor for the detection of GSH using folic acid-functionalized reduced graphene oxide-modified BSA gold nanoclusters (FA-rGO-BSA/AuNCs) based on the fluorescence quenching interactions is presented. Firstly, a facile and optimized protocol for the fabrication of BSA/AuNCs is developed. Functionalization of rGO with folic acid is performed using EDC/NHS cross-linking reagents, and their interaction after loading with BSA/AuNCs is demonstrated. The formation of FA-rGO, BSA/AuNCs and FA-rGO-BSA/AuNCs are confirmed by the state-of-art characterization techniques. Finally, a fluorescence turn-off sensing strategy is developed using the as-synthesized FA-rGO-BSA/AuNCs for the detection of GSH. The nanobiosensor revealed an excellent sensing performance for the detection of GSH with high sensitivity and desirable selectivity over other potential interfering species. The fluorescence quenching is linearly proportional to the concentration of GSH between 0 and 1.75 µM, with a limit of detection of 0.1 µM under the physiological pH conditions (pH 7.4). Such a sensitive nanobiosensor paves the way to fabricate a “turn-on” or “turn-off” fluorescent sensor for important biomarkers in cancer cells, presenting potential nanotheranostic applications in biological detection and clinical diagnosis.

Student populations are susceptible to the COVID-19 pandemic and may easy develop mental health problems related to their immaturity of psychological development and fluctuation of mood. However, little has been known about the effects of the pandemic on college students and the associated influencing factors. This study aimed to explore the role of psychological resilience as a mediator between general self-efficacy and mental health. A cross-sectional survey was conducted with 480 Chinese college students from 12 universities in Hunan province of China. The participants responded anonymously to the Generalized Self-Efficacy Scale (GSES), the Chinese version of the Resilience Scale for College Students (RSCS), and the 12-item General Health Questionnaire (GHQ-12). Hierarchical linear regression and structural equation modeling were used in this study. The average of GSES and RSCS scores of college students were 25.00 ± 4.68 and 137.97 ± 15.50, which were at a medium level. The average score for the GHQ-12 was 1.59 ± 1.59, and 22.03% of the college students scored ≥ 3 on the GHQ-12, indicating that they were at risk of developing mental disorders. According to the analyses of mediation effect, psychological resilience played a fully mediating role in the relationship between general self-efficacy and mental health. In conclusion, Chinese college students were at high risk of developing mental disorders during the COVID-19 period. General self-efficacy was positively associated with psychological resilience, and psychological resilience played a fully mediating role in the relationship between general self-efficacy and mental health. Future studies and interventions should aim to promote psychological resilience and general self-efficacy.

Abstract. Background:. B-cell activating factor (BAFF) is vital for B cell survival. Serum BAFF levels are elevated in thrombotic antiphospholipid syndrome, but little is known about levels in patients with positive antiphospholipid antibodies (aPLs) and previous adverse pregnancy outcomes (APOs). We aimed to analyze serum BAFF concentrations of these patients in early pregnancy along with different pregnancy outcomes. Methods:. Thirty-six pregnant patients positive for aPLs and previous APOs (patient group), 25 healthy pregnant females (HP group) and 35 healthy non-pregnant females (HNP group) from the Peking University Third Hospital, between October 2018 and March 2019, were enrolled in this study. Serum of HNP and serum of patients as well as HP in the first gestational trimester were collected. Enzyme-linked immunosorbent assay kits were used to measure serum BAFF and interferon-alpha (IFN-α) concentrations. Cytometric bead array analysis was used to measure serum concentrations of cytokines. The patient group was further divided into APOs and non-APOs (NAPOs) group, fetal loss and live birth group according to pregnancy outcomes. The Mann-Whitney U-test was used to assess significance between and within groups. Spearman rank-order was used to evaluate correlation coefficients between BAFF and related cytokines. Results:. The serum BAFF level in HP group was significantly lower than HNP group (245.24 [218.80, 265.90] vs. 326.94 [267.31, 414.80] pg/mL, Z = −3.966, P

