NDRG1 enhances the sensitivity to Cetuximab by promoting Stat1 ubiquitylation in colorectal cancer.

INTRODUCTION: Cetuximab (CTX) is an effective targeted drug for the treatment of metastatic colorectal cancer, but it is effective only in patients with wild-type KRAS genes. Even in this subset of patients, the sensitivity of CTX in patients with right hemi-colon cancer is much lower than that in patients with left hemi-colon cancer. This significantly limits its clinical application. Therefore, further elucidation of the underlying molecular mechanisms is needed. N-myc downstream-regulated gene 1 (NDRG1) plays an important role in solid tumor invasion and metastasis, but whether it can influence CTX sensitivity has not been thoroughly investigated. OBJECTIVE: Our study aimed to identify a novel mechanism by which NDRG1 affects CTX sensitivity. METHODS: Through mass spectrometry analysis of our previously constructed CTX-resistant RKO and HCT116 cells, we found that the signal transducer and activator of transcription-1 (Stat1) might be a potential target of NDRG1. By knocking out NDRG1 or/and Stat1 genes, we then applied the loss-of-function experiments to explore the regulatory relationship between NDRG1 and Stat1 and their roles in the cell cycle, epithelial-mesenchymal transition (EMT), and the sensitivity to CTX in these two colorectal cancer (CRC) cells. Finally, we used the nude-mouse transplanted tumor model and human CRC samples to verify the expression of NDRG1 and Stat1 and their impact on CTX sensitivity in vivo. RESULTS: Stat1 was upregulated in CTX-resistant cells, whereas NDRG1 was downregulated. Mechanically, NDRG1 was inversely correlated with Stat1 expression. It suppressed CRC cell proliferation, migration, and invasion, and promoted apoptosis and epithelial-mesenchymal transition (EMT) by inhibiting Stat1. In addition, NDRG1 directly interacted with Stat1 and promoted Smurf1-induced Stat1 ubiquitination. Importantly, this novel NDRG1-dependent regulatory loop also enhanced CTX sensitivity both in vitro and in vivo. CONCLUSION: Our study revealed that NDRG1 enhanced the sensitivity to Cetuximab by inhibiting Stat1 expression and promoting its ubiquitination in colorectal cancer, elucidating NDRG1 might be a potential therapeutic target for refractory CTX-resistant CRC tumors. But its clinical value still needs to be validated in a larger sample size as well as a different genetic background.

Cell-Specific Effects of Insulin in a Murine Model of Restenosis Under Insulin-Sensitive and Insulin-Resistant Conditions.

Restenosis following percutaneous revascularization is a major challenge in patients with insulin resistance and diabetes. Currently, the vascular effects of insulin are not fully understood. In vitro, insulin's effects on endothelial cells (ECs) are beneficial, whereas on vascular smooth muscle cells (SMCs), they are mitogenic. We previously demonstrated a suppressive effect of insulin on neointimal growth under insulin-sensitive conditions that was abolished in insulin-resistant conditions. Here, we aimed to determine the cell-specific effects of insulin on neointimal growth in a model of restenosis under insulin-sensitive and insulin-resistant conditions. Vascular cell-specific insulin receptor (IR)-deficient mice were fed a low-fat diet (LFD) or a high-fat, high-sucrose diet (HFSD) and implanted with an insulin pellet or vehicle prior to femoral artery wire injury. In insulin-sensitive conditions, insulin decreased neointimal growth only in controls. However, under insulin-resistant conditions, insulin had no effect in either control, EC-specific or SMC-specific IR-deficient mice. These data demonstrate that EC and SMC IRs are required for the anti-restenotic effect of insulin in insulin-sensitive conditions and that, in insulin resistance, insulin has no adverse effect on vascular SMCs in vivo.

Maternal gut Bifidobacterium breve modifies fetal brain metabolism in germ-free mice.

