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1.
Int J Cancer ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696517

RESUMO

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of this study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n=1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma, small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (PTWAS =1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (PTWAS =3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (PTWAS =6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influence lung cancer risk. This article is protected by copyright. All rights reserved.

2.
Environ Int ; 133(Pt B): 105243, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31675560

RESUMO

BACKGROUND: Pesticide exposure during pregnancy is thought to adversely affect fetal growth, which in turn may impact child growth, but results have been inconsistent across studies and few have explored these effects in developing countries. OBJECTIVES: To quantify urinary concentrations of pesticide biomarkers in early pregnancy (<16 weeks' gestation), and to estimate the association of these concentrations with preterm birth, low birth weight, small for gestational age, and stunting at ~1 and 2 years of age. METHODS: Eight pesticide biomarkers were quantified in urine collected from 289 pregnant women (aged 18-40 years) participating in a birth cohort study in Bangladesh. Anthropometry measurements were conducted on the index child at birth and approximately 1 and 2 years of age. A directed acyclic graph was used to identify minimal sufficient adjustment sets. Log-binomial regression was used to estimate the relative risk (RR) with 95% confidence intervals (CI). RESULTS: 3,5,6-trichloro-2-pyridinol (TCPY), a metabolite of chlorpyrifos and chlorpyrifos methyl, and 4-nitrophenol, a metabolite of parathion and methyl parathion, were detected in nearly all women with geometric mean (95% CI) values of 3.17 (2.82-3.56) and 18.66 (17.03-20.46) µg/g creatinine, respectively. 3-phenoxybenzoic acid (3-PBA), a non-specific metabolite of several pyrethroids, and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPY), a diazinon metabolite, were detected in 19.8% and 16.1% of women, respectively. The remaining four pesticide biomarkers were detected in <10% of women. Women in the highest quartile of 4-nitrophenol were more than 3 times more likely to deliver preterm than women in the lowest quartile: unadjusted RR (95% CI), 3.57 (1.65, 7.73). Women in the highest quartile of 4-nitrophenol were also at increased risk of having a child born small for gestational age: RR (95% CI) adjusted for household income, maternal education, and maternal total energy and meat intake, 3.81 (1.10, 13.21). Women with detectable concentrations of IMPY were at increased risk of having a child born with low birth weight compared to women with non-detectable concentrations: adjusted RR (95% CI), 2.13 (1.12, 4.08). We observed no association between any of the pesticide biomarkers and stunting at 1 or 2 years of age. DISCUSSION: Exposure to the insecticides parathion and diazinon during early pregnancy may increase the risk of adverse birth outcomes.

3.
Mol Carcinog ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31713888

RESUMO

The CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression.

4.
Int J Cancer ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577861

RESUMO

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.

5.
Int J Cancer ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31618441

RESUMO

The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with non-small cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a single locus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression model in the PLCO datasets identified three potentially functional and independent SNPs (KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 [95% confidence interval (CI)=0.79-0.94, P=0.0007], 1.31 (1.16-1.47, P=6.0×10-5 ) and 1.27 (1.12-1.44, P=0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (Ptrend <0.0001 for OS and Ptrend <0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes. This article is protected by copyright. All rights reserved.

