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1.
Cancer Res ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653773

RESUMO

Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose-response relationship in a retrospective observational study of 931 patients treated for advanced stage non-small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women's Hospital. Doubling smoking pack-years was associated with increased KRASG12C mutations and less frequent EGFRdel19 and EGFRL858R mutations, while doubling smoking-free months was associated with more frequent EGFRL858R. In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, while doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender and stage. There is a significant dose-response association of smoking history with genetic alterations in cancer-related pathways and tumor mutation burden in advanced lung adenocarcinoma.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33651148

RESUMO

BACKGROUND: Cellular immunity against tumor cells is highly dependent on antigen presentation by major histocompatibility complex class I (MHC-I) molecules. However, few published studies have investigated associations between functional variants of MHC-I-related genes and clinical outcomes of lung cancer patients. METHODS: We performed a two-phase Cox proportional hazards regression analysis by using two previously published genome-wide association studies to evaluate associations between genetic variants in the MHC-I-related gene set and the survival of non-small cell lung cancer (NSCLC) patients, followed by expression quantitative trait loci analysis. RESULTS: Of the 7811 single-nucleotide polymorphisms (SNPs) in 89 genes of 1185 NSCLC patients in the discovery dataset of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 24 SNPs remained statistically significant after validation in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. In a multivariate stepwise Cox model, three independent functional SNPs (ERAP1 rs469783 T > C, PSMF1 rs13040574 C > A and NCF2 rs36071574 G > A) remained significant with an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.77-0.89, P = 8.0 × 10-7], 0.86 (0.80-0.93, P = 9.4 × 10-5) and 1.31 (1.11-1.54, P = 0.001) for overall survival (OS), respectively. Further combined genotypes revealed a poor survival in a dose-response manner in association with the number of unfavorable genotypes (Ptrend < 0.0001 and 0.0002 for OS and disease-specific survival, respectively). Also, ERAP1 rs469783C and PSMF1 rs13040574A alleles were associated with higher mRNA expression levels of their genes. CONCLUSION: These potentially functional SNPs of the MHC-I-related genes may be biomarkers for NSCLC survival, possibly through modulating the expression of corresponding genes.

4.
Environ Int ; 151: 106448, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33618327

RESUMO

BACKGROUND: Lead (Pb) is known to induce detrimental health effects in exposed populations, including hematotoxicity and genotoxicity. Complete blood count (CBC) is a cost-effective and easy way to determine toxicity, and variations in proportion of different types of leukocytes: neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are further evidence of hematotoxicity. However, few studies have been conducted to systematically evaluate effects of occupational Pb exposure on NLR and LMR, and their associations with genotoxicity. OBJECTIVES: Our study was aimed to systematically assess the effects of current occupational Pb exposure on NLR and LMR, and their associations with genotoxicity. METHODS: Our investigation was performed on 1176 workers from a newly built battery factory in North China. The workers had just entered their current job position in recent years and most of them had no previous history of occupational exposure to Pb. Blood lead levels (BLLs) and leukocytes indices were detected for all participants. Cytokinesis-blocked micronucleus assay (MN; n = 675) and alkaline comet assay (% tail DNA; n = 869) were used to assess genotoxicity. Multivariate linear and Poisson regression analyses were conducted to examine associations between leukocytes indices, genotoxic biomarkers and BLLs with adjustment for covariates. Spearman correlation and mediation analyses were used to investigate relationships between NLR and genotoxicity. RESULTS: Among all the exposed workers, NLR increased with increasing BLLs. However, WBC and LMR did not change significantly. Significant and dose-dependent increases in both MN frequencies and % tail DNA were observed among groups with different exposure doses. Compared with the normal NLR group (1.48 ≤ NLR < 4.58), the high NLR group (NLR ≥ 4.58) had higher % tail DNA. In addition, there was a significant and positive association between NLR and % tail DNA among all the workers, and % tail DNA mediated 15% of the effect of Pb on increasing NLR. CONCLUSION: Our large-scale population study shows that Pb exposure increased NLR and induced genotoxicity. There was an association between elevated NLR and DNA damage. In addition, the mediation effect of % tail DNA on the relationship between BLLs and NLR provided mechanistic evidence that certain mechanisms, e.g. inflammation, may be involved in elevation of NLR from Pb exposure. Therefore, NLR may be a convenient and sensitive biomarker for indication of Pb toxicity. Further studies are needed to validate the proposed mechanism and NLR as a biomarker.

