COVID-19 and Mortality in the Global Surgical Population: A Systematic Review and Meta-Analysis.

INTRODUCTION: To date, no systematic review or meta-analysis has comprehensively estimated the risk of mortality by surgery type on an international scale. We aim to delineate the risk of mortality in patients with COVID-19 who undergo surgery. METHODS: PubMed (MEDLINE), Scopus, OVID, the World Health Organization Global Literature on Coronavirus Disease, and Corona-Central databases were searched from December 2019 through January 2022. Studies providing data on mortality in patients undergoing surgery were included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for abstracting data were followed and performed independently by two reviewers. The main outcome was mortality in patients with COVID-19. RESULTS: Of a total of 4023 studies identified, 46 studies with 80,015 patients met our inclusion criteria. The mean age was 67 y; 57% were male. Surgery types included general (14.9%), orthopedic (23.4%), vascular (6.4%), thoracic (10.6%), and urologic (8.5%). Patients undergoing surgery with COVID-19 elicited a nine-fold increased risk of mortality (relative risk [RR] 8.99, 95% confidence interval [CI] 4.96-16.32) over those without COVID-19. In low-income and middle-income countries (RR: 16.04, 95% CI: 4.59-56.12), the mortality risk was twice as high compared to high-income countries (RR: 7.50, 95% CI: 4.30-13.09). CONCLUSIONS: Mortality risk in surgical patients with COVID-19 compared to those without is increased almost 10-fold. The risk was highest in low-income and middle-income countries compared to high-income countries, suggesting a disproportionate effect of the pandemic on resource-constrained regions.

In vitro bioassays for monitoring drinking water quality of tap water, domestic filtration and bottled water.

BACKGROUND: Location-specific patterns of regulated and non-regulated disinfection byproducts (DBPs) were detected in tap water samples of the Barcelona Metropolitan Area. However, it remains unclear if the detected DBPs together with undetected DPBs and organic micropollutants can lead to mixture effects in drinking water. OBJECTIVE: To evaluate the neurotoxicity, oxidative stress response and cytotoxicity of 42 tap water samples, 6 treated with activated carbon filters, 5 with reverse osmosis and 9 bottled waters. To compare the measured effects of the extracts with the mixture effects predicted from the detected concentrations and the relative effect potencies of the detected DBPs using the mixture model of concentration addition. METHODS: Mixtures of organic chemicals in water samples were enriched by solid phase extraction and tested for cytotoxicity and neurite outgrowth inhibition in the neuronal cell line SH-SY5Y and for cytotoxicity and oxidative stress response in the AREc32 assay. RESULTS: Unenriched water did not trigger neurotoxicity or cytotoxicity. After up to 500-fold enrichment, few extracts showed cytotoxicity. Disinfected water showed low neurotoxicity at 20- to 300-fold enrichment and oxidative stress response at 8- to 140-fold enrichment. Non-regulated non-volatile DBPs, particularly (brominated) haloacetonitriles dominated the predicted mixture effects of the detected chemicals and predicted effects agreed with the measured effects. By hierarchical clustering we identified strong geographical patterns in the types of DPBs and their association with effects. Activated carbon filters did not show a consistent reduction of effects but domestic reverse osmosis filters decreased the effect to that of bottled water. IMPACT STATEMENT: Bioassays are an important complement to chemical analysis of disinfection by-products (DBPs) in drinking water. Comparison of the measured oxidative stress response and mixture effects predicted from the detected chemicals and their relative effect potencies allowed the identification of the forcing agents for the mixture effects, which differed by location but were mainly non-regulated DBPs. This study demonstrates the relevance of non-regulated DBPs from a toxicological perspective. In vitro bioassays, in particular reporter gene assays for oxidative stress response that integrate different reactive toxicity pathways including genotoxicity, may therefore serve as sum parameters for drinking water quality assessment.

An early interactive human coaching via a mobile application to improve quality of life in patients who underwent gastrectomy for gastric cancer: Design and protocol of a randomized controlled trial.