Background Pre-gestational diabetes mellitus (PGDM) has been known to be a risk factor for congenital heart defects (CHDs) for decades. However, the associations between maternal PGDM and gestational diabetes mellitus (GDM) and the risk of specific types of CHDs and congenital anomalies (CAs) in other systems remain under debate. We aimed to investigate type-specific CAs in offspring of women with diabetes and to examine the extent to which types of maternal diabetes are associated with increased risk of CAs in offspring. Methods and findings We searched PubMed and Embase from database inception to 15 October 2021 for population-based studies reporting on type-specific CAs in offspring born to women with PGDM (combined type 1 and 2) or GDM, with no limitation on language. Reviewers extracted data for relevant outcomes and performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. Risk of bias appraisal was performed using the Cochrane Risk of Bias Tool. This study was registered in PROSPERO (CRD42021229217). Primary outcomes were overall CAs and CHDs. Secondary outcomes were type-specific CAs. Overall, 59 population-based studies published from 1990 to 2021 with 80,437,056 participants met the inclusion criteria. Of the participants, 2,407,862 (3.0%) women had PGDM and 2,353,205 (2.9%) women had GDM. The meta-analyses showed increased risks of overall CAs/CHDs in offspring born to women with PGDM (for overall CAs, relative risk [RR] = 1.99, 95% CI 1.82 to 2.17, P < 0.001; for CHDs, RR = 3.46, 95% CI 2.77 to 4.32, P < 0.001) or GDM (for overall CAs, RR = 1.18, 95% CI 1.13 to 1.23, P < 0.001; for CHDs, RR = 1.50, 95% CI 1.38 to 1.64, P < 0.001). The results of the meta-regression analyses showed significant differences in RRs of CAs/CHDs in PGDM versus GDM (all P < 0.001). Of the 23 CA categories, excluding CHD-related categories, in offspring, maternal PGDM was associated with a significantly increased risk of CAs in 21 categories; the corresponding RRs ranged from 1.57 (for hypospadias, 95% CI 1.22 to 2.02) to 18.18 (for holoprosencephaly, 95% CI 4.03 to 82.06). Maternal GDM was associated with a small but significant increase in the risk of CAs in 9 categories; the corresponding RRs ranged from 1.14 (for limb reduction, 95% CI 1.06 to 1.23) to 5.70 (for heterotaxia, 95% CI 1.09 to 29.92). The main limitation of our analysis is that some high significant heterogeneity still persisted in both subgroup and sensitivity analyses. Conclusions In this study, we observed an increased rate of CAs in offspring of women with diabetes and noted the differences for PGDM versus GDM. The RRs of overall CAs and CHDs in offspring of women with PGDM were higher than those in offspring of women with GDM. Screening for diabetes in pregnant women may enable better glycemic control, and may enable identification of offspring at risk for CAs. In a systematic review and meta analysis, Tie-Ning Zhang and colleagues investigate the associations between maternal pre-gestational diabetes and gestational diabetes and congenital heart defects and other congenital anomalies in offspring. Author summary Why was this study done? It is controversial whether maternal pre-gestational or gestational diabetes affects specific types of congenital heart defects (CHDs) and congenital anomalies (CAs) in other systems. Comprehensive estimates of the risks of specific CAs for offspring of women with maternal diabetes are needed to counsel patients and for public health purposes. What did the researchers do and find? To the best of our knowledge, this is the first comprehensive systematic review and meta-analysis of population-based studies of over 80 million participants that demonstrates an increased risk of type-specific CAs, especially CHDs, in offspring born to women with pre-gestational or gestational diabetes. Our study shows that maternal pre-gestational diabetes is associated with a significant increase in the risk of 38 out of 45 categories of CAs in offspring, while maternal gestational diabetes is associated with a small but significant increase in the risk of 16 out of the 45 categories. The corresponding relative risks (RRs) of overall CAs/CHDs in offspring of women with pre-gestational diabetes are higher than those in offspring of women with gestational diabetes, with no overlap in the 95% CIs. What do these findings mean? In this study, we observed that there is an increased rate of CAs in offspring of women with maternal diabetes and noted the differences between pre-gestational and gestational diabetes. Considering the substantial rise in the prevalence of maternal diabetes over recent decades, the expectation that this prevalence will continue to increase, the number of pregnancies worldwide, and the significant individual and global burdens associated with CAs, it is crucial that healthcare providers are aware of this association and can identify women and offspring who are at risk.