5.
Mol Cancer ; 20(1): 13, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430880

RESUMO

Cancer is a leading cause of death worldwide, particularly because of its high mortality rate in patients who are diagnosed at late stages. Conventional biomarkers originating from blood are widely used for cancer diagnosis, but their low sensitivity and specificity limit their widespread application in cancer screening among the general population. Currently, emerging studies are exploiting novel, highly-accurate biomarkers in human body fluids that are obtainable through minimally invasive techniques, which is defined as liquid biopsy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs generated mainly by pre-mRNA splicing. Following the rapid development of high-throughput transcriptome analysis techniques, numerous circRNAs have been recognized to exist stably and at high levels in body fluids, including plasma, serum, exosomes, and urine. CircRNA expression patterns exhibit distinctly differences between patients with cancer and healthy controls, suggesting that circRNAs in body fluids potentially represent novel biomarkers for monitoring cancer development and progression. In this study, we summarized the expression of circRNAs in body fluids in a pan-cancer dataset and characterized their clinical applications in liquid biopsy for cancer diagnosis and prognosis. In addition, a user-friendly web interface was developed to visualize each circRNA in fluids ( https://mulongdu.shinyapps.io/circrnas_in_fluids/ ).

6.
JAMA Netw Open ; 4(1): e2034569, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33502483

RESUMO

Importance: Acute respiratory distress syndrome (ARDS) confers high mortality risk among critically ill patients. Identification of biomarkers associated with ARDS risk may guide clinical diagnosis and prognosis. Objective: To systematically evaluate the association of blood metabolites with ARDS risk and survival. Design, Setting, and Participants: In this cohort study, data from the Molecular Epidemiology of ARDS (MEARDS) study, a prospective cohort of 403 patients with ARDS and 1227 non-ARDS controls, were analyzed. Patients were recruited in intensive care units (ICUs) at Massachusetts General Hospital and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts, from January 1, 1998, to December 31, 2014. Data analysis was performed from December 9, 2018, to January 4, 2019. Main Outcomes and Measures: Participants were followed up daily for ARDS development defined by Berlin criteria, requiring fulfillment of chest radiograph and oxygenation criteria on the same calendar day during invasive ventilatory assistance. A 2-stage study design was used to explore novel metabolites associated with ARDS risk and survival. Results: Of the 1630 participants from MEARDS who were admitted to the ICU , 403 (24.7%) were diagnosed with ARDS (mean [SD] age, 63.0 [17.0] years; 251 [62.3%] male) and 1227 (75.3%) were at-risk but did not have ARDS (mean [SD] age, 62.3 [16.9] years; 753 [61.4%] male). Mendelian randomization suggested that genetically regulated serum mannose was associated with ARDS risk (odds ratio [OR], 0.64; 95% CI, 0.53-0.78; P = 7.46 × 10-6) in the discovery stage. In the functional validation stage incorporating 83 participants with ARDS and matched at-risk participants in the control group from the ICU, the protective association of mannose with ARDS risk was validated (OR, 0.67; 95% CI, 0.46-0.97; P = .03). Furthermore, serum mannose was associated with 28-day (OR, 0.25; 95% CI, 0.11-0.56; P = 6.95 × 10-4) and 60-day (OR, 0.36; 95% CI, 0.19-0.71; P = 3.12 × 10-3) mortality and 28-day (hazard ratio, 0.49; 95% CI, 0.32-0.74; P = 6.41 × 10-4) and 60-day (hazard ratio, 0.55; 95% CI, 0.37-0.80; P = 2.11 × 10-3) survival. Conclusions and Relevance: In this study, genetically regulated serum mannose appeared to be associated with ARDS risk and outcome, and increased serum mannose at admission was associated with reduced ARDS risk and better survival. These findings could inform prevention and clinical intervention in ARDS cases, which have increased with the expansion of the coronavirus disease 2019 pandemic.


Assuntos
Manose/sangue , /mortalidade , APACHE , Idoso , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Admissão do Paciente/estatística & dados numéricos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco
7.
Artigo em Inglês | MEDLINE | ID: mdl-33419122

RESUMO

Up to 95% of the liquid volume in an e-cigarette consists of propylene glycol. Previous research has shown that propylene glycol can generate diacetyl and formaldehyde when heated. New research shows that propylene glycol can also generate methylglyoxal, an alpha di-carbonyl compound recently shown to cause epithelial necrosis at even lower concentrations than diacetyl, the flavoring chemical associated with bronchiolitis obliterans ("Popcorn Lung"). We analyzed chemical emissions from 13 JUUL pod flavors. Diacetyl and methylglyoxal was detected in 100% of samples with median concentration (range) of 20 µg/m3 (less than limit of quantification: 54 µg/m3) and 4219 µg/m3 (677-15,342 µg/m3), respectively. We also detected acetaldehyde (median concentration: 341 µg/m3) and propionaldehyde (median concentration: 87 µg/m3) in all samples. The recent evidence that methylglyoxal is more cytotoxic to airway epithelial cells than diacetyl makes this an urgent public health concern. Current smokers considering e-cigarettes as a smoking cessation tool, and never users, who may be under the impression that e-cigarettes are harmless, need information on emissions and potential risks to make informed decisions.

