Updated Intrinsic Role of Phytochemicals against Glyphosate-induced Neurotoxicity: Systematic Review.

BACKGROUND: Glyphosate-based herbicide (GBH) formulations are organophosphorus pesticides implicated for agricultural use. Several epidemiological reports have reported that the occupational exposure of farmers to glyphosate can cause age-related neurodegeneration. OBJECTIVE: the objective of this study is to examine the neurotoxic effects of glyphosate and its intricate role in triggering several neurodegenerative diseases like dementia, nootropic defects, Parkinson's disease, and neurological teratogenic effects due to its negative effects on the nervous system. Furthermore, the efficacy of phytochemicals against glyphosate-induced neurotoxicity was discussed. METHODS: We have searched public databases such as NLM, Pubmed, google scholar and collected a total of 103 articles including reviews, original articles, and obtained information related to glyphosate-induced neurotoxicity and novel phytochemicals implicated to ameliorate the glyphosate-induced neurotoxicity. We performed a systematic review without comprehensive meta-analysis. RESULTS: the efficacy of several phytochemicals as a nutritional intervention against glyphosate-induced neurotoxicity including Parkinsonism was elucidated by vivid review analysis of neurobehavioral alterations from in vitro and in vivo study models. CONCLUSION: These kinds of research projects will bring awareness about the neurotoxic effects of glyphosate and the protective nutritional intervention strategies against glyphosate-induced neurotoxicity including Parkinsonism for farmers.

Effectiveness of nurse-home visiting in improving child and maternal outcomes prenatally to age two years: a randomised controlled trial (British Columbia Healthy Connections Project).

BACKGROUND: We investigated the effectiveness of Nurse-Family Partnership (NFP), a prenatal-to-age-two-years home-visiting programme, in British Columbia (BC), Canada. METHODS: For this randomised controlled trial, we recruited participants from 26 public health settings who were: <25 years, nulliparous, <28 weeks gestation and experiencing socioeconomic disadvantage. We randomly allocated participants (one-to-one; computer-generated) to intervention (NFP plus existing services) or comparison (existing services) groups. Prespecified outcomes were prenatal substance exposure (reported previously); child injuries (primary), language, cognition and mental health (problem behaviour) by age two years; and subsequent pregnancies by 24 months postpartum. Research interviewers were masked. We used intention-to-treat analyses. (ClinicalTrials.gov, NCT01672060.) RESULTS: From 2013 to 2016 we enrolled 739 participants (368 NFP, 371 comparison) who had 737 children. Counts for child injury healthcare encounters [rate per 1,000 person-years or RPY] were similar for NFP (223 [RPY 316.17]) and comparison (223 [RPY 305.43]; rate difference 10.74, 95% CI -46.96, 68.44; rate ratio 1.03, 95% CI 0.78, 1.38). Maternal-reported language scores (mean, M [SD]) were statistically significantly higher for NFP (313.46 [195.96]) than comparison (282.77 [188.15]; mean difference [MD] 31.33, 95% CI 0.96, 61.71). Maternal-reported problem-behaviour scores (M [SD]) were statistically significantly lower for NFP (52.18 [9.19]) than comparison (54.42 [9.02]; MD -2.19, 95% CI -3.62, -0.75). Subsequent pregnancy counts were similar (NFP 115 [RPY 230.69] and comparison 117 [RPY 227.29]; rate difference 3.40, 95% CI -55.54, 62.34; hazard ratio 1.01, 95% CI 0.79, 1.29). We observed no unanticipated adverse events. CONCLUSIONS: NFP did not reduce child injuries or subsequent maternal pregnancies but did improve maternal-reported child language and mental health (problem behaviour) at age two years. Follow-up of long-term outcomes is warranted given that further benefits may emerge across childhood and adolescence.

Inflammation and Stem Cell Stochasticity of HPV-induced Cervical Cancer: Epigenetics Based Biomarkers through Microbiome and Metabolome for Personalized Medicine: A Systematic Review.