Objectives Mental health resources are an important basis for coping with mental health services. The equity is an important index of a reasonable allocation of health resources. This study aims to evaluate the mental health resources and its equity allocation in Hunan Province, which is one of the typical central south areas of China, so as to provide reference for the development of mental health in China and other areas. Methods Data related to mental health resources was obtained from the Project of Mental Health Resources in Hunan Province, which was conducted by the Department of Hunan Mental Health Center in 2019. The Gini coefficient, the Theil index and other indicators were employed to quantitatively evaluate the equity of mental health resources’ allocation. Results By the end of 2018, there were a total of 141 mental health institutions in Hunan Province of China, the bed density was 5.31 beds per 10,000 people, the ratio of doctors to nurses was 2.20, the number of outpatients of mental health institutions was 1288,047 per year. The mental health resources’ allocation in terms of demographic dimension were in a preferred status with the Gini values all less than 0.3, and the Gini values for mental health resources`allocation in terms of geographical dimension ranged from 0.24 to 0.35. The Theil index for mental health allocation in terms of demographic dimension was lower than 0.05, and the Theil index for mental health allocation in terms of geographical dimension ranged from 0.04 to 0.11. Conclusions The shortage of mental health resources is still the priority issue to be increased and optimized by policy-makers in Hunan in the future, especially the human resources. Moreover, the utilization of mental health resources was low though its equity was fair. Policy-makers need to consider the high utilization and geographical accessibility of health resources among different regions to ensure people in different regions could get access to available health services.

Bone marrow stromal cells (BMSCs) have an important application prospect in the field of cell therapy for various neurodegenerative diseases, and inducing factors that regulate BMSC differentiation are proposed as a promising therapeutic strategy. In this study, we explored the effect of glial cell-derived neurotrophic factor (GDNF) on the course of BMSC differentiation.

Abstract Background Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. Methods Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-β1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. Results Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-β1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-β1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. Conclusions Our data suggests TGF-β1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis. Video Abstract Graphical abstract

Abstract. The chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is widely expressed in the immune system. Abnormal expression of CMTM is associated with the development of various diseases. This article summarizes the relevant research on the role of the CMTM family in immune disorders. This information will increase our understanding of pathogenesis and identify promising targets for the diagnosis and treatment of autoimmune diseases. The CMTM family is highly expressed in peripheral blood mononuclear cells. CKLF1 may be involved in the development of arthritis through its interaction with C-C chemokine receptor 4. CKLF1 is associated with the pathogenesis of lupus nephritis and psoriasis. Both CMTM4 and CMTM5 are associated with the pathogenesis of systemic lupus erythematosus. CMTM1, CMTM2, CMTM3, and CMTM6 play a role in rheumatoid arthritis, systemic sclerosis, Sjögren syndrome, and anti-phospholipid syndrome, respectively. The CMTM family has been implicated in various autoimmune diseases. Further research on the mechanism of the action of CMTM family members may lead to the development of new treatment strategies for autoimmune diseases.

Background: Rheumatoid arthritis (RA) is a destructive chronic inflammatory disease with intra- and extra-articular manifestations. It is associated with accelerated formation of arteriosclerosis. The aim of this study was to ascertain the correlation between endothelial dysfunction using carotid intima–media thickness (cIMT) and tumor necrosis factor-alpha (TNF-α) levels among the three main ethnic groups in Malaysia: Malay, Chinese, and Indian. Methods: This cross-sectional study included 23 females with RA belonging to three different ethnic groups who were free from cardiovascular risk factors. Blood sample was taken from each patient to measure serum TNF-α level, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Carotid ultrasonography was performed for cIMT analysis. The Disease Activity Score (DAS)-28 scoring system was used to assess disease activity. Results: Patients’ median age and disease duration were 47 and 5 years, respectively. No thickened cIMT was found in any of the patients. The duration of disease, TNF-α level, cIMT, DAS-28 CRP, and DAS-28 ESR showed no significant correlations in the different ethnic groups (p > 0.05). Conclusion: This study indicates that cIMT and serum TNF-α levels among females with RA in Malaysia may not be affected by ethnicity.