BACKGROUND: After gastrectomy, patients may experience the postgastrectomy syndrome and face difficulties adapting to everyday diet. Recently, human health coaching via a mobile application (app) has been used for obese patients or patients with chronic diseases, with significant improvements in clinical outcomes. The aim of this study is to evaluate and compare the effects of human health coaching via a mobile app and conventional face-to-face counseling in patients who underwent gastrectomy for gastric cancers. METHODS: This study is a single-institution, prospective randomized controlled trial comparing the mobile health and face-to-face counselling groups. After randomization, participants assigned to the mobile health coaching group will receive health coaching via a mobile app for 3 months after discharge, and the assigned coaches will provide personalized advice based on the self-recorded health data. Participants in the face-to-face group will have 1- and 3-months postoperative dietary consultations with a clinical dietitian. The primary endpoint is the food restriction score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-STO22, and secondary endpoints included all other quality of life scale scores and nutritional parameters. The calculated sample size is 180, and the outcomes will be measured until 1-year post-surgery. SIGNIFICANCE: This study will show the efficacy of human health coaching via a mobile app on dietary adaptation in patients who underwent gastrectomy. A relational approach based on personal data and timely intervention using a mobile platform could reduce patients' trial and error and improve quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04394585, Registered 19 May, 2020 -Retrospectively registered, http://clinicaltrials.gov/ct2/show/NCT040394585.

Changes in sexual identity and substance use during young adulthood.

BACKGROUND: Sexual identity is dynamic, and changes in identity (e.g., from heterosexual to lesbian, gay, bisexual, or queer [LGBQ+]) are common during young adulthood. It is not well-understood how sexual identity changes may be associated with substance use risk. METHODS: Two waves of data (baseline: October, 2018-October, 2019; follow-up: May-October, 2020) were used from a prospective cohort of young adults (N = 1896; mean age=21.2). Frequency of past 30-day use and new initiation of five substance use outcomes (alcohol, any tobacco, e-cigarettes, cannabis, illicit drugs) were compared across four groups: consistently heterosexual (N = 1567), consistently LGBQ+ (N = 244), heterosexual to LGBQ+ (N = 65), and LGBQ+ to heterosexual (N = 20). RESULTS: Consistently LGBQ+ (vs. consistently heterosexual) participants reported greater frequency of past 30-day use of alcohol (aOR=1.34, 95% CI=1.04-1.72), any tobacco products (aOR=1.88, CI=1.34-2.63), e-cigarettes (aOR=1.49, CI=1.01-2.19), cannabis (aOR=1.36, CI=1.01-1.84), and illicit drugs (aOR=2.84, CI=1.77-4.56). Heterosexual to LGBQ+ (vs. consistently heterosexual) participants reported greater frequency of past 30-day use of any tobacco products (aOR=1.87, CI=1.06-3.33) and illicit drugs (aOR=2.48, CI=1.10-5.62), and had greater risk of initiating alcohol (aRR=1.82, CI=1.02-3.25) and cannabis use (aRR=2.90, CI=1.81-4.64). LGBQ+ to heterosexual (vs. consistently LGBQ+) participants reported lower frequency of past 30-day use of alcohol (aOR=0.35, CI=0.14-0.88) and any tobacco products (aOR=0.15, CI=0.03-0.80). CONCLUSIONS: Identifying as LGBQ+ was associated with increased risk for frequent substance use, and newly adopting an LGBQ+ identity was associated with increased risk for new substance use initiation. Prevention and treatment interventions may need to tailor messaging to young people who have newly adopted an LGBQ+ identity.

Associations of attention problems and family context in childhood and adolescence with young adult daily smoking: General and smoking-specific family contexts.

BACKGROUND: The potential heterogeneity in daily smoking across young adulthood has been relatively understudied. Relatedly, the unique and joint associations of earlier risk factors with young adults' daily smoking largely remain unknown. To address these gaps, this work identified subgroups of daily smoking trajectories during young adulthood and linked them to earlier attention problems and smoking-specific and general family context. METHODS: Data came from the Seattle Social Development Project, a longitudinal study following a community sample (N = 808). Participants' daily smoking was measured from ages 21-33. Earlier attention problems were assessed at ages 14-16 and 18. Earlier smoking-specific and general family factors were assessed at ages 10-16 and 18. RESULTS: Growth mixture models produced four profiles: chronic daily smokers, increasers, decreasers, and no-daily smokers. Results from multinomial logistic regressions revealed that earlier attention problems and smoking-specific family factors may contribute to daily smoking in the early 20 s, whereas earlier general family context provided protection for trajectories of daily smoking characterized by changes in the late 20 s and early 30 s DISCUSSION: Selective prevention strategies that expand people's repertoire of healthy options to address attention problems might be helpful, considering the possibility of using tobacco as means to mitigate attention problems. Our findings also highlight the importance of nurturing earlier general family context, a relatively overlooked dimension in smoking prevention efforts, to facilitate young adult smokers' desistence from daily smoking, particularly those who have attention problems in adolescence.