BACKGROUND: Chemoresistance by stemness in HPV-induced cervical carcinogenesis has significant implications for the overall disease-specific survival of the patients. To date, there are no reports related to the implications of significant aspects of inflammation and microbiome-- mediated epigenetics in cervical cancers. OBJECTIVE: The current systematic review delineates the significant aspects of the inflammation-related pathophysiology, cervical cancer diagnosis based on the HPV-indued stemness, and microbiome- mediated epigenetic markers to develop personalized therapies to target the stemness-acquired indefinitely dividing cancer stem cells. METHODS: We performed a systematic review without a meta- analysis. We searched several public databases, such as Pubmed, ReleMed, National Library of Medicine, and Scopus, related to inflammation, metabolomics, microbiome-mediated epigenetic markers, and HPV-induced stemness. RESULTS AND CONCLUSION: The review significantly described the correlation between microbial inflammation and stem cell stochasticity of HPV-Induced cervical cancer and the expression of epigenetics- based biomarkers through microbiome and metabolome to foster the cervical cancer progression. These are major risk factors that can cause cervical dysplasia with substantial therapy resistance in cervical cancer patients. The qualitative and quantitative examination of the spatial transcriptomic expression of these stemness markers in the dividing cervical cancer stem cells has significant implications in the clinical sector to develop early personalized medicine to prevent cervical precancerous lesions depending on the prognosis of the cervical cancer patients. Mainly, the combinatorial regimen of current therapeutic modalities, along with microbiome-related therapies with future landscape of epigenetics-modulated therapies, may enhance overall disease-specific survival by modulating the stochastic dynamics of basal epithelial cells across the cervical region.

Artificially reprogrammed stem cells deliver transcytosable nanocomplexes for improved spinal cord repair.

Stem cell transplantation holds great promise for restoring function after spinal cord injury (SCI), but its therapeutic efficacy heavily depends on the innate capabilities of the cells and the microenvironment at the lesion site. Herein, a potent cell therapeutic (NCs@SCs) is engineered by artificially reprogramming bone marrow mesenchymal stem cells (BMSCs) with oxidation-responsive transcytosable gene-delivery nanocomplexes (NCs), which endows cells with robust oxidative stress resistance and improved cytokine secretion. NCs@SCs can accumulate in the injured spinal cord after intravenous administration via chemotaxis and boost successive transcytosis to deliver NCs to neurons, augmenting ciliary neurotrophic factor (CNTF) production in both BMSCs and neurons in response to elevated ROS levels. Furthermore, NCs@SCs can actively sense and eliminate ROS and re-educate recruited M1-like macrophages into the anti-inflammatory M2 phenotype via a paracrine pathway, ultimately reshaping the inflammatory microenvironment. Synergistically, NCs@SCs exhibit durable survival and provide neuroprotection against secondary damage, enabling significant locomotor function recovery in SCI rats. Transcriptome analysis reveals that regulation of the ROS/MAPK signaling pathway is involved in SCI therapy by NCs@SCs. This study presents a nanomaterial-mediated cell-reprogramming approach for developing live cell therapeutics, showing significant potential in the treatment of SCI and other neuro-injury disorders.

Chinese Clinical Trial Registry 13-year data collection and analysis: geographic distribution, financial support, research phase, duration, and disease categories.