6.
Cancer Invest ; : 1-11, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31584296

RESUMO

Background: Non-small cell lung cancer (NSCLC) is the first cause of cancer-related mortality for men and women in the United States. In spite of curative resection in early-stage, patient survival is not optimal and recurrence rate is high. Consequently, early detection and staging is essential to increase the patient's survival. Methods: Copy number (CN) changes in cancer populations have been broadly investigated to identify CN gains and deletions associated with cancer. In contrast, in this research, we quantify the similarities and disparities between cancer and paired peripheral blood samples using maximal information coefficient (MIC). We then detect the spatial locations with substantially high and the spatial locations with very low MICs in each chromosome. These locations can potentially help with early diagnosis, treatment, and prevention of cancer by identifying the similarities and disparities between cancer and healthy tissues. Results: Lung cancer data used in this project contains CN pairs for cancer and blood (non-involved) samples for 63 subjects. MIC was obtained to quantify the relation (linear or nonlinear) between cancer-blood pair samples for 63 subjects at each location for each chromosome. MIC values above a high threshold and MIC values below a low threshold were located. Among them top five (with lowest MIC's and with highest MIC's) were identified for each chromosome. For these identified locations, a high MIC score indicates high similarity between blood (non-involved) and cancer samples, while a low MIC score shows lack of similarity between the two samples. Conclusions: The results showed that a few chromosomes have a large number of MICs exceeding a high threshold. These locations can potentially be used to identify early indicators of NSCLC. In contrast, second group of chromosomes have several locations with small MICs which are potential candidates to develop biomarkers for discriminating cancer from the matched blood sample. Moreover, there is a third group of chromosomes with a large number of MICs exceeding a high threshold and a large set of MICs below a low threshold. These locations can help with both finding early indicators of cancer and developing biomarkers for discriminating cancer from non-involved tissue.

7.
Ann Am Thorac Soc ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31599647

RESUMO

RATIONALE: Medical treatment can improve quality of life and avert exacerbations for those with chronic obstructive pulmonary disease (COPD). High-deductible health plans (HDHPs) can increase exposure to medical costs, and might compromise healthcare access and financial well-being for patients with COPD. OBJECTIVES: To examine the association of HDHPs with healthcare access, utilization, and financial strain among individuals with COPD. METHODS: We analyzed privately-insured adults aged 40-64 with COPD in the 2011-2017 National Health Interview Survey, which uses Internal Revenue Service-specified thresholds to classify health plans as "high" or "traditional" deductible coverage. We assessed the association between enrollment in a high deductible plan and indicators of cost-related impediments to care, financial strain, and healthcare utilization, adjusting for potential confounders. RESULTS: Our sample included 803 individuals with a HDHP and 1,334 with a traditional plan. The two groups' demographic and health characteristics were similar. Individuals enrolled in a HDHP more frequently reported delayed or foregone care, cost-related medication non-adherence, medical bill problems, and financial strain. They also more frequently reported out-of-pocket healthcare spending in excess of $5,000 a year. While the two groups' office visit rates were similar, those enrolled in a HDHP were more likely to report a hospitalization or ER visit in the past year. CONCLUSIONS: For patients with COPD, enrollment in a HDHP was associated with cost-related barriers to care, financial strain, and more frequent ER visits and hospitalizations.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31548623

RESUMO

With advances in technologies that facilitate metabolome-wide analyses, the incorporation of metabolomics in the pursuit of biomarkers of exposure and effect is rapidly evolving in population health studies. However, many analytic approaches are limited in their capacity to address high-dimensional metabolomics data within an epidemiologic framework, including the highly collinear nature of the metabolites and consideration of confounding variables. In this Children's Health Exposure Analysis Resource (CHEAR) network study, we showcase various analytic approaches that are established as well as novel in the field of metabolomics, including univariate single metabolite models, least absolute shrinkage and selection operator (LASSO), random forest, weighted quantile sum (WQSRS) regression, exploratory factor analysis (EFA), and latent class analysis (LCA). Here, in a Bangladeshi birth cohort (n = 199), we illustrate research questions that can be addressed by each analytic method in the assessment of associations between cord blood metabolites (1H NMR measurements) and birth anthropometric measurements (birth weight and head circumference).