Validation of an SH-SY5Y Cell-Based Acetylcholinesterase Inhibition Assay for Water Quality Assessment.

The acetylcholinesterase (AChE) inhibition assay has been frequently applied for environmental monitoring to capture insecticides such as organothiophosphates (OTPs) and carbamates. However, natural organic matter such as dissolved organic carbon (DOC) co-extracted with solid-phase extraction from environmental samples can produce false-negative AChE inhibition in free enzyme-based AChE assays. We evaluated whether disturbance by DOC can be alleviated in a cell-based AChE assay using differentiated human neuroblastoma SH-SY5Y cells. The exposure duration was set at an optimum of 3 h considering the effects of OTPs and carbamates. Because loss to the airspace was expected for the more volatile OTPs (chlorpyrifos, diazinon, and parathion), the chemical loss in this bioassay setup was investigated using solid-phase microextraction followed by chemical analysis. The three OTPs were relatively well retained (loss <34%) during 3 h of exposure in the 384-well plate, but higher losses occurred on prolonged exposure, accompanied by slight cross-contamination of adjacent wells. Inhibition of AChE by paraoxon-ethyl was not altered in the presence of up to 68 mgc /L Aldrich humic acid used as surrogate for DOC. Binary mixtures of paraoxon-ethyl and water extracts showed concentration-additive effects. These experiments confirmed that the matrix in water extracts does not disturb the assay, unlike purified enzyme-based AChE assays. The cell-based AChE assay proved to be suitable for testing water samples with effect concentrations causing 50% inhibition of AChE at relative enrichments of 0.5-10 in river water samples, which were distinctly lower than corresponding cytotoxicity, confirming the high sensitivity of the cell-based AChE inhibition assay and its relevance for water quality monitoring. Environ Toxicol Chem 2022;41:3046-3057. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Development of PD3 and PD3-B for PDEδ inhibition to modulate KRAS activity.

Despite extensive efforts over 40 years, few effective KRAS inhibitors have been developed to date, mainly due to the undruggable features of KRAS proteins. In addition to the direct approach to KRAS via covalent inhibition, modulation of the prenyl-binding protein PDEδ that binds with farnesylated KRAS has emerged as an alternative strategy to abrogate KRAS activity. For the verification of new therapeutic strategies, chemical probes with the dual functions of visualisation and pharmacological inhibition against oncogenic proteins are enormously valuable to understand cellular events related to cancer. Here, we report indolizino[3,2-c]quinoline (IQ)-based fluorescent probes (PD3 and PD3-B) for PDEδ inhibition. By using the unique fluorescent characteristics of the IQ scaffold, a fluorescence polarisation (FP)-based binding assay identified PD3 as the most effective PDEδ probe among the tested PD analogues, with a low Kd value of 0.491 µM and long retention time in the binding site of PDEδ. In particular, a FP-based competition assay using deltarasin verified that PD3 occupies the farnesylation binding site of PDEδ, excluding the possibility that the FP signals resulted from non-specific hydrophobic interactions between the ligand and protein in the assay. We also designed and synthesised PD3-B (5), an affinity-based probe (ABP) from the PD3 structure, which enabled us to pull down PDEδ from bacterial lysates containing a large number of intrinsic bacterial proteins. Finally, KRAS relocalization was verified in PANC-1 cells by treatment with PD3, suggesting its potential as an effective probe to target PDEδ.

Inhibition of neurite outgrowth and enhanced effects compared to baseline toxicity in SH-SY5Y cells.