Objective: To evaluate the current status of trial registration on the Chinese Clinical Trial Registry (ChiCTR). Design: In this descriptive study, a multi-dimensional grouping analysis was conducted to estimate trends in the annual trial registration, geographical distribution, sources of funding, targeted diseases, and trial subtypes. Setting: We have analyzed all clinical trial records (over 30,000) registered on the Chinese Clinical Trial Registry (ChiCTR) from 2007 to 2020 executed in China. Main outcomes and measures: The main outcome was the baseline characteristics of registered trials. These trials were categorized and analyzed based on geographical distribution, year of implementation, disease type, resource and funding type, trial duration, trial phase, and the type of experimental approach. Results: From 2008 to 2017, a consistent upward trend in clinical trial registrations was observed, showing an average annual growth rate of 29.2%. The most significant year-on-year (yoy%) growth in registrations occurred in 2014 (62%) and 2018 (68.5%). Public funding represented the predominant source of funding in the Chinese healthcare system. The top five ChiCTR registration sites for all disease types were highly populated urban regions of China, including Shanghai (5,658 trials, 18%), Beijing (5,127 trials, 16%), Guangdong (3,612 trials, 11%), Sichuan (2,448 trials, 8%), and Jiangsu (2,196 trials, 7%). Trials targeting neoplastic diseases accounted for the largest portion of registrations, followed by cardio/cerebrovascular disease (CCVD) and orthopedic diseases-related trials. The largest proportions of registration trial duration were 1-2 years, less than 1 year, and 2-3 years (at 27.36, 26.71, and 22.46%). In the case of the research phase, the top three types of all the registered trials are exploratory research, post-marketing drugs, and clinical trials of new therapeutic technology. Conclusion and relevance: Oncological and cardiovascular diseases receive the highest share of national public funding for medical clinical trial-based research in China. Publicly funded trials represent a major segment of the ChiCTR registry, indicating the dominating role of public governance in this health research sector. Furthermore, the growing number of analyzed records reflect the escalation of clinical research activities in China. The tendency to distribute funding resources toward exceedingly populated areas with the highest incidence of oncological and cardiovascular diseases reveals an aim to reduce the dominating disease burden in the urban conglomerates in China.

Molecular classification of human papilloma virus-negative head and neck squamous cell carcinomas: Cell cycle-based classifier and prognostic signature.

The molecular classification of human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) remains questionable. Differentially expressed genes were detected between tumor and normal tissues and GSEA showed they are associated with cell cycle pathways. This study aimed to classify HPV-negative HNSCCs based on cell cycle-related genes. The established gene pattern was correlated with tumor progression, clinical prognosis, and drug treatment efficacy. Biological analysis was performed using HNSCC patient sample data obtained from the Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Gene Expression Omnibus (GEO) databases. All samples included in this study contained survival information. RNA sequencing data from 740 samples were used for the analysis. Previously characterized cell cycle-related genes were included for unsupervised consensus clustering. Two subtypes of HPV-negative HNSCCs (C1, C2) were identified. Subtype C1 displayed low cell cycle activity, 'hot' tumor microenvironment (TME), earlier N stage, lower pathological grade, better prognosis, and higher response rate to the immunotherapy and targeted therapy. Subtype C2 was associated with higher cell cycle activity, 'cold' TME, later N stage, higher pathological grade, worse prognosis, and lower response rate to the treatment. According to the nearest template prediction method, classification rules were established and verified. Our work explored the molecular mechanism of HPV-negative HNSCCs in the view of cell cycle and might provide new sights for personalized anti-cancer treatment.

AIFM2 promotes hepatocellular carcinoma metastasis by enhancing mitochondrial biogenesis through activation of SIRT1/PGC-1α signaling.

AIFM2 is a crucial NADH oxidase involved in the regulation of cytosolic NAD+. However, the role of AIFM2 in the progression of human cancers remains largely unexplored. Here, we elucidated the clinical implications, biological functions, and molecular mechanisms of AIFM2 in hepatocellular carcinoma (HCC). We found that AIFM2 is significantly upregulated in HCC, which is most probably caused by DNA hypomethylation and downregulation of miR-150-5p. High expression of AIFM2 is markedly associated with poor survival in patients with HCC. Knockdown of AIFM2 significantly impaired, while forced expression of AIFM2 enhanced the metastasis of HCC both in vitro and in vivo. Mechanistically, increased mitochondrial biogenesis and oxidative phosphorylation by activation of SIRT1/PGC-1α signaling contributed to the promotion of metastasis by AIFM2 in HCC. In conclusion, AIFM2 upregulation plays a crucial role in the promotion of HCC metastasis by activating SIRT1/PGC-1α signaling, which strongly suggests that AIFM2 could be targeted for the treatment of HCC.

Evaluating the effectiveness and cost-effectiveness of a digital, app-based intervention for depression (VMood) in community-based settings in Vietnam: Protocol for a stepped-wedge randomized controlled trial.

