The effect of early child care attendance on childhood asthma and wheezing: A meta-analysis.

ObjectiveResearch evidence offers mixed results regarding the relationship between early child care attendance and childhood asthma and wheezing. A meta-analysis was conducted to synthesize the current research evidence of the association between early child care attendance and the risk of childhood asthma and wheezing.MethodPeer reviewed studies published from 1964-January 2017 were identified in MEDLINE, CINAL, and EMBASE using MeSH headings relevant to child care and asthma. Two investigators independently reviewed the selected articles from this search. All relevant articles that met our inclusion criteria were selected for further analysis. Data were extracted from studies that had sufficient data to analyze the odds of asthma or wheezing among children who attended child care.ResultsThe meta-analysis of 32 studies found that (1) early child care attendance is protective against asthma in children 3-5 years of age but not for children with asthma 6 years of age or older. (2) Early child care attendance increases the risk of wheezing among children 2 years of age or younger, but not the risk of wheezing for children over 2 years of age.ConclusionsThis meta-analysis shows that early child care attendance is not significantly associated with the risk of asthma or wheeze in children 6 years of age or older

Prozone Masks Elevated Sars-Cov-2 Antibody Level Measurements

We report a prozone effect in measurement of SARS-CoV-2 spike protein antibody levels from an antibody surveillance program. Briefly, the prozone effect occurs in immunoassays when excessively high antibody concentration disrupts the immune complex formation, resulting in a spuriously low reported result. Following participant inquiries, we observed anomalously low measurement of SARS-CoV-2 spike protein antibody levels using the Roche Elecsys® Anti-SARS-CoV-2 S immunoassay from participants in the Texas Coronavirus Antibody Research survey (Texas CARES), an ongoing prospective, longitudinal antibody surveillance program. In July, 2022, samples were collected from ten participants with anomalously low results for serial dilution studies, and a prozone effect was confirmed. From October, 2022 to March, 2023, serial dilution of samples detected 74 additional cases of prozone out of 1,720 participants\u27 samples. Prozone effect may affect clinical management of at-risk populations repeatedly exposed to SARS-CoV-2 spike protein through multiple immunizations or serial infections, making awareness and mitigation of this issue paramount

Toxicogenomic analysis incorporating operon-transcriptional coupling and toxicant concentration-expression response: analysis of MX-treated Salmonella

<p>Abstract</p> <p>Background</p> <p>Deficiencies in microarray technology cause unwanted variation in the hybridization signal, obscuring the true measurements of intracellular transcript levels. Here we describe a general method that can improve microarray analysis of toxicant-exposed cells that uses the intrinsic power of transcriptional coupling and toxicant concentration-expression response data. To illustrate this approach, we characterized changes in global gene expression induced in <it>Salmonella typhimurium </it>TA100 by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(<it>5H</it>)-furanone (MX), the primary mutagen in chlorinated drinking water. We used the co-expression of genes within an operon and the monotonic increases or decreases in gene expression relative to increasing toxicant concentration to augment our identification of differentially expressed genes beyond Bayesian-t analysis.</p> <p>Results</p> <p>Operon analysis increased the number of altered genes by 95% from the list identified by a Bayesian t-test of control to the highest concentration of MX. Monotonic analysis added 46% more genes. A functional analysis of the resulting 448 differentially expressed genes yielded functional changes beyond what would be expected from only the mutagenic properties of MX. In addition to gene-expression changes in DNA-damage response, MX induced changes in expression of genes involved in membrane transport and porphyrin metabolism, among other biological processes. The disruption of porphyrin metabolism might be attributable to the structural similarity of MX, which is a chlorinated furanone, to ligands indigenous to the porphyrin metabolism pathway. Interestingly, our results indicate that the <it>lexA </it>regulon in <it>Salmonella</it>, which partially mediates the response to DNA damage, may contain only 60% of the genes present in this regulon in <it>E. coli</it>. In addition, <it>nanH </it>was found to be highly induced by MX and contains a putative <it>lexA </it>regulatory motif in its regulatory region, suggesting that it may be regulated by <it>lexA</it>.</p> <p>Conclusion</p> <p>Operon and monotonic analyses improved the determination of differentially expressed genes beyond that of Bayesian-t analysis, showing that MX alters cellular metabolism involving pathways other than DNA damage. Because co-expression of similarly functioning genes also occurs in eukaryotes, this method has general applicability for improving analysis of toxicogenomic data.</p

Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and Nutritional Risk Factors for Lung Cancer

Purpose: Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions. Methods: We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status. Results: Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95% credible interval [CI]: 1.20–3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26–0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10–2.87) and two SNP*nutrient interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19–0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30–0.91)] were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11–0.58; rs10512948; OR = 0.61; 95% CI: 0.41–0.90; rs2924471; OR = 3.31; 95% CI: 1.66–6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43–0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11–2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27–0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15–0.95) were associated with lung cancer risk in never smokers. Conclusions: This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk

Identifying Sensitive Windows of Exposure to NO2 and Fetal Growth Trajectories in a Spanish Birth Cohort