BACKGROUND: Recent advances have significantly expanded our understanding of the gut microbiome's influence on host physiology and metabolism. However, the specific role of certain microorganisms in gestational health and fetal development remains underexplored. OBJECTIVE: This study investigates the impact of Bifidobacterium breve UCC2003 on fetal brain metabolism when colonized in the maternal gut during pregnancy. METHODS: Germ-free pregnant mice were colonized with or without B. breve UCC2003 during pregnancy. The metabolic profiles of fetal brains were analyzed, focusing on the presence of key metabolites and the expression of critical metabolic and cellular pathways. RESULTS: Maternal colonization with B. breve resulted in significant metabolic changes in the fetal brain. Specifically, ten metabolites, including citrate, 3-hydroxyisobutyrate, and carnitine, were reduced in the fetal brain. These alterations were accompanied by increased abundance of transporters involved in glucose and branched-chain amino acid uptake. Furthermore, supplementation with this bacterium was associated with elevated expression of critical metabolic pathways such as PI3K-AKT, AMPK, STAT5, and Wnt-ß-catenin signaling, including its receptor Frizzled-7. Additionally, there was stabilization of HIF-2 protein and modifications in genes and proteins related to cellular growth, axogenesis, and mitochondrial function. CONCLUSIONS: The presence of maternal B. breve during pregnancy plays a crucial role in modulating fetal brain metabolism and growth. These findings suggest that Bifidobacterium could modify fetal brain development, potentially offering new avenues for enhancing gestational health and fetal development through microbiota-targeted interventions.

Concatemer Assisted Stoichiometry Analysis (CASA): targeted mass spectrometry for protein quantification.

Large multi-protein machines are central to multiple biological processes. However, stoichiometric determination of protein complex subunits in their native states presents a significant challenge. This study addresses the limitations of current tools in accuracy and precision by introducing concatemer-assisted stoichiometry analysis (CASA). CASA leverages stable isotope-labeled concatemers and liquid chromatography parallel reaction monitoring mass spectrometry (LC-PRM-MS) to achieve robust quantification of proteins with sub-femtomole sensitivity. As a proof-of-concept, CASA was applied to study budding yeast kinetochores. Stoichiometries were determined for ex vivo reconstituted kinetochore components, including the canonical H3 nucleosomes, centromeric (Cse4CENP-A) nucleosomes, centromere proximal factors (Cbf1 and CBF3 complex), inner kinetochore proteins (Mif2CENP-C, Ctf19CCAN complex), and outer kinetochore proteins (KMN network). Absolute quantification by CASA revealed Cse4CENP-A as a cell-cycle controlled limiting factor for kinetochore assembly. These findings demonstrate that CASA is applicable for stoichiometry analysis of multi-protein assemblies.

The Health Status of Women with Children Living in Public and Assisted Housing: Linkage of the National Health Interview Survey to U.S. Department of Housing and Urban Development Administrative Data.

For more than a decade, the U.S. Department of Housing and Urban Development (HUD) and the National Center for Health Statistics (NCHS) have partnered to link NCHS national health survey data with HUD administrative records on persons participating in federal public and assisted housing programs. This study used 2015-18 National Health Interview Survey (NHIS)-HUD linked data to examine women 18-44 years old with children and renting their home who were receiving HUD assistance (n=852) and a comparison population of women of the same age with children, who were low-income renters but did not link to HUD records at the time of their NHIS interview (n=894). The population of HUD-assisted women differed from the comparison group on key sociodemographic characteristics and health indicators. HUD-assisted women were more likely to report their health as fair or poor and to being a current smoker. HUD-assisted women also were less likely to be uninsured and more likely to have a regular source of care. The findings in this article are exploratory but demonstrate how the NCHS-HUD-linked data can be a resource for researchers and policymakers in further examining housing status as an important social determinant of health.

Clinical significance of cefazolin inoculum effect in serious MSSA infections: a systematic review.