The COVID-19 pandemic has amplified mental health problems and highlighted inequitable gaps in care worldwide. In response there has been an explosion of digital interventions such as smartphone applications ("apps") to extend care. The objective of this trial is to evaluate the effectiveness and cost-effectiveness of a digital depression intervention (VMood), delivered via a smartphone app. VMood is adapted from an in-person intervention that was delivered by non-specialist providers and shown to be effective in the Vietnamese context in our previous trial (2016-2019). A stepped-wedge, randomized controlled trial will be conducted across eight provinces in Vietnam. Adults aged 18 years and over will be recruited through community-based primary care centres and screened for depression using the embedded Patient Health Questionnaire-9 (primary outcome measure). Participants scoring 10-19, indicating depression caseness, will be randomly allocated to the intervention or control group until the target of 336 is reached. Secondary outcome measures will examine the effect of the intervention on commonly co-occuring anxiety, quality of life and work productivity, along with use of alcohol and tobacco products. Assessments will be administered through an online survey platform (REDCap) at baseline, and at every 3 months until 3 months post-intervention. Intervention-group participants will receive VMood for a 3-month period, with online support provided by social workers. Control-group participants will receive a limited version of the app until they cross into the intervention group. Generalized Linear Mixed-effect Models for clustered measures will be used for all outcomes data. We will conduct a cost-effectiveness analysis alongside the trial to capture VMood's costs and benefits. This trial will provide evidence on the effectiveness and cost-effectiveness of a digital mental health intervention adapted from an in-person intervention. This trial will also contribute important information to the growing and promising field of digital mental health. Trail regulation. Registered at ClinicalTrials.gov, identifier [NCT05783531].

MicroRNA-183 cluster: a promising biomarker and therapeutic target in gastrointestinal malignancies.

Small non-coding RNAs (microRNA, miR), powerful epigenetic regulators, were found involved in the regulation of most biological functions via post-translational inhibition of protein expression. Increased expression of pro-oncogenic miRs (known as miR cancer biomarkers) and inhibition of pro-apoptotic miR expression have been demonstrated in different tumors. The recently identified miR-183 was found implicated in gastrointestinal tumor metabolism regulation. Elevated miR-183 expression and cancer-promoting effects were reported in esophageal and colorectal cancers, which was partially contradicted by controversial data observed in gastric cancers. Anti-cancer effect of miR-183 in gastric cancer cells was associated with the Bim-1 and Ezrin genes regulation. Many studies indicated that miR-183 can inhibit tumor suppressor genes in most cell lines, promoting tumor cell proliferation and migration. Increased miR-183 level results in the downregulation of FOXO1, PDCD4, and other tumor suppressor genes in gastrointestinal tumor cells. MiR-183 also influences the signaling of PI3K/AKT/mTOR, Wnt/ß-catenin, and Bcl-2/p53 signaling pathways. Mir-183 inhibits apoptosis and autophagy, and promotes epithelial-to-mesenchymal transition, cancer cell proliferation, and migration. Accordingly, gastrointestinal cancer occurrence, development of chemoradiotherapy resistance, recurrence/metastasis, and prognosis were associated with miR-183 expression. The current study assessed reported miR-183 functions and signaling, providing new insights for the diagnosis and treatment of gastrointestinal malignancies.

Genetic divergence and functional convergence of gut bacteria between the Eastern honey bee Apis cerana and the Western honey bee Apis mellifera.