Background: We previously identified associations between trimester-specific NO2 exposures and reduced fetal growth in the Spanish INfancia y Medio Ambiente (INMA) project. Here, we use temporally refined exposure estimates to explore the impact of narrow (weekly) windows of exposure on fetal growth. Methods: We included 1,685 women from INMA with serial ultrasounds at 12, 20, and 34 gestational weeks. We measured biparietal diameter (BPD), femur length, and abdominal circumference (AC) and from them calculated estimated fetal weight (EFW). We calculated z-scores describing trajectories of each parameter during early (0-12 weeks), mid (12-20 weeks), and late (20-34 weeks) pregnancy, based on longitudinal growth curves from mixed-effects models. We estimated weekly NO2 exposures at each woman's residence using land-use regression models. We applied distributed lag nonlinear models to identify sensitive windows of exposure. We present effect estimates as the percentage change in fetal growth per 10 mu g/m(3) increase in NO2 exposure, and we calculated cumulative effect estimates by aggregating estimates across adjacent lags. Results: We identified weeks 5-12 as a sensitive window for NO2 exposure on late EFW (cumulative beta = -3.0%; 95% CI = -4.1%, -1.9%). We identified weeks 6-19 as a sensitive window for late growth in BPD (cumulative beta = -2.0%; 95% CI = -2.7%, -1.4%) and weeks 8-13 for AC (cumulative beta = -0.68%; 95% CI = -0.97%, -0.40%). We found suggestive evidence that third trimester NO2 exposure is associated with increased AC, BPD, and EFW growth in late pregnancy. Conclusions: Our findings are consistent with the hypothesis that NO2 exposure is associated with alterations in growth of EFW, BPD, and AC dependent on the specific timing of exposure during gestation.K.W.W. and E.S. were partially supported by the P30 Environmental Health Sciences Core Center grant P30ES030285 from the National Institute

Association of Cancer Diagnosis With Disability Status among Older Survivors of Colorectal Cancer: a Population-Based Retrospective Cohort Study

BACKGROUND: Older cancer survivors likely experience physical function limitations due to cancer and its treatments, leading to disability and early mortality. Existing studies have focused on factors associated with surgical complications and mortality risk rather than factors associated with the development of poor disability status (DS), a proxy measure of poor performance status, in cancer survivors. We aimed to identify factors associated with the development of poor DS among older survivors of colorectal cancer (CRC) and compare poor DS rates to an age-sex-matched, non-cancer cohort. METHODS: This retrospective cohort study utilized administrative data from the Texas Cancer Registry Medicare-linked database. The study cohort consisted of 13,229 survivors of CRC diagnosed between 2005 and 2013 and an age-sex-matched, non-cancer cohort of 13,225 beneficiaries. The primary outcome was poor DS, determined by Davidoff\u27s method, using predictors from 12 months of Medicare claims after cancer diagnosis. Multivariable Cox proportional hazards regression was used to identify risk factors associated with the development of poor DS. RESULTS: Among the survivors of CRC, 97% were 65 years or older. After a 9-year follow-up, 54% of survivors of CRC developed poor DS. Significant factors associated with future poor DS included: age at diagnosis (hazard ratio [HR] = 3.50 for \u3e80 years old), female sex (HR = 1.50), race/ethnicity (HR = 1.34 for Hispanic and 1.21 for Black), stage at diagnosis (HR = 2.26 for distant metastasis), comorbidity index (HR = 2.18 for \u3e1), and radiation therapy (HR = 1.21). Having cancer (HR = 1.07) was significantly associated with developing poor DS in the pooled cohorts; age and race/ethnicity were also significant factors. CONCLUSIONS: Our findings suggest that a CRC diagnosis is independently associated with a small increase in the risk of developing poor DS after accounting for other known factors. The study identified risk factors for developing poor DS in CRC survivors, including Hispanic and Black race/ethnicity, age, sex, histologic stage, and comorbidities. These findings underscore the importance of consistent physical function assessments, particularly among subsets of older survivors of CRC who are at higher risk of disability, to prevent developing poor DS

Predicting HIV Pre-exposure Prophylaxis Efficacy for Women using a Preclinical Pharmacokinetic-Pharmacodynamic In Vivo Model

The efficacy of HIV pre-exposure prophylaxis (PrEP) relies on adherence and may also depend on the route of HIV acquisition. Clinical studies of systemic tenofovir disoproxil fumarate (TDF) PrEP revealed reduced efficacy in women compared to men with similar degrees of adherence. To select the most effective PrEP strategies, preclinical studies are critically needed to establish correlations between drug concentrations (pharmacokinetics [PK]) and protective efficacy (pharmacodynamics [PD]). We utilized an in vivo preclinical model to perform a PK-PD analysis of systemic TDF PrEP for vaginal HIV acquisition. TDF PrEP prevented vaginal HIV acquisition in a dose-dependent manner. PK-PD modeling of tenofovir (TFV) in plasma, female reproductive tract tissue, cervicovaginal lavage fluid and its intracellular metabolite (TFV diphosphate) revealed that TDF PrEP efficacy was best described by plasma TFV levels. When administered at 50 mg/kg, TDF achieved plasma TFV concentrations (370 ng/ml) that closely mimicked those observed in humans and demonstrated the same risk reduction (70%) previously attained in women with high adherence. This PK-PD model mimics the human condition and can be applied to other PrEP approaches and routes of HIV acquisition, accelerating clinical implementation of the most efficacious PrEP strategies