Background: The cefazolin inoculum effect (CzIE) is a phenomenon whereby some MSSA isolates demonstrate resistance to cefazolin when a high bacterial inoculum is used for susceptibility testing. The clinical significance of this phenotypic phenomenon remains unclear. We conducted a systematic review to answer the following question: In patients with serious MSSA infection treated with cefazolin, does infection due to CzIE-positive MSSA isolates result in worse clinical outcomes than infection due to CzIE-negative MSSA isolates? Methods: Ovid MEDLINE, Embase, Cochrane CENTRAL, medRxiv and bioRxiv were searched from inception until 12 April 2023. Studies were included if they tested for CzIE in clinical isolates from MSSA infections in humans. Two independent reviewers extracted data and conducted risk-of-bias assessment. Main outcomes were treatment failure and mortality. Pooling of study estimates was not performed given the heterogeneity of patient populations and outcome definitions. Results: Twenty-three observational studies were included. CzIE presence amidst MSSA isolates ranged from 0% to 55%. There was no statistically significant mortality difference in two studies that compared MSSA infections with and without CzIE, with ORs ranging from 0.72 to 19.78. Of four studies comparing treatment failure, ORs ranged from 0.26 to 13.00. One study showed a significantly higher treatment failure for the CzIE group, but it did not adjust for potential confounders. Conclusions: The evidence on CzIE is limited by small observational studies. In these studies, CzIE did not predict higher mortality in MSSA infections treated with cefazolin. Our findings do not support CzIE testing in clinical practice currently.

Obesogenic Diet in Mice Leads to Inflammation and Oxidative Stress in the Mother in Association with Sex-Specific Changes in Fetal Development, Inflammatory Markers and Placental Transcriptome.

BACKGROUND: Obesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress, and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity. The aim of this study on mice was to determine the effect of obesity on maternal lipid handling, inflammatory and redox state, and placental oxidative stress, inflammatory signaling, and gene expression relative to female and male fetal growth. METHODS: Female mice were fed control or obesogenic high-fat/high-sugar diet (HFHS) from 9 weeks prior to, and during, pregnancy. On day 18.5 of pregnancy, maternal plasma, and liver, placenta, and fetal serum were collected to examine the immune and redox states. The placental labyrinth zone (Lz) was dissected for RNA-sequencing analysis of gene expression changes. RESULTS: the HFHS diet induced, in the dams, hepatic steatosis, oxidative stress (reduced catalase, elevated protein oxidation) and the activation of pro-inflammatory pathways (p38-MAPK), along with imbalanced circulating cytokine concentrations (increased IL-6 and decreased IL-5 and IL-17A). HFHS fetuses were asymmetrically growth-restricted, showing sex-specific changes in circulating cytokines (GM-CSF, TNF-α, IL-6 and IFN-γ). The morphology of the placenta Lz was modified by an HFHS diet, in association with sex-specific alterations in the expression of genes and proteins implicated in oxidative stress, inflammation, and stress signaling. Placental gene expression changes were comparable to that seen in models of intrauterine inflammation and were related to a transcriptional network involving transcription factors, LYL1 and PLAG1. CONCLUSION: This study shows that fetal growth restriction with maternal obesity is related to elevated oxidative stress, inflammatory pathways, and sex-specific placental changes. Our data are important, given the marked consequences and the rising rates of obesity worldwide.

A Systematic Review of the Impacts of Media Mental Health Awareness Campaigns on Young People.

Mental health issues are prevalent among young people. An estimated 10% of children and adolescents worldwide experience a mental disorder, yet most do not seek or receive care. Media mental health awareness campaigns, defined as marketing efforts to raise awareness of mental health issues through mass media, are an effort to address this concern. While previous research has evaluated the outcomes of specific media mental health awareness campaigns, there is limited data synthesizing their overall effects. This study addresses the knowledge gap by reviewing the existing literature on the impact of media mental health awareness campaigns on young people. A search was conducted on MEDLINE, EMBASE, PsychINFO, Web of Science, and Google Scholar for studies published between 2004 and 2022 with results specific to people aged 10 to 24. Out of 20,902 total studies identified and screened, 18 studies were included in the review. The following data were extracted from each study: characteristics and descriptions of the campaign, evaluation design and sampling, and summary of impact. The review identified evaluations of 15 campaigns from eight different countries. Outcome evaluation methods commonly comprised of surveys and quantitative data. The campaigns were generally associated with positive changes in the attitudes, beliefs, and intentions of young people (e.g., reduced stigma) and positive changes in behaviors (e.g., increased help-seeking behaviors). The inclusion of few studies in the review indicates a need for ongoing evaluations of media mental health awareness campaigns for young people to inform good practices in their development and distribution.