Introduction: The functional relevance of intra-species diversity in natural microbial communities remains largely unexplored. The guts of two closely related honey bee species, Apis cerana and A. mellifera, are colonised by a similar set of core bacterial species composed of host-specific strains, thereby providing a good model for an intra-species diversity study. Objectives: We aim to assess the functional relevance of intra-species diversity of A. cerana and A. mellifera gut microbiota. Methods: Honey bee workers were collected from four regions of China. Their gut microbiomes were investigated by shotgun metagenomic sequencing, and the bacterial compositions were compared at the species level. A cross-species colonisation assay was conducted, with the gut metabolomes being characterised by LC-MS/MS. Results: Comparative analysis showed that the strain composition of the core bacterial species was host-specific. These core bacterial species presented distinctive functional profiles between the hosts. However, the overall functional profiles of the A. cerana and A. mellifera gut microbiomes were similar; this was further supported by the consistency of the honey bees' gut metabolome, as the gut microbiota of different honey bee species showed rather similar metabolic profiles in the cross-species colonisation assay. Moreover, this experiment also demonstrated that the gut microbiota of A. cerana and A. mellifera could cross colonise between the two honey bee species. Conclusion: Our findings revealed functional differences in most core gut bacteria between the guts of A. cerana and A. mellifera, which may be associated with their inter-species diversity. However, the functional profiles of the overall gut microbiomes between the two honey bee species converge, probably as a result of the overlapping ecological niches of the two species. Our findings provide critical insights into the evolution and functional roles of the mutualistic microbiota of honey bees and reveal that functional redundancy could stabilise the gene content diversity at the strain-level within the gut community.

Prevalence of childhood mental disorders in high-income countries: a systematic review and meta-analysis to inform policymaking.

QUESTION: Mental disorders typically start in childhood and persist, causing high individual and collective burdens. To inform policymaking to address children's mental health in high-income countries we aimed to identify updated data on disorder prevalence. METHODS: We identified epidemiological studies reporting mental disorder prevalence in representative samples of children aged 18 years or younger-including a range of disorders and ages and assessing impairment (searching January 1990 through February 2021). We extracted associated service-use data where studies assessed this. We conducted meta-analyses using a random effects logistic model (using R metafor package). FINDINGS: Fourteen studies in 11 countries met inclusion criteria, published from 2003 to 2020 with a pooled sample of 61 545 children aged 4-18 years, including eight reporting service use. (All data were collected pre-COVID-19.) Overall prevalence of any childhood mental disorder was 12.7% (95% CI 10.1% to 15.9%; I2=99.1%). Significant heterogeneity pertained to diagnostic measurement and study location. Anxiety (5.2%), attention-deficit/hyperactivity (3.7%), oppositional defiant (3.3%), substance use (2.3%), conduct (1.3%) and depressive (1.3%) disorders were the most common. Among children with mental disorders, only 44.2% (95% CI 37.6% to 50.9%) received any services for these conditions. CONCLUSIONS: An estimated one in eight children have mental disorders at any given time, causing symptoms and impairment, therefore requiring treatment. Yet even in high-income countries, most children with mental disorders are not receiving services for these conditions. We discuss the implications, particularly the need to substantially increase public investments in effective interventions. We also discuss the policy urgency, given the emerging increases in childhood mental health problems since the onset of the COVID-19 pandemic (PROSPERO CRD42020157262).

Chinese Propolis Suppressed Pancreatic Cancer Panc-1 Cells Proliferation and Migration via Hippo-YAP Pathway.

Pancreatic cancer is one of the most malignant cancers with high mortality. Therefore, it is of great urgency to develop new agents that could improve the prognosis of Pancreatic cancer patients. Chinese propolis (CP), a flavonoid-rich beehive product, has been reported to have an anticancer effect. In this study, we applied CP to the human Pancreatic cancer cell line Panc-1 to verify its impact on tumor development. CP induced apoptosis in Panc-1 cells from 12.5 µg/mL in a time- and dose-dependent manner with an IC50 value of approximately 50 µg/mL. Apoptosis rate induced by CP was examined by Annexing FITC/PI assay. We found that 48 h treatment with 50 µg/mL CP resulted in 34.25 ± 3.81% apoptotic cells, as compared to 9.13 ± 1.76% in the control group. We further discovered that the Panc-1 cells tended to be arrested at G2/M phase after CP treatment, which is considered to contribute to the anti-proliferation effect of CP. Furthermore, our results demonstrated that CP suppressed Panc-1 cell migration by regulating epithelial-mesenchymal transition (EMT). Interestingly, the Hippo pathway was activated in Panc-1 cells after CP treatment, serving as a mechanism for the anti-pancreatic cancer effect of CP. These findings provide a possibility of beehive products as an alternative treatment for pancreatic cancer.