8.
Cancer Res ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472890

RESUMO

Lung cancer is the leading cause of cancer death globally. An improved risk stratification strategy can increase efficiency of low-dose computed tomography (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. Based on 13,119 lung cancer patients and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK biobank data (N=335,931). Absolute risk was estimated based on age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial, N=50,772 participants). The lung cancer odds ratio (ORs) for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 (95%CI=1.92-3.00, P=1.80x10-14) in the validation set (trend p-value of 5.26 x 10-20). The OR per standard deviation of PRS increase was 1.26 (95%CI=1.20-1.32, P=9.69x10-23) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status and family history. Collectively, these results suggest that Individual's genetic background may inform the optimal lung cancer LDCT screening strategy.

9.
Cancer Imaging ; 21(1): 14, 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33468255

RESUMO

BACKGROUND: Interstitial lung abnormalities (ILA) can be detected on computed tomography (CT) in lung cancer patients and have an association with mortality in advanced non-small cell lung cancer (NSCLC) patients. The aim of this study is to demonstrate the significance of ILA for mortality in patients with stage I NSCLC using Boston Lung Cancer Study cohort. METHODS: Two hundred and thirty-one patients with stage I NSCLC from 2000 to 2011 were investigated in this retrospective study (median age, 69 years; 93 males, 138 females). ILA was scored on baseline CT scans prior to treatment using a 3-point scale (0 = no evidence of ILA, 1 = equivocal for ILA, 2 = ILA) by a sequential reading method. ILA score 2 was considered the presence of ILA. The difference of overall survival (OS) for patients with different ILA scores were tested via log-rank test and multivariate Cox proportional hazards models were used to estimate hazard ratios (HRs) including ILA score, age, sex, smoking status, and treatment as the confounding variables. RESULTS: ILA was present in 22 out of 231 patients (9.5%) with stage I NSCLC. The presence of ILA was associated with shorter OS (patients with ILA score 2, median 3.85 years [95% confidence interval (CI): 3.36 - not reached (NR)]; patients with ILA score 0 or 1, median 10.16 years [95%CI: 8.65 - NR]; P <  0.0001). In a Cox proportional hazards model, the presence of ILA remained significant for increased risk for death (HR = 2.88, P = 0.005) after adjusting for age, sex, smoking and treatment. CONCLUSIONS: ILA was detected on CT in 9.5% of patients with stage I NSCLC. The presence of ILA was significantly associated with a shorter OS and could be an imaging marker of shorter survival in stage I NSCLC.

10.
Transl Res ; 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33400994

RESUMO

The gonadotropin-releasing hormone (GnRH) signaling pathway controls reproductive functions and cancer growth and progression. However, few studies investigated roles of genetic variants of GnRH pathway genes in survival of patients with non-small cell lung cancer (NSCLC). Therefore, we first evaluated associations between 22,528 single-nucleotide polymorphisms (SNPs) in 101 GnRH pathway genes and survival of 1185 NSCLC patients using a dataset from Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We found 572 SNPs to be significantly associated with overall survival (OS) of NSCLC (P ≤ 0.05, Bayesian false discovery probability ≤0.80). We then validated these SNPs in another dataset with 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. Finally, two independent SNPs (HBEGF rs4150236G>A and ITPR3 rs116454384C>T) remained significantly associated with NSCLC OS in the combined analysis with hazards ratios of 0.84 (95% confidence interval = 0.76-0.92, P = 0.0003) and 0.85 (0.78-0.94, 0.0012), respectively; their genetic score (the number of protective genotypes) was associated with a better OS and disease-specific survival (Ptrend = 0.0002 and 0.0001, respectively). Further expression quantitative trail loci analysis showed a significant correlation between ITPR3 rs116454384 T allele and an increased mRNA expression level in both whole blood and normal lung tissue, and high ITPR3 mRNA expression levels in tumors were associated with a better survival of NSCLC patients. Because ITPR3 mutations were rare in tumors, ITPR3 rs116454384C>T likely had an effect on cancer progression by regulating the gene expression. Therefore, genetic variants of HBEGF rs4150236G>A and ITPR3 rs116454384C>T may be predictors for NSCLC survival, but HBEGF rs4150236G>A functional relevance remains to be determined.