9.
N Engl J Med ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31491071
10.
Artigo em Inglês | MEDLINE | ID: mdl-31487195

RESUMO

RATIONALE: Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of the soluble receptor for advanced glycation end products (sRAGE) strongly associate with ARDS risk. However, whether plasma sRAGE contributes causally to ARDS remains unknown. OBJECTIVES: Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian Randomization (MR), a statistical method to infer causality using observational data. METHODS: We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole genome-genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with significant associations in both populations (p<0.01, R^2>0.02). We applied the inverse-variance weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk. MEASUREMENTS AND MAIN RESULTS: There were 393 European and 266 African ancestry patients in the first cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (OR 1.86; 95% CI [1.54, 2.25]; 2.56 [2.14-3.06] per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a ß estimate of 0.50 95% CI [0.09, 0.91] per log increase. CONCLUSIONS: Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk suggesting plasma sRAGE acts a causal intermediate in sepsis-related ARDS.

11.
Aging (Albany NY) ; 11(16): 6312-6335, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434796

RESUMO

Limited studies have focused on developing prognostic models with trans-omics biomarkers for early-stage lung adenocarcinoma (LUAD). We performed integrative analysis of clinical information, DNA methylation, and gene expression data using 825 early-stage LUAD patients from 5 cohorts. Ranger algorithm was used to screen prognosis-associated biomarkers, which were confirmed with a validation phase. Clinical and biomarker information was fused using an iCluster plus algorithm, which significantly distinguished patients into high- and low-mortality risk groups (Pdiscovery = 0.01 and Pvalidation = 2.71×10-3). Further, potential functional DNA methylation-gene expression-overall survival pathways were evaluated by causal mediation analysis. The effect of DNA methylation level on LUAD survival was significantly mediated through gene expression level. By adding DNA methylation and gene expression biomarkers to a model of only clinical data, the AUCs of the trans-omics model improved by 18.3% (to 87.2%) and 16.4% (to 85.3%) in discovery and validation phases, respectively. Further, concordance index of the nomogram was 0.81 and 0.77 in discovery and validation phases, respectively. Based on systematic review of published literatures, our model was superior to all existing models for early-stage LUAD. In summary, our trans-omics model may help physicians accurately identify patients with high mortality risk.

12.
Environ Health ; 18(1): 73, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429759

RESUMO

BACKGROUND: Most of the global burden of pollution-related morbidity and mortality is believed to occur in resource-limited settings, where HIV serostatus and sex may influence the relationship between air pollution exposure and respiratory morbidity. The lack of air quality monitoring networks in these settings limits progress in measuring global disparities in pollution-related health. Personal carbon monoxide monitoring may identify sub-populations at heightened risk for air pollution-associated respiratory morbidity in regions of the world where the financial cost of air quality monitoring networks is prohibitive. METHODS: From September 2015 through May 2017, we measured 48-h ambulatory carbon monoxide (CO) exposure in a longitudinal cohort of HIV-infected and uninfected adults in rural southwestern Uganda. We fit generalized mixed effects models to identify correlates of CO exposure exceeding international air quality thresholds, quantify the relationship between CO exposure and respiratory symptoms, and explore potential effect modification by sex and HIV serostatus. RESULTS: Two hundred and sixty study participants completed 419 sampling periods. Personal CO exposure exceeded international thresholds for 50 (19%) participants. In covariate-adjusted models, living in a home where charcoal was the main cooking fuel was associated with CO exposure exceeding international thresholds (adjusted odds ratio [AOR] 11.3, 95% confidence interval [95%CI] 4.7-27.4). In sex-stratified models, higher CO exposure was associated with increased odds of respiratory symptoms among women (AOR 3.3, 95%CI 1.1-10.0) but not men (AOR 1.3, 95%CI 0.4-4.4). In HIV-stratified models, higher CO exposure was associated with increased odds of respiratory symptoms among HIV-infected (AOR 2.5, 95%CI 1.01-6.0) but not HIV-uninfected (AOR 1.4, 95%CI 0.1-14.4) participants. CONCLUSIONS: In a cohort in rural Uganda, personal CO exposure frequently exceeded international thresholds, correlated with biomass exposure, and was associated with respiratory symptoms among women and people living with HIV. Our results provide support for the use of ambulatory CO monitoring as a low-cost, feasible method to identify subgroups with heightened vulnerability to pollution-related respiratory morbidity in resource-limited settings and identify subgroups that may have increased susceptibility to pollution-associated respiratory morbidity.