Has the excess risk of acute myocardial infarction in rheumatoid arthritis relative to the general population declined? A population study of trends over time.

OBJECTIVE: To evaluate secular trend in ten-year risk of incident acute myocardial infarction (AMI) in incident rheumatoid arthritis (RA) relative to the general population. METHODS: We conducted a retrospective study of population-based incident RA cohorts with RA incidence from 1997 to 2004 in British Columbia, Canada, with matched general population comparators, using administrative health data. RA and their matched cohorts were divided according to the year of RA incidence, defined according to the first RA visit of the case definition. Incident AMI was defined as the first event occurring within 10 years from RA incidence. Secular trend was assessed using delayed-entry Cox models with an interaction term between the year of RA onset and indicator of RA vs. general population. Linear, quadratic and spline functions of year of RA onset were compared to assess possibility of nonlinear trends. The model with the lowest AIC was selected to interpret the results. Sensitivity analyses were conducted to account for potential effect of unmeasured (e.g. smoking) or partially measured (e.g. obesity) confounders in administrative data, on the interaction term. RESULTS: Overall, 23,237 RA and 46,474 general population controls experienced 1,133 and 1,606 incident AMIs, respectively. A linear Cox model was selected as the model best fitting the AMI events. Overall, RA patients were found to have a 21% higher risk of AMI than the matched general population controls [1.21 (1.10, 1.32); p < 0.001]. A significant linear decline in risk of AMI was observed in RA patients [0.94 (95% CI 0.91, 0.97) p = <0.0001], and in the general population [0.93 (0.91, 0.95); p = <0.0001]. The change in AMI risk over time did not differ in RA compared to the general population [p-value of interaction term=0.49]. Our results remained similar after adjusting for the potential effect of confounders on the interaction term, and no difference in the change in risk of AMI over time was observed between RA and the general population. CONCLUSION: Our findings suggest a decline in 10-year risk of AMI in RA, and in the general population. The decline in the risk of AMI over time did not differ between RA and the general population, such that the excess risk of AMI in RA relative to the general population, has remained the same.

Inflammation Mediates the Development of Aggressive Breast Cancer Following Radiotherapy.

PURPOSE: Women treated with radiotherapy before 30 years of age have increased risk of developing breast cancer at an early age. Here, we sought to investigate mechanisms by which radiation promotes aggressive cancer. EXPERIMENTAL DESIGN: The tumor microenvironment (TME) of breast cancers arising in women treated with radiotherapy for Hodgkin lymphoma was compared with that of sporadic breast cancers. To investigate radiation effects on carcinogenesis, we analyzed tumors arising from Trp53-null mammary transplants after irradiation of the target epithelium or host using immunocompetent and incompetent mice, some of which were treated with aspirin. RESULTS: Compared with age-matched specimens of sporadic breast cancer, radiation-preceded breast cancers (RP-BC) were characterized by TME rich in TGFß, cyclooxygenase 2, and myeloid cells, indicative of greater immunosuppression, even when matched for triple-negative status. The mechanism by which radiation impacts TME construction was investigated in carcinomas arising in mice bearing Trp53-null mammary transplants. Immunosuppressive TMEs (iTME) were recapitulated in mice irradiated before transplantation, which implicated systemic immune effects. In nu/nu mice lacking adaptive immunity irradiated before Trp53-null mammary transplantation, cancers also established an iTME, which pointed to a critical role for myeloid cells. Consistent with this, irradiated mammary glands contained more macrophages and human cells cocultured with polarized macrophages underwent dysplastic morphogenesis mediated by IFNγ. Treating mice with low-dose aspirin for 6 months postirradiation prevented establishment of an iTME and resulted in less aggressive tumors. CONCLUSIONS: These data show that radiation acts via nonmutational mechanisms to promote markedly immunosuppressive features of aggressive, RP-BCs.

The risk and trend of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a general population-based study.