Placental inflammation, oxidative stress, and fetal outcomes in maternal obesity.

The obesity epidemic has led to a growing body of research investigating the consequences of maternal obesity on pregnancy and offspring health. The placenta, traditionally viewed as a passive intermediary between mother and fetus, is known to play a critical role in modulating the intrauterine environment and fetal development, and we now know that maternal obesity leads to increased inflammation, oxidative stress, and altered placental function. Here, we review recent research exploring the involvement of inflammation and oxidative stress as mechanisms impacting the placenta and fetus during obese pregnancy. Understanding them is crucial for informing strategies that can mitigate the adverse health effects of maternal obesity on offspring development and disease risk.

Rates of out-of-home care among children in Canada: an analysis of national administrative child welfare data. / Taux de placement des enfants hors de leur foyer familial : analyse des données administratives nationales du système de protection de l'enfance au Canada.

INTRODUCTION: As a part of the public health approach to child welfare, data about children placed in out-of-home care are needed to assess population trends, understand drivers of social and health inequities, and examine outcomes for children and families. We analyzed administrative data from Canada to describe the population of children in out-of-home care, and estimate and compare rates of out-of-home care by province/territory, year, sex/gender, age group and placement type. METHODS: We conducted a cross-sectional analysis of point-in-time data from all provinces and territories for the period 2013/2014 to 2021/2022. We used frequencies and percentages to describe the population of children (and youth up to age 21 years) in out-of-home care and estimated overall and stratified rates and rate ratios. RESULTS: An estimated 61 104 children in Canada were in out-of-home care on 31 March 2022. The national rate of out-of-home care was 8.24 children per 1000 population. Rate variations by province/territory were substantial and changed over time. Rates were highest among males and children aged 1 to 3 and 16 to 17 years. Foster homes were the most common type of placement, although kinship homes accounted for an increasing share. CONCLUSION: This analysis demonstrated that administrative data can be used to generate national indicators about children involved in the child welfare system. These data can be used for tracking progress towards health and social equity for children and youth in Canada.

Clofazimine pharmacokinetics in HIV-infected adults with diarrhea: Implications of diarrheal disease on absorption of orally administered therapeutics.

Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter gastrointestinal physiology and cause diarrhea. The extent of diarrhea-associated impact on drug pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used a population pharmacokinetic modeling approach with data collected in a phase IIa study of matched human immunodeficiency virus (HIV)-infected adults with/without cryptosporidiosis and diarrhea to examine diarrhea-associated impact on oral clofazimine pharmacokinetics. A population pharmacokinetic model was developed with 428 plasma samples from 23 HIV-infected adults with/without Cryptosporidium infection using nonlinear mixed-effects modeling. Covariates describing cryptosporidiosis-associated diarrhea severity (e.g., number of diarrhea episodes, diarrhea grade) or HIV infection (e.g., viral load, CD4+ T cell count) were evaluated. A two-compartment model with lag time and first-order absorption and elimination best fit the data. Maximum diarrhea grade over the study duration was found to be associated with a more than sixfold reduction in clofazimine bioavailability. Apparent clofazimine clearance, intercompartmental clearance, central volume of distribution, and peripheral volume of distribution were 3.71 L/h, 18.2 L/h (interindividual variability [IIV] 45.0%), 473 L (IIV 3.46%), and 3434 L, respectively. The absorption rate constant was 0.625 h-1 (IIV 149%) and absorption lag time was 1.83 h. In conclusion, the maximum diarrhea grade observed for the duration of oral clofazimine administration was associated with a significant reduction in clofazimine bioavailability. Our results highlight the importance of studying disease impacts on oral therapeutic pharmacokinetics to inform dose optimization and maximize the chance of treatment success.

Debate: Social media content moderation may do more harm than good for youth mental health.