Early life exposure to environmental chemicals can cause developmental neurotoxicity (DNT). The impairment of key neurodevelopmental processes such as neurite outgrowth inhibition can be used as endpoints for screening of DNT effects. We quantified neurite-specific effects using the ratio of effect concentrations for cytotoxicity and neurite outgrowth inhibition (SRcytotoxicity). Baseline cytotoxicity, the minimal toxicity of any chemical, was used to quantify enhanced cytotoxicity (toxic ratio, TR) and neuronal-specific toxicity (SRbaseline) by comparing baseline cytotoxicity with the effects on cell viability and neurite outgrowth, respectively. The effects on cell viability and neurite length were measured based on image analysis in human neuroblastoma SH-SY5Y cells. Baseline cytotoxicity was predicted from hydrophobicity descriptors using a previously published model for SH-SY5Y cells. Enhanced cytotoxicity and neuronal-specific toxicity were more often observed for hydrophilic chemicals, which indicates that they are more likely to act through specific modes of action (MOA) on cell viability and neurite outgrowth. Hydrophobic chemicals showed a tendency to act through baseline toxicity without showing specific or enhanced toxicity, but were highly potent considering their low effect concentrations for both cytotoxicity and neurite outgrowth inhibition. The endpoint-specific controls (narciclasine, colchicine, cycloheximide, and rotenone), two carbamates (3-hydroxycarbofuran and carbaryl), and two redox cyclers (diquat and paraquat) showed distinct neurite-specific effects (SRcytotoxicity > 4). By comparing neurite-specific effects with enhanced cytotoxicity, one can explain whether the observed effects involve specific inhibition of neurite outgrowth, other specific MOAs, or merely baseline toxicity arising from hydrophobicity.

Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome.

Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels increased with WHO glioma grade, and this association was correlated with low survival. We investigated NLRC4 inflammasome formation by genetically regulating Tim-3 and its ligand Gal-9. Tim-3/Gal-9 regulation was positively correlated with the NLRC4 inflammasome, NLRC4, and caspase-1 expression. Tim-3/Gal-9 did not trigger IL-1ß secretion but were strongly positively correlated with caspase-1 activity as they induced programmed cell death in glioma cells. A protein-protein interaction analysis revealed that the FYN-JAK1-ZNF384 pathways are bridges in NLRC4 inflammasome regulation by Tim-3/Gal-9. The present study showed that Tim-3/Gal-9 are associated with poor prognosis in glioma patients and induce NLRC4 inflammasome formation and activation. We proposed that a Tim-3/Gal-9 blockade could be beneficial in glioma therapy as it would reduce the inflammatory microenvironment by downregulating the NLRC4 inflammasome.

Monitoring Mixture Effects of Neurotoxicants in Surface Water and Wastewater Treatment Plant Effluents with Neurite Outgrowth Inhibition in SH-SY5Y Cells.

Cell-based assays covering environmentally relevant modes of action are widely used for water quality monitoring. However, no high-throughput assays are available for testing developmental neurotoxicity of water samples. We implemented an assay that quantifies neurite outgrowth, which is one of the neurodevelopmental key events, and cell viability in human neuroblastoma SH-SY5Y cells using imaging techniques. We used this assay for testing of extracts of surface water collected in agricultural areas during rain events and effluents from wastewater treatment plants (WWTPs), where more than 200 chemicals had been quantified. Forty-one chemicals were tested individually that were suspected to contribute to the mixture effects among the detected chemicals in environmental samples. Sample sensitivity distributions indicated higher neurotoxicity for surface water samples than for effluents, and the endpoint of neurite outgrowth inhibition was six times more sensitive than cytotoxicity in the surface water samples and only three times more sensitive in the effluent samples. Eight environmental pollutants showed high specificity, and those ranged from pharmaceuticals (mebendazole and verapamil) to pesticides (methiocarb and clomazone), biocides (1,2-benzisothiazolin-3-one), and industrial chemicals (N-methyl-2-pyrrolidone, 7-diethylamino-4-methylcoumarin, and 2-(4-morpholinyl)benzothiazole). Although neurotoxic effects were newly detected for some of our test chemicals, less than 1% of the measured effects were explained by the detected and toxicologically characterized chemicals. The neurotoxicity assay was benchmarked against other bioassays: activations of the aryl hydrocarbon receptor and the peroxisome proliferator-activated receptor were similar in sensitivity, highly sensitive and did not differ much between the two water types, with surface water having slightly higher effects than the WWTP effluent. Oxidative stress response mirrored neurotoxicity quite well but was caused by different chemicals in the two water types. Overall, the new cell-based neurotoxicity assay is a valuable complement to the existing battery of effect-based monitoring tools.

Vaping and psychotic experiences among college students in the United States.