13.
Lancet Respir Med ; 7(10): 881-891, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326317

RESUMO

BACKGROUND: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. METHODS: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. FINDINGS: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10-8, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; ptrend=2·02 × 10-9). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. INTERPRETATION: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations. FUNDING: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.

14.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1228-1237, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31263055

RESUMO

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus. METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases. RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3). CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration. IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

15.
Sci Rep ; 9(1): 10319, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311965

RESUMO

Low-dose CT has shown promise in detecting early stage lung cancer. However, concerns about the adverse health effects of radiation and high cost prevent its use as a population-wide screening tool. Effective and feasible screening methods to triage suspicious patients to CT are needed. We investigated human lung cancer metabolomics from 93 paired tissue-serum samples with magnetic resonance spectroscopy and identified tissue and serum metabolomic markers that can differentiate cancer types and stages. Most interestingly, we identified serum metabolomic profiles that can predict patient overall survival for all cases (p = 0.0076), and more importantly for Stage I cases alone (n = 58, p = 0.0100), a prediction which is significant for treatment strategies but currently cannot be achieved by any clinical method. Prolonged survival is associated with relative overexpression of glutamine, valine, and glycine, and relative suppression of glutamate and lipids in serum.

16.
Cancer Epidemiol Biomarkers Prev ; 28(9): 1534-1543, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31217167

RESUMO

BACKGROUND: Few epidemiologic studies have investigated trace element exposure and skin cancer risk. METHODS: Toenail levels of mercury, selenium, chromium, iron, and zinc were measured from 6,708 women in the Nurses' Health Study (1984-2012) and 3,730 men in the Health Professionals Follow-up Study (1986-2012) with data from prior nested case-control studies. Participants were free of skin cancer at toenail collection and followed for incident basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of skin cancer associated with the elements in each study. We calculated pooled multivariable HRs using a fixed-effects model. During 26 to 28 years of follow-up, 2,433 BCC, 334 SCC, and 130 melanoma cases were documented. RESULTS: Higher toenail mercury levels were associated with risk of BCC [pooled HR for top vs. bottom quintiles = 1.34 (95% CI, 1.18-1.52), P trend < 0.0001]. Similar direct associations were found with risks of SCC [pooled HR for top vs. bottom quartiles = 1.41 (95% CI, 1.03-1.94), P trend = 0.04] and melanoma [pooled HR for top vs. bottom quartiles = 1.88 (95% CI, 1.12-3.16), P trend = 0.02]. Chromium was positively associated with BCC in women only. No associations were found between other metals and skin cancer risk. CONCLUSIONS: Our prospective data found that increased toenail mercury concentrations were associated with increased skin cancer risk. IMPACT: If our novel findings are confirmed, mercury may play a role in skin carcinogenesis.