Most social media platforms censor and moderate content related to mental illness to protect users from harm, though this may be at the expense of potential positive outcomes for youth mental health. Current evidence does not offer strong support for the relationship between censoring mental health content and preventing harm. In fact, existing moderation strategies can perpetuate negative consequences for mental health by creating isolated and polarized communities where at-risk youth remain exposed to harmful content, such as pro-eating disorder communities that use lexical variants to evade censorship. Social media censorship of content related to mental illness can also silence positive discourse about mental health, create barriers to accessing online support and resources, and hinder research efforts on youth well-being. Social media content about mental health can have important positive impacts on youth mental health by facilitating help-seeking, depicting positive coping strategies, and promoting a sense of belonging for struggling youth, but these benefits are minimized under existing moderation and censorship practices. This article presents a call to action for evidence-based social media policies and for practitioners to consider the clinical implications of social media engagement when connecting with young patients.

Potential and Challenges in Application of Physiologically Based Pharmacokinetic Modeling in Predicting Diarrheal Disease Impact on Oral Drug Pharmacokinetics.

Physiologically based pharmacokinetic (PBPK) modeling is a physiologically relevant approach that integrates drug-specific and system parameters to generate pharmacokinetic predictions for target populations. It has gained immense popularity for drug-drug interaction, organ impairment, and special population studies over the past two decades. However, an application of PBPK modeling with great potential remains rather overlooked - prediction of diarrheal disease impact on oral drug pharmacokinetics. Oral drug absorption is a complex process involving the interplay between physicochemical characteristics of the drug and physiological conditions in the gastrointestinal tract. Diarrhea, a condition common to numerous diseases impacting many worldwide, is associated with physiological changes in many processes critical to oral drug absorption. In this review, we outline key processes governing oral drug absorption, provide a high-level overview of key parameters for modeling oral drug absorption in PBPK models, examine how diarrheal diseases may impact these processes based on literature findings, illustrate the clinical relevance of diarrheal disease impact on oral drug absorption, and discuss the potential and challenges of applying PBPK modeling in predicting disease impacts. Significance Statement Statement Pathophysiological changes resulting from diarrheal diseases can alter important factors governing oral drug absorption, contributing to suboptimal drug exposure and treatment failure. Physiologically based pharmacokinetic (PBPK) modeling is an in silico approach that has been increasingly adopted for drug-drug interaction potential, organ impairment, and special population assessment. This minireview highlights the potential and challenges of using PBPK modeling as a tool to improve our understanding of how diarrheal diseases impact oral drug pharmacokinetics.

Vitamin D and Calcium Supplement Use and High-Risk Breast Cancer: A Case-Control Study among BRCA1 and BRCA2 Mutation Carriers.

The role of vitamin D and calcium use in the development of breast cancer among women in the general population is not clear. Furthermore, whether vitamin D and calcium supplement use are associated with breast cancer in high-risk populations has not been evaluated. Thus, we evaluated the association between vitamin D and/or calcium supplement use and breast cancer among women with a pathogenic variant (mutation) in BRCA1 or BRCA2. BRCA mutation carriers enrolled in a longitudinal study were invited to complete a supplemental questionnaire on lifetime supplement use. Cases included women with a prevalent diagnosis of invasive breast cancer, and controls had no history of breast cancer. Vitamin D and calcium use were categorized as never/ever use, and as tertiles of supplement intake (total average daily supplement use). Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CIs) of breast cancer. This study included 134 breast cancer cases and 276 controls. Women who used vitamin D-containing supplements had 46% lower odds of having breast cancer compared to those who never used supplements (OR 0.54; 95% CI 0.31, 0.91; p = 0.02). Increasing vitamin D and calcium supplement intake was inversely associated with the odds of having breast cancer (p-trend = 0.04). Findings were suggestively stronger among BRCA1 mutation carriers; however, analyses were limited by small strata. These findings suggest a potential inverse association between vitamin D and calcium supplementation and BRCA breast cancer. Additional studies are warranted to confirm these findings and accurately inform clinical care guidelines.

A Comparison of the Mortality Experience of U.S. Adults Estimated With the 2006-2018 National Health Interview Survey Linked Mortality Files and the Annual U.S. Life Tables.

Objective-Linking data is a powerful mechanism to provide policy-relevant information. The National Center for Health Statistics' Data Linkage Program produces linked mortality files (LMFs) for research by linking data from the National Center for Health Statistics' surveys, including the National Health Interview Survey (NHIS), to mortality data from the National Death Index. Assessing the accuracy of the linked data is an important step in ensuring its analytic use. This report compares the cumulative survival probabilities estimated with the 2006-2018 NHIS LMFs to those from the annual U.S. life tables.

Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles: A Systematic Review.

Importance: Randomized clinical trials (RCTs) on COVID-19 are increasingly being posted as preprints before publication in a scientific, peer-reviewed journal. Objective: To assess time to journal publication for COVID-19 RCT preprints and to compare differences between pairs of preprints and corresponding journal articles. Evidence Review: This systematic review used a meta-epidemiologic approach to conduct a literature search using the World Health Organization COVID-19 database and Embase to identify preprints published between January 1 and December 31, 2021. This review included RCTs with human participants and research questions regarding the treatment or prevention of COVID-19. For each preprint, a literature search was done to locate the corresponding journal article. Two independent reviewers read the full text, extracted data, and assessed risk of bias using the Cochrane Risk of Bias 2 tool. Time to publication was analyzed using a Cox proportional hazards regression model. Differences between preprint and journal article pairs in terms of outcomes, analyses, results, or conclusions were described. Statistical analysis was performed on October 17, 2022. Findings: This study included 152 preprints. As of October 1, 2022, 119 of 152 preprints (78.3%) had been published in journals. The median time to publication was 186 days (range, 17-407 days). In a multivariable model, larger sample size and low risk of bias were associated with journal publication. With a sample size of less than 200 as the reference, sample sizes of 201 to 1000 and greater than 1000 had hazard ratios (HRs) of 1.23 (95% CI, 0.80-1.91) and 2.19 (95% CI, 1.36-3.53) for publication, respectively. With high risk of bias as the reference, medium-risk articles with some concerns for bias had an HR of 1.77 (95% CI, 1.02-3.09); those with a low risk of bias had an HR of 3.01 (95% CI, 1.71-5.30). Of the 119 published preprints, there were differences in terms of outcomes, analyses, results, or conclusions in 65 studies (54.6%). The main conclusion in the preprint contradicted the conclusion in the journal article for 2 studies (1.7%). Conclusions and Relevance: These findings suggest that there is a substantial time lag from preprint posting to journal publication. Preprints with smaller sample sizes and high risk of bias were less likely to be published. Finally, although differences in terms of outcomes, analyses, results, or conclusions were observed for preprint and journal article pairs in most studies, the main conclusion remained consistent for the majority of studies.

THOR is a targetable epigenetic biomarker with clinical implications in breast cancer.

BACKGROUND: Breast cancer (BC) is the most frequently diagnosed cancer and a leading cause of death among women worldwide. Early BC is potentially curable, but the mortality rates still observed among BC patients demonstrate the urgent need of novel and more effective diagnostic and therapeutic options. Limitless self-renewal is a hallmark of cancer, governed by telomere maintenance. In around 95% of BC cases, this process is achieved by telomerase reactivation through upregulation of the human telomerase reverse transcriptase (hTERT). The hypermethylation of a specific region within the hTERT promoter, termed TERT hypermethylated oncological region (THOR) has been associated with increased hTERT expression in cancer. However, its biological role and clinical potential in BC have never been studied to the best of our knowledge. Therefore, we aimed to investigate the role of THOR as a biomarker and explore the functional impact of THOR methylation status in hTERT upregulation in BC. RESULTS: THOR methylation status in BC was assessed by pyrosequencing on discovery and validation cohorts. We found that THOR is significantly hypermethylated in malignant breast tissue when compared to benign tissue (40.23% vs. 12.81%, P < 0.0001), differentiating malignant tumor from normal tissue from the earliest stage of disease. Using a reporter assay, the addition of unmethylated THOR significantly reduced luciferase activity by an average 1.8-fold when compared to the hTERT core promoter alone (P < 0.01). To further investigate its biological impact on hTERT transcription, targeted THOR demethylation was performed using novel technology based on CRISPR-dCas9 system and significant THOR demethylation was achieved. Cells previously demethylated on THOR region did not develop a histologic cancer phenotype in in vivo assays. Additional studies are required to validate these observations and to unravel the causality between THOR hypermethylation and hTERT upregulation in BC. CONCLUSIONS: THOR hypermethylation is an important epigenetic mark in breast tumorigenesis, representing a promising biomarker and therapeutic target in BC. We revealed that THOR acts as a repressive regulatory element of hTERT and that its hypermethylation is a relevant mechanism for hTERT upregulation in BC.