AIM: While cigarette and marijuana use has been linked to psychotic experiences, few empirical studies have examined the relation between vaping and psychotic experiences. METHODS: We analyzed data from the Healthy Minds Survey (September 2020 - December 2020; N = 29,232 students from 36 universities), and used multiple logistic regression models to examine the associations between vaping over the past 30 days and psychotic experiences over the past 12 months, adjusting for age, gender, and race/ethnicity. We then additionally adjusted for cigarette and marijuana use, as well as depression and anxiety. RESULTS: Roughly 14 % of students in the sample reported psychotic experiences over the past year, and around 14-15 % of students reported vaping over the past month. In multiple logistic regression models, vaping was significantly associated with psychotic experiences (aOR 1.88; 95 % CI: 1.63-2.18). This association attenuated but remained statistically significant even after adjusting for any cigarette use and marijuana use, and after adjusting for depression and anxiety. CONCLUSIONS: Among college students, vaping was significantly associated with psychotic experiences, even after accounting for simple measures of cigarette and marijuana use, and mental health problems, calling for more prospective studies to examine the association.

Critical Membrane Concentration and Mass-Balance Model to Identify Baseline Cytotoxicity of Hydrophobic and Ionizable Organic Chemicals in Mammalian Cell Lines.

All chemicals can interfere with cellular membranes and this leads to baseline toxicity, which is the minimal toxicity any chemical elicits. The critical membrane burden is constant for all chemicals; that is, the dosing concentrations to trigger baseline toxicity decrease with increasing hydrophobicity of the chemicals. Quantitative structure-activity relationships, based on hydrophobicity of chemicals, have been established to predict nominal concentrations causing baseline toxicity in human and mammalian cell lines. However, their applicability is limited to hydrophilic neutral compounds. To develop a prediction model that includes more hydrophobic and charged organic chemicals, a mass balance model was applied for mammalian cells (AREc32, AhR-CALUX, PPARγ-BLA, and SH-SY5Y) considering different bioassay conditions. The critical membrane burden for baseline toxicity was converted into nominal concentration causing 10% cytotoxicity by baseline toxicity (IC10,baseline) using a mass balance model whose main chemical input parameter was the liposome-water partition constants (Klip/w) for neutral chemicals or the speciation-corrected Dlip/w(pH 7.4) for ionizable chemicals plus the bioassay-specific protein, lipid, and water contents of cells and media. In these bioassay-specific models, log(1/IC10,baseline) increased with increasing hydrophobicity, and the relationship started to level off at log Dlip/w around 2. The bioassay-specific models were applied to 392 chemicals covering a broad range of hydrophobicity and speciation. Comparing the predicted IC10,baseline and experimental cytotoxicity IC10, known baseline toxicants and many additional chemicals were identified as baseline toxicants, while the others were classified based on specificity of their modes of action in the four cell lines, confirming excess toxicity of some fungicides, antibiotics, and uncouplers. Given the similarity of the bioassay-specific models, we propose a generalized baseline-model for adherent human cell lines: log[1/IC10,baseline (M)] = 1.23 + 4.97 × (1 - e-0.236 log Dlip/w). The derived models for baseline toxicity may serve for specificity analysis in reporter gene and neurotoxicity assays as well as for planning the dosing for cell-based assays.

Adverse childhood experiences and the substance use behaviors of Latinx youth.

PURPOSE: Adverse childhood experiences (ACEs) are associated with substance use, how cultural factors influence this association for Latinx youth is unknown. This study uses longitudinal data to examine associations of cultural factors, ACEs and substance use among Latinx young adults. METHODS: Latinx youth (N = 1179) completed surveys from a longitudinal study at seven assessment points from 2005 to 2016; ACEs was assessed when participants were on average 21.6 and substance use 23.9 years. ACEs measured psychological, physical, and sexual abuse, parental violence, divorce, substance use, mental illness, and incarceration. A three-stage hierarchical ordinary least squares (alcohol use) and negative binomial regression models (problematic alcohol, marijuana and tobacco use) were estimated to evaluate the role of cultural factors (acculturation, enculturation and ethnic identity) and ACEs in shaping substance use behaviors. RESULTS: Controlling for cultural variables, ACEs sum (B = 0.03, p = .01), maltreatment (B = 0.16, p < .01), and household (B = 0.12, p = .03) subdomains predicted alcohol use. One additional increase in maltreatment (IRR=1.23, 95 % CI: 1.00, 1.53) predicted 23 % higher count of problematic alcohol use. Maltreatment (IRR=1.50, 95 % CI: 1.05, 2.13) and household (IRR=1.66, 95 % CI: 1.18, 2.32) subdomains predicted increased counts of marijuana use. Four or more ACEs predicted increased counts of tobacco use (IRR=1.49, 95 % CI: 1.08, 2.06) among Latinx young adults. CONCLUSIONS: Results suggest a predictive relationship between ACEs, and alcohol, marijuana and tobacco use, after accounting for cultural factors. Beyond acculturation, enculturation and ethnic identity, findings identify ACEs as a salient predictor of substance use among Latinx young adults.