The microbiome has been implicated in the development of metabolic conditions which occur at high rates in people with schizophrenia and related psychoses. This exploratory proof-of-concept study aimed to: (i) characterize the gut microbiota in antipsychotic naïve or quasi-naïve people with first-episode psychosis, and people with established schizophrenia receiving clozapine therapy; (ii) test for microbiome changes following a lifestyle intervention which included diet and exercise education and physical activity. Participants were recruited from the Eastern Suburbs Mental Health Service, Sydney, Australia. Anthropometric, lifestyle and gut microbiota data were collected at baseline and following a 12-week lifestyle intervention. Stool samples underwent 16S rRNA sequencing to analyse microbiota diversity and composition. Seventeen people with established schizophrenia and five people with first-episode psychosis were recruited and matched with 22 age-sex, BMI and ethnicity matched controls from a concurrent study for baseline comparisons. There was no difference in α-diversity between groups at baseline, but microbial composition differed by 21 taxa between the established schizophrenia group and controls. In people with established illness pre-post comparison of α-diversity showed significant increases after the 12-week lifestyle intervention. This pilot study adds to the current literature that detail compositional differences in the gut microbiota of people with schizophrenia compared to those without mental illness and suggests that lifestyle interventions may increase gut microbial diversity in patients with established illness. These results show that microbiome studies are feasible in patients with established schizophrenia and larger studies are warranted to validate microbial signatures and understand the relevance of lifestyle change in the development of metabolic conditions in this population.

Objective: To explore the molecular targets and associated potential pathways of Lycii Fructus (LF, Gou Qi Zi, 枸杞子) in the treatment of retinitis pigmentosa (RP) by the approaches of network pharmacology and bioinformatics. Methods: The potential blood-entry active ingredients and targets of LF were retrieved by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). RP-related gene targets were retrieved through disease comprehensive databases. Protein-protein interaction (PPI) network of LF component-targets and RP disease-targets was constructed by STRING, and the intersection of the 2 networks was extracted. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of theintersection network were conducted by Database for Annotation, Visualization and Integrated Discovery (DAVID). CytoHubba was used to screen the key targets. Results: A total of 188 chemical constituents related to LF was retrieved from TCMSP database. 45 active ingredients were screened according to pharmacokinetic parameters oral bioavailability (OB) and drug similarity (DL). 36 active ingredients were further screened and 201 targets related to these constituents were obtained. 206 target genes directly related to RP were obtained from the disease comprehensive databases, and 89 genes were obtained from the intersection of component-target and disease-target PPI network. These genes were mainly involved in intracellular signal transduction, GTPase activity regulation, cell morphology regulation, and other biological processes. Molecular functions were mainly related to Rho guanine nucleotide exchange factor activity, GTPase activator activity, receptor signal protein serine/threonine kinase activity and so on. They were enriched in the cytoplasm, cell membrane, Golgi apparatus, and other regions. The mechanism was related to cell cycle pathways, neurotrophin signaling pathways, Ras signaling pathways, and so on. 10 key gene targets of LF in the treatment of RP were screened. Conclusions: The material basis for LF to exert its pharmacodynamic effect is 36 active ingredients such as cycloartenol, mandenol, and so on. The key targets of LF in the treatment of RP include 10 genes, such as Rho, PAK, and so on. The main mechanism is related to the regulation of the Ras signaling pathway, neurotrophin signaling pathway, cell cycle related pathway, and other signaling networks. Keywords: Network pharmacology, Retinitis pigmentosa, Lycii Fructus (Gou Qi Zi, 枸;杞;子;), Molecular mechanism, Target, Signaling pathway