Assessing Associations Between COVID-19 Symptomology and Adverse Outcomes After Piloting Crowdsourced Data Collection: Cross-sectional Survey Study.

BACKGROUND: Crowdsourcing is a useful way to rapidly collect information on COVID-19 symptoms. However, there are potential biases and data quality issues given the population that chooses to participate in crowdsourcing activities and the common strategies used to screen participants based on their previous experience. OBJECTIVE: The study aimed to (1) build a pipeline to enable data quality and population representation checks in a pilot setting prior to deploying a final survey to a crowdsourcing platform, (2) assess COVID-19 symptomology among survey respondents who report a previous positive COVID-19 result, and (3) assess associations of symptomology groups and underlying chronic conditions with adverse outcomes due to COVID-19. METHODS: We developed a web-based survey and hosted it on the Amazon Mechanical Turk (MTurk) crowdsourcing platform. We conducted a pilot study from August 5, 2020, to August 14, 2020, to refine the filtering criteria according to our needs before finalizing the pipeline. The final survey was posted from late August to December 31, 2020. Hierarchical cluster analyses were performed to identify COVID-19 symptomology groups, and logistic regression analyses were performed for hospitalization and mechanical ventilation outcomes. Finally, we performed a validation of study outcomes by comparing our findings to those reported in previous systematic reviews. RESULTS: The crowdsourcing pipeline facilitated piloting our survey study and revising the filtering criteria to target specific MTurk experience levels and to include a second attention check. We collected data from 1254 COVID-19-positive survey participants and identified the following 6 symptomology groups: abdominal and bladder pain (Group 1); flu-like symptoms (loss of smell/taste/appetite; Group 2); hoarseness and sputum production (Group 3); joint aches and stomach cramps (Group 4); eye or skin dryness and vomiting (Group 5); and no symptoms (Group 6). The risk factors for adverse COVID-19 outcomes differed for different symptomology groups. The only risk factor that remained significant across 4 symptomology groups was influenza vaccine in the previous year (Group 1: odds ratio [OR] 6.22, 95% CI 2.32-17.92; Group 2: OR 2.35, 95% CI 1.74-3.18; Group 3: OR 3.7, 95% CI 1.32-10.98; Group 4: OR 4.44, 95% CI 1.53-14.49). Our findings regarding the symptoms of abdominal pain, cough, fever, fatigue, shortness of breath, and vomiting as risk factors for COVID-19 adverse outcomes were concordant with the findings of other researchers. Some high-risk symptoms found in our study, including bladder pain, dry eyes or skin, and loss of appetite, were reported less frequently by other researchers and were not considered previously in relation to COVID-19 adverse outcomes. CONCLUSIONS: We demonstrated that a crowdsourced approach was effective for collecting data to assess symptomology associated with COVID-19. Such a strategy may facilitate efficient assessments in a dynamic intersection between emerging infectious diseases, and societal and environmental changes.

A red nucleus-VTA glutamate pathway underlies exercise reward and the therapeutic effect of exercise on cocaine use.

Physical exercise is rewarding and protective against drug abuse and addiction. However, the neural mechanisms underlying these actions remain unclear. Here, we report that long-term wheel-running produced a more robust increase in c-fos expression in the red nucleus (RN) than in other brain regions. Anatomic and functional assays demonstrated that most RN magnocellular portion (RNm) neurons are glutamatergic. Wheel-running activates a subset of RNm glutamate neurons that project to ventral tegmental area (VTA) dopamine neurons. Optogenetic stimulation of this pathway was rewarding, as assessed by intracranial self-stimulation and conditioned place preference, whereas optical inhibition blocked wheel-running behavior. Running wheel access decreased cocaine self-administration and cocaine seeking during extinction. Last, optogenetic stimulation of the RNm-to-VTA glutamate pathway inhibited responding to cocaine. Together, these findings indicate that physical exercise activates a specific RNm-to-VTA glutamatergic pathway, producing exercise reward and reducing cocaine intake.