Feasibility of an Interactive Health Coaching Mobile App to Prevent Malnutrition and Muscle Loss in Esophageal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy: Prospective Pilot Study.

BACKGROUND: Excessive muscle loss is an important prognostic factor in esophageal cancer patients undergoing neoadjuvant chemoradiotherapy (NACRT), as reported in our previous research. OBJECTIVE: In this pilot study, we prospectively tested the feasibility of a health coaching mobile app for preventing malnutrition and muscle loss in this patient population. METHODS: Between July 2019 and May 2020, we enrolled 38 male patients with esophageal cancer scheduled for NACRT. For 8 weeks from the start of radiotherapy (RT), the patients used Noom, a health coaching mobile app that interactively provided online advice about food intake, exercise, and weight changes. The skeletal muscle index (SMI) measured based on computed tomography and nutrition-related laboratory markers were assessed before and after RT. We evaluated the changes in the SMI, nutrition, and inflammatory factors between the patient group that used the mobile app (mHealth group) and our previous study cohort (usual care group). Additionally, we analyzed the factors associated with walk steps recorded in the app. RESULTS: Two patients dropped out of the study (no app usage; treatment changed to a definitive aim). The use (or activation) of the app was noted in approximately 70% (25/36) of the patients until the end of the trial. Compared to the 1:2 matched usual care group by propensity scores balanced with their age, primary tumor location, tumor stage, pre-RT BMI, and pre-RT SMI level, 30 operable patients showed less aggravation of the prognostic nutritional index (PNI) (-6.7 vs -9.8; P=.04). However, there was no significant difference in the SMI change or the number of patients with excessive muscle loss (∆SMI/50 days >10%). In patients with excessive muscle loss, the walk steps significantly decreased in the last 4 weeks compared to those in the first 4 weeks. Age affected the absolute number of walk steps (P=.01), whereas pre-RT sarcopenia was related to the recovery of the reduced walk steps (P=.03). CONCLUSIONS: For esophageal cancer patients receiving NACRT, a health care mobile app helped nutritional self-care with less decrease in the PNI, although it did not prevent excessive muscle loss. An individualized care model with proper exercise as well as nutritional support may be required to reduce muscle loss and malnutrition.

Associations of General and Abdominal Obesity with the Risk of Glioma Development.

The association between obesity and the risk of glioma remains unclear. We sought to evaluate the potential association between general and abdominal obesity and the risk of glioma based on a nationwide population-based cohort study of Koreans. Using data from the Korean National Health Insurance System cohort, 6,833,744 people older than 20 years who underwent regular national health examination in both 2009 and 2011 were followed until the end of 2017. We documented 4771 glioma cases based on an ICD-10 code of C71 during the median follow-up period of 7.30 years. Individuals with a body mass index (BMI) ≥ 25.0 kg/m2 were at significantly higher risk of developing glioma than those with a BMI < 25.0 kg/m2 (HR 1.08 CI 1.02-1.15). Individuals with a waist circumference (WC) ≥ 90 cm (males)/85 cm (females) also had a significantly higher risk of glioma than those with a WC < 90 cm (males)/85 cm (females) (HR 1.16 CI 1.09-1.24). In the group with a BMI ≥ 25.0 kg/m2, individuals with abdominal obesity were at significantly higher risk of developing glioma (HR 1.18 CI 1.09-1.27) than those without abdominal obesity. The role of abdominal obesity in this association was stronger in women than in men. To the best of our knowledge, this is the first demonstration that obese people may be at higher risk of glioma, especially centrally obese people from an Asian population with a BMI ≥ 25.0 kg/m2. Loss of visceral fat in people with abdominal obesity may reduce their risk of developing glioma.