OBJECTIVES: To estimate the overall risk of venous thromboembolism (VTE), pulmonary embolism (PE) and deep vein thrombosis (DVT) among patients newly diagnosed with RA compared with the general population without RA; and to estimate the risk trends of VTE, PE and DVT after RA diagnosis up to 5 years compared with the general population. METHODS: Using previously validated RA case definition, we conducted a matched cohort study using the population-based administrative health database from the province of British Columbia, Canada. We calculated incidence rates (IRs) and fully adjusted hazard ratios (HRs) for the risk of VTE, DVT and PE after RA index date. RESULTS: Among 39 142 incident RA patients (66% female, mean age 60), 1432, 543 and 1068 developed VTE, PE and DVT, respectively. IRs for the RA cohort were 3.79, 1.43 and 2.82 per 1000 person-years vs 2.70, 1.03 and 1.94 per 1000 person-years for the non-RA cohort. After adjusting for VTE risk factors, the HRs (95% CI) were 1.28 (1.20, 1.36), 1.25 (1.13, 1.39) and 1.30 (1.21, 1.40) for VTE, PE and DVT, respectively. The fully adjusted HRs for VTE during the first five years after RA diagnosis were 1.60, 1.47, 1.40, 1.30 and 1.28, respectively. A similar trend was shown in PE. CONCLUSION: This population-based study demonstrates that RA patients have an increased risk of VTE, PE and DVT after diagnosis compared with the general population. This risk is independent of traditional VTE risk factors and is highest during the first year after RA diagnosis, then progressively declined.

Hydroxychloroquine and Mortality Among Patients With Systemic Lupus Erythematosus in the General Population.

OBJECTIVE: Hydroxychloroquine (HCQ) has been associated with improved survival among patients with systemic lupus erythematosus (SLE) from tertiary referral centers. We aimed to determine the potential impact of HCQ use on the risk of mortality among SLE patients in the general population. METHODS: We conducted a nested case-control study within an incident SLE cohort from the entire population of British Columbia, Canada. Deceased patients were matched with up to 3 living controls by age, sex, and SLE disease duration. HCQ exposure was categorized by the time between the last HCQ prescription date covered (i.e., end of supply) and the index date (i.e., death date) as current (<30 days), recent (30-365 days), remote (>365 days), or never used. We used conditional logistic regression to assess the risk of all-cause mortality associated with current or recent HCQ exposure compared with remote HCQ users. RESULTS: Among 6,241 patients with incident SLE, we identified 290 deceased patients and 502 matched SLE controls. Adjusted odd ratios for all-cause mortality were 0.50 (95% confidence interval [95% CI] 0.30-0.82) for current users and 2.47 (95% CI 1.21-5.05) for recent users compared with remote users. Associations were similar in subgroups according to SLE duration (≤5 years versus >5 years). CONCLUSION: Our general population data support a substantial survival benefit associated with current HCQ use. Increased mortality among patients who had discontinued HCQ recently could be due to a sick stopper effect or the loss of actual HCQ benefits.

Ten-year risk of cerebrovascular accidents in incident rheumatoid arthritis: a population-based study of trends over time.

OBJECTIVE: To evaluate secular trends in 10-year risk of incident cerebrovascular accidents (CVA), in incident RA relative to the general population. METHODS: We conducted a retrospective study of a population-based incident cohort with RA onset from 1997 to 2004 in British Columbia, Canada, with matched general population controls (2:1), using administrative health data. RA and general population cohorts were divided according to year of RA onset, defined according to the first RA visit of the case definition. Incident CVA was defined as the first CVA occurring within 10 years from the first RA visit. Secular trend was assessed using delayed-entry Cox models with a two-way interaction term between the year of RA onset and indicator of RA vs general population. Linear, quadratic and spline functions of year of RA onset were compared with assess non-linear effects. The model with the lowest Akaike Information Criterion was selected. RESULTS: Overall, 23 545 RA and 47 090 general population experienced 658 and 1220 incident CVAs, respectively. A spline Cox model with a knot at year of onset 1999 was selected. A significant decline in risk of CVA was observed in individuals with RA onset after 1999 [0.90 (0.86, 0.95); P = 0.0001]. The change in CVA risk over time differed significantly in RA with onset from 1999 onwards compared with the general population (P-value of interaction term = 0.03), but not before 1999 (P = 0.06). CONCLUSION: Our findings suggest that people with RA onset from 1999 onwards, had a significantly greater decline in 10-year risk of CVA compared with the general population.