17.
J Glob Health ; 9(1): 010434, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31217961

RESUMO

Background: The global burden of chronic obstructive pulmonary disease (COPD) disproportionately affects resource-limited settings such as sub-Saharan Africa (SSA), but population-based prevalence estimates in SSA are rare. We aimed to estimate the population prevalence of COPD and chronic respiratory symptoms in rural southwestern Uganda. Methods: Adults at least 18 years of age who participated in a population-wide census in rural southwestern Uganda completed respiratory questionnaires and lung function testing with bronchodilator challenge at health screening events in June 2015. We defined COPD as post-bronchodilator forced expiratory volume in one second to forced vital capacity ratio less than the lower limit of normal. We fit multivariable linear and log binomial regression models to estimate correlates of abnormal lung function and respiratory symptoms, respectively. We included inverse probability of sampling weights in models to facilitate population-level estimates. Results: Forty-six percent of census participants (843/1814) completed respiratory questionnaires and spirometry, of which 565 (67%) met acceptability standards. COPD and respiratory symptom population prevalence were 2% (95% confidence interval (CI) = 1%-3%) and 30% (95% CI = 25%-36%), respectively. Respiratory symptoms were more prevalent and lung function was lower among women and ever-smokers (P < 0.05). HIV serostatus was associated with neither respiratory symptoms nor lung function. Conclusions: COPD population prevalence was low despite prevalent respiratory symptoms. This work adds to the growing body of literature depicting lower-than-expected COPD prevalence estimates in SSA and raises questions about whether the high respiratory symptom burden in rural southwestern Uganda represents underlying structural lung disease not identified by screening spirometry.


Assuntos
Doença Pulmonar Obstrutiva Crônica/epidemiologia , Transtornos Respiratórios/epidemiologia , Saúde da População Rural/estatística & dados numéricos , População Rural/estatística & dados numéricos , Adolescente , Adulto , Idoso , Doença Crônica , Estudos Transversais , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Espirometria , Inquéritos e Questionários , Uganda/epidemiologia , Capacidade Vital , Adulto Jovem
18.
Cancer Epidemiol Biomarkers Prev ; 28(8): 1379-1387, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31186263

RESUMO

BACKGROUND: Higher levels of circulating 25-hydroxyvitamin D [25(OH)D] are associated with longer survival in several cancers, but the results have differed across cancer sites. The association between serum 25(OH)D levels and overall survival (OS) time in esophageal adenocarcinoma remains unclear. METHODS: We utilized serum samples from 476 patients with primary esophageal adenocarcinoma, recruited from Massachusetts General Hospital (Boston, MA) between 1999 and 2015. We used log-rank tests to test the difference in survival curves across quartiles of 25(OH)D levels and extended Cox modeling to estimate adjusted HRs. We tested for interactions between clinical stage or BMI on the association between 25(OH)D and OS. We additionally performed sensitivity analyses to determine whether race or timing of blood draw (relative to treatment) affected these results. RESULTS: We found no evidence that survival differed across quartiles of 25(OH)D (log rank P = 0.48). Adjusting for confounders, we found no evidence that the hazard of death among the highest quartile of 25(OH)D (quartile 1) differed from any other quartile [quartile 2 HR = 0.90, 95% confidence interval (CI), 0.67-1.23; quartile 3 HR = 1.03, 95% CI, 0.76-1.38; quartile 4 (lowest) HR = 0.98, 95% CI, 0.72-1.33]. Sensitivity analyses yielded consistent results when accounting for race or time between diagnosis and blood draw. Moreover, we did not find evidence of interaction between 25(OH)D and clinical stage or BMI on OS. CONCLUSIONS: Serum level of 25(OH)D near time of diagnosis was not associated with OS in patients with esophageal adenocarcinoma. IMPACT: Screening 25(OH)D levels among patients with esophageal adenocarcinoma at diagnosis is not clinically relevant to their cancer prognosis based on present evidence.