Associations between prospective and retrospective measures of child abuse and self-reported adult health at midlife.

BACKGROUND: The long-term health effects of physical child abuse are well documented in self-report, retrospective studies. However, there have been few longitudinal, multimethod studies on physiological responses to stress and the onset of chronic disease, thereby slowing the advancement of prevention and intervention programs. OBJECTIVES: This study used survey data from an extended longitudinal study to examine prospective and retrospective associations between measures of physical child abuse and adult health in the 40s. PARTICIPANTS AND SETTING: Data are from an ongoing longitudinal study of the correlates and consequences of child maltreatment that began in the 1970s with a sample of 457 children. METHODS: Bivariate correlations and multiple regression models with covariates were used to assess associations between measures of physical child abuse and outcomes of self-reported health in adulthood. RESULTS: Physical child abuse, measured retrospectively, was moderately related to reports of overall health, as well as a number of adult health problems and conditions, such as back and chest pain, hypertension, and certain forms of cancer. Associations were also observed for lifetime alcohol problems and past-year doctor and emergency room visits. Fewer associations between prospective parent self-report measures of physical child abuse and adult health were identified, although child welfare (official record) reports performed similarly to retrospective measures. CONCLUSIONS: This study adds important information on the long-term health effects of child physical abuse, as well as measurement differences in the prediction of adult health outcomes. Conclusions drawn from prospective and retrospective studies of abuse are at best inconsistent, and possibly incompatible.

Lipidomics reveals that acupuncture modulates the lipid metabolism and inflammatory interaction in a mouse model of depression.

Depression is a serious disease that has considerable impact on lipid metabolism and inflammatory responses. Recent studies have shown that leptin, which is well known as a mediator of energy homeostasis and is a cytokine in inflammatory response, plays an important role in depression. Acupuncture is widely used to treat depression; however, the underlying mechanisms and the effect of acupuncture on depression remain poorly understood. In this study, we utilized the chronic restraint stress (CRS) induced depression model and acupuncture treatment was performed at KI10, LR8, LU8, LR4 (AP) or non-acupoint (NP). Then, lipidomics was applied to investigate the effects of acupuncture on lipid metabolism and analyze leptin signals in the brain and changes of immune markers. Acupuncture treatment at AP improved depression-like behavior in an open-field test, forced swimming test, and marble burying test. Concurrently, CRS mice treated with AP acupuncture (CRS + AP) had significantly lower levels of aspartate aminotransaminase (AST, liver injury markers) and exhibited different lipid patterns in liver lipidomic profiles. In particular, triglycerides (TGs) contributed the change of lipid patterns. Compared to the CRS mice, TGs with relatively high degrees of unsaturated fatty acids increased in the CRS + AP mice, but did not change in CRS mice treated with NP acupuncture (CRS + NP). The levels of leptin in plasma and leptin receptor positive cells in the brain (hypothalamus and hippocampus) decreased and increased, respectively, in the CRS + AP mice, while opposite patterns were exhibited in the CRS and CRS + NP mice. These results indicated that acupuncture treatment at AP attenuated leptin insensitivity in CRS mice. Additionally, expression of pro-inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor-alpha were decreased in the spleen, plasma, and liver of CRS + AP mice, which was one of results of alleviation of leptin resistance. In conclusion, these results show that AP acupuncture treatment effectively alleviated the depression-like behavior, affected immune responses, and altered hepatic lipid metabolism through the attenuation of leptin insensitivity.

Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells.

Activation of quiescent hepatic stellate cells (HSCs) to myofibroblasts plays a key role in liver fibrosis. We had previously shown that albumin and its derivative, R-III (a retinol-binding protein-albumin domain III fusion protein), inhibited HSC activation by sequestering retinoic acid (RA) and that R-III administration reduced carbon tetrachloride (CCl4)-induced liver fibrosis. In this study, we aimed to elucidate the mechanism of action of albumin downstream of RA sequestration. Nuclear factor-κB p65 was evenly distributed in the cytoplasm in activated mouse HSCs, whereas albumin expression or R-III treatment (albumin/R-III) caused the nuclear translocation of p65, probably via RA sequestration, resulting in a dramatic increase in interleukin-1beta (IL-1ß) expression. Albumin/R-III in turn induced the phosphorylation of Smad3 at the linker region, inhibiting its nuclear import in an IL-1ß-dependent manner. Consistent with the in vitro results, the level of IL-1ß mRNA expression was higher in CCl4/R-III-treated livers than in CCl4-treated livers. These findings reveal that albumin/R-III inhibits the transforming growth factor-ß-Smad3 signaling as well as the retinoic acid receptor-mediated pathway, which probably contributes to the inhibition of HSC activation, and suggest that R-III may be an anti-fibrotic drug candidate.