Nurse home visiting and prenatal substance use in a socioeconomically disadvantaged population in British Columbia: analysis of prenatal secondary outcomes in an ongoing randomized controlled trial.

BACKGROUND: Nurse-Family Partnership (NFP) involves public health nurses providing frequent home visits from early pregnancy until children reach age 2 years, focusing on first-time parents experiencing socioeconomic disadvantage. Our aim was to evaluate NFP's effectiveness in improving child and maternal health. METHODS: We conducted an analysis of prenatal secondary outcomes in an ongoing randomized controlled trial in British Columbia; the data used in this analysis were collected from January 2014 to May 2017. Participants were pregnant girls and women aged 14-24 years who were preparing to parent for the first time and experiencing socioeconomic disadvantage. They were randomly allocated 1:1 to the intervention (NFP plus existing services) or control group (existing services). Prespecified prenatal secondary outcome indicators were changes in use of nicotine cigarettes and alcohol use by 34-36-weeks' gestation. We also report on prespecified exploratory cannabis and street drug use measures. We used mixed-effect models for longitudinal and clustered data to estimate intervention effects. Analyses were by intention to treat. RESULTS: The median gestational age at baseline for the 739 participants (368 participants in the intervention group, 371 in the comparison group) was 20 weeks, 6 days. By 34-36 weeks' gestation, NFP significantly reduced cigarette counts (over the past 2 d) (difference in changes [DIC] of count -1.6, 95% confidence interval [CI] -6.4 to -1.3) in those who smoked. NFP also significantly reduced rates of prenatal cannabis use (DIC -6.4, 95% CI -17.0 to -1.7), but not rates of street drug or "any" substance use. While we observed decreased rates of cigarette and alcohol use in both groups (DIC of proportions -2.8, 95% CI -15.3 to 0.6; DIC -0.5, 95% CI -8.7 to 1.8, respectively), these changes were not statistically significant. INTERPRETATION: We found no evidence that NFP was effective in reducing rates of prenatal cigarette and alcohol use; however, it led to reduced prenatal cannabis use, and in smokers it led to modest reductions in cigarette use. NFP may therefore hold promise for reducing some types of prenatal substance use in disadvantaged populations. Trial registration: ClinicalTrials.gov, no. NCT01672060.

Chinese Propolis Inhibits the Proliferation of Human Gastric Cancer Cells by Inducing Apoptosis and Cell Cycle Arrest.

Special Chinese propolis sourced from the Changbai Mountains (CBMP) in Northeast China is rich in specific flavonoids and phenolic acids and its bioactivity has not been reported. This study aimed to investigate the antiproliferative effect of CBMP on cancer cells and its molecular mechanisms. Different cancer cell lines were treated with the ethanol extracts of CBMP for 24 hours before the cell viability and mechanism measurements. The results showed CBMP had weak activities against human pancreatic cancer cell PANC1, human lung cancer cell A549, human colon cancer cell HCT116, human liver cancer cell HepG2, human bladder cancer cell T24, and human breast cancer cell MDA-MB-231, but it significantly inhibited the growth of human gastric cancer SGC-7901 cells, caused cell apoptosis and cell cycle arrest in S phase, with increased production of reactive oxygen species (ROS) and reduced mitochondrial membrane potential (MMP). The results indicate that Chinese propolis sourced from the Changbai Mountains selectively inhibits the proliferation of human gastric cancer SGC-7901 cells by inducing both death receptor-induced apoptosis and mitochondria-mediated apoptosis, and cell cycle arrest in S phase. These activities and mechanisms help understand the anticancer action of propolis and its active compounds.