19.
Ann Am Thorac Soc ; 16(9): 1171-1178, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31199665

RESUMO

Rationale: Clinical and research training opportunities in global health are of increasing interest to medical trainees, but little is known about such opportunities in U.S.-based pulmonary and pulmonary/critical care medicine (PCCM) fellowship programs.Objectives: Summarize currently available global health-related training opportunities and identify potential barriers to implementing global health curricula among U.S.-based PCCM fellowship programs.Methods: We sent a confidential, online, targeted needs assessment to PCCM fellowship program directors and associate program directors. Data collected included program demographics, currently available global health-related clinical and research training opportunities, potential barriers to the implementation of global health-related programmatic content, and perceived interest in global health-related training opportunities by current and/or prospective trainees. To evaluate for nonresponse bias, we performed an online search to identify global health-related training opportunities offered by nonresponding programs.Results: Out of 171 surveyed programs, 63 PCCM fellowship programs (37%) provided survey responses. Most responses (n = 56, 89%) were from combined PCCM training programs; 66% (n = 40) of programs offered at least one component of global health-related clinical or research training. Overall, 27% (n = 17) had a Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant (National Institutes of Health T32), 73% (n = 46) had fewer than 35 faculty members, and 51% (n = 32) had at least one faculty member conducting global health-focused research. Most responding programs (66%, n = 40) offered at least one global health-related educational component. Among programs that would like to offer global health-related training components, the most common barriers included competing priorities for lecture content and a lack of in-division mentors with global health experience, a champion for global health-related activities, and established partnerships outside the United States.Conclusions: PCCM program leaders are interested in offering global health-related training opportunities, but important barriers include lack of mentorship, dedicated fellowship time, and established global partnerships. Future research is needed to better understand global health-related interests and training needs of incoming fellows and to design creative solutions for providing global health-related training across academic institutions with variable global health-related training capacities.

20.
Environ Int ; 127: 810-818, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31051324

RESUMO

BACKGROUND: Arsenic can impair immune function. Timing of exposure can influence potential immunotoxicity of arsenic exposure. We examined the association between drinking water arsenic concentrations (W-As) measured repeatedly during different exposure windows in early life and serum concentrations of IgG antibodies against diphtheria and tetanus toxoids (diphtheria and tetanus antibody). METHODS: A prospective cohort of pregnant women was recruited in Bangladesh (2008-2011). Averaged W-As levels were calculated for: pregnancy (W-Aspregnancy): ≤16 weeks gestation and <1 month; toddlerhood (W-Astoddlerhood): 12 and 20-40 months; and early childhood (W-Aschildhood): 4-5 years. Serum was collected from 502 vaccinated children at age 5 and concentrations of diphtheria and tetanus toxoid IgG (i.e. antibody) were quantified. Antibody concentrations >0.1 IU/mL were considered clinically sufficient for protection. Associations were estimated using linear and logistic regression models. RESULTS: Inverse associations were observed between W-Aspregnancy and serum diphtheria antibody levels, while null associations were observed between W-As and tetanus antibody. Children within the highest versus lowest tertile of W-Aspregnancy had 91% greater odds of having clinically insufficient concentrations of diphtheria antibody (Odds ratio:1.91, 95% confidence interval (CI): 1.03, 3.56). Among females, a doubling in W-Aspregnancy was associated with 12.3% (95%CI: -20.1%, -4.5%) lower median concentrations of diphtheria antibody. Tetanus antibody was only associated with W-Aspregnancy among females (percent change in median: -9.5%, 95%CI: -17.6%, -1.3%). Among children who were stunted or underweight, a doubling in W-Aspregnancy was associated with decreased diphtheria antibody of 19.8% (95%CI: -32%, -7.5%) and 14.3% (95%CI: -26.7%, -2%), respectively. CONCLUSIONS: Among vaccinated children, W-As measured during pregnancy was associated with decreased diphtheria antibody levels, but not tetanus antibody. However, W-As measured during toddlerhood and early childhood were not associated with either antibody outcome. Children's sex and malnutrition status were important effect modifiers of W-As for both diphtheria and tetanus antibody levels, highlighting the importance of these factors and the timing of the exposure when evaluating the effect of arsenic on humoral immunity.


Assuntos
Anticorpos Antibacterianos/sangue , Arsênico/sangue , Arsênico/química , Vacina contra Difteria e Tétano/imunologia , Bangladesh , Criança , Pré-Escolar , Estudos de Coortes , Difteria/prevenção & controle , Água Potável/química , Feminino , Humanos , Imunidade Humoral , Masculino , Razão de Chances , Estudos Prospectivos , Tétano/prevenção & controle
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