Screening and Genetic Network Analysis of Genes Involved in Freezing and Thawing Resistance in DaMDHAR-Expressing Saccharomyces cerevisiae Using Gene Expression Profiling.

The cryoprotection of cell activity is a key determinant in frozen-dough technology. Although several factors that contribute to freezing tolerance have been reported, the mechanism underlying the manner in which yeast cells respond to freezing and thawing (FT) stress is not well established. Therefore, the present study demonstrated the relationship between DaMDHAR encoding monodehydroascorbate reductase from Antarctic hairgrass Deschampsia antarctica and stress tolerance to repeated FT cycles (FT2) in transgenic yeast Saccharomyces cerevisiae. DaMDHAR-expressing yeast (DM) cells identified by immunoblotting analysis showed high tolerance to FT stress conditions, thereby causing lower damage for yeast cells than wild-type (WT) cells with empty vector alone. To detect FT2 tolerance-associated genes, 3'-quant RNA sequencing was employed using mRNA isolated from DM and WT cells exposed to FT (FT2) conditions. Approximately 332 genes showed ≥2-fold changes in DM cells and were classified into various groups according to their gene expression. The expressions of the changed genes were further confirmed using western blot analysis and biochemical assay. The upregulated expression of 197 genes was associated with pentose phosphate pathway, NADP metabolic process, metal ion homeostasis, sulfate assimilation, ß-alanine metabolism, glycerol synthesis, and integral component of mitochondrial and plasma membrane (PM) in DM cells under FT2 stress, whereas the expression of the remaining 135 genes was partially related to protein processing, selenocompound metabolism, cell cycle arrest, oxidative phosphorylation, and α-glucoside transport under the same condition. With regard to transcription factors in DM cells, MSN4 and CIN5 were activated, but MSN2 and MGA1 were not. Regarding antioxidant systems and protein kinases in DM cells under FT stress, CTT1, GTO, GEX1, and YOL024W were upregulated, whereas AIF1, COX2, and TRX3 were not. Gene activation represented by transcription factors and enzymatic antioxidants appears to be associated with FT2-stress tolerance in transgenic yeast cells. RCK1, MET14, and SIP18, but not YPK2, have been known to be involved in the protein kinase-mediated signalling pathway and glycogen synthesis. Moreover, SPI18 and HSP12 encoding hydrophilin in the PM were detected. Therefore, it was concluded that the genetic network via the change of gene expression levels of multiple genes contributing to the stabilization and functionality of the mitochondria and PM, not of a single gene, might be the crucial determinant for FT tolerance in DaMDAHR-expressing transgenic yeast. These findings provide a foundation for elucidating the DaMDHAR-dependent molecular mechanism of the complex functional resistance in the cellular response to FT stress.

Suppressive Effect of Carnosol on Ovalbumin-Induced Allergic Asthma.

Asthma is a chronic obstructive lung disease characterized by recurrent episodes of bronchoconstriction and wheezing. Conventional asthma treatment involves the suppression of airway inflammation or improving airway flow. Rosmarinus officialis, also known as rosemary, is a Mediterranean plant that is used for the treatment of inflammatory diseases. Carnosol, a diterpenoid found in rosemary extracts, has been known to exhibit anti-inflammatory, anti-tumor, and anti-oxidant effects. The effect of carnosol on allergic responses has not been tested yet. The effect of carnosol on a murine allergic asthma model were investigated. Carnosol inhibited the degranulation of RBL-2H3 mast cells. Carnosol treatment inhibited the increase in the number of eosinophils in the bronchoalveolar lavage fluids (BALF) of mice treated with ovalbumin. Carnosol treatment also inhibited inflammatory responses and mucin production in histologic studies. Carnosol treatment inhibited the increases of IL-4 and IL-13 cytokines expression in both BALF and the lungs. These results suggest that carnosol may have a potential for allergic asthma therapy.