11.
Thorax ; 76(3): 216-217, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33318238
12.
J Neurodev Disord ; 12(1): 39, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33327931

RESUMO

BACKGROUND: Many children in Bangladesh experience poor nutritional status and environmental lead exposure, both of which are associated with lower scores on neurodevelopmental assessments. Recent studies have suggested that part of lead's adverse effects on neurodevelopment are caused in part by lead's effect on growth. New statistical methods are now available to evaluate potential causal pathways in observational studies. This study used a novel statistical method to test the hypothesis that stunting, a measure of linear growth related to poor nutrition, is a mediator and/or an effect modifier of the lead exposure's adverse effect on cognitive development. METHODS: Participants were 734 children from a longitudinal birth cohort established in rural Bangladesh to study the health effects of prenatal and early childhood environmental metal exposures. Lead exposure was estimated using umbilical cord blood samples obtained at birth and blood obtained via venipuncture at age 20-40 months. Stunting was determined using the World Health Organization's standards. Neurodevelopment was assessed at age 20-40 months years using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). We evaluated the effect of lead on stunting and whether the effect of lead on cognitive scores is modified by stunting status in multivariable regression analyses. We then conducted a novel 4-way mediation analysis that allows for exposure-mediator interaction to assess how much of the effect of lead on cognitive scores is explained by the pathway through stunting (mediation) and how much is explained by the interaction between lead and stunt (effect modification). RESULTS: Stunting was not a mediator of the effect of lead in our analyses. Results suggested effect modification by stunting. In an area of Bangladesh with lower lead exposures (median umbilical cord blood lead concentration, 1.7 µg/dL), stunting modified the relationship between prenatal blood lead concentrations and cognitive score at age 2-3 years. A 1-unit increase in natural log cord blood lead concentration in the presence of stunting was associated with a 2.1-unit decrease in cognitive scores (ß = - 2.10, SE = 0.71, P = 0.003). This interaction was not found in a second study site where lead exposures were higher (median umbilical cord blood lead concentration, 6.1 µg/dL, ß = - 0.45, SE = 0.49, P = 0.360). CONCLUSIONS: We used a novel method of mediation analysis to test whether stunting mediated the adverse effect of prenatal lead exposure on cognitive outcomes in Bangladesh. While we did not find that stunting acted as mediator of lead's effect on cognitive development, we found significant effect modification by stunting. Our results suggest that children with stunting are more vulnerable to the adverse effects of low-level lead exposure.

13.
Chest ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33189655

RESUMO

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a devastating syndrome with heterogeneous subtypes, but few causal biomarkers have been identified. RESEARCH QUESTION: Would multi-stage Mendelian randomization identify new causal protein biomarkers for ARDS 28-day mortality? STUDY DESIGN AND METHODS: Three hundred moderate to severe ARDS patients were randomly selected from the Molecular Epidemiology of ARDS (MEARDS) cohort for proteomics analysis. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was applied to detect the association between proteins and ARDS 28-day mortality. Candidate proteins were analyzed using generalized summary data-based Mendelian randomization (GSMR). Protein quantitative trait summary statistics were retrieved from the INTERVAL study (n=2,504), and a genome-wide association study for ARDS was conducted from the Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR) consortium study (n=534). Causal mediation analysis detected the role of platelet count in mediating the effect of protein on ARDS prognosis. RESULTS: Plasma IGFBP7 moderately increased ARDS 28-day mortality [Odd Ratio (OR)=1·11, 95%CI=1·04-1·19, P=1·80×10-3] per log2-increase. GSMR analysis coupled with four other Mendelian randomization methods revealed IGFBP7 as a causal biomarker for ARDS 28-day mortality (OR=2·61, 95%CI=1·33-5·13, P=5·31×10-3). Causal mediation analysis indicated that the association between IGFBP7 and ARDS 28-day mortality is mediated by platelet count (OR=1·03, 95%CI=1·02-1·04, P=0·01). INTERPRETATION: We identified plasma IGFBP7 as a novel causal protein involved in the pathogenesis of ARDS 28-day mortality and platelet function in ARDS, a topic for further experimental and clinical investigation.

14.
Patterns (N Y) ; 1(6): 100057, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-33205126

RESUMO

The genetic effect explains the causality from genetic mutations to the development of complex diseases. Existing genome-wide association study (GWAS) approaches are always built under a linear assumption, restricting their generalization in dissecting complicated causality such as the recessive genetic effect. Therefore, a sophisticated and general GWAS model that can work with different types of genetic effects is highly desired. Here, we introduce a deep association kernel learning (DAK) model to enable automatic causal genotype encoding for GWAS at pathway level. DAK can detect both common and rare variants with complicated genetic effects where existing approaches fail. When applied to four real-world GWAS datasets including cancers and schizophrenia, our DAK discovered potential casual pathways, including the association between dilated cardiomyopathy pathway and schizophrenia.

15.
Crit Care Explor ; 2(10): e0241, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33134939

RESUMO

Objectives: Acute respiratory distress syndrome is characterized by an overly exuberant inflammatory state in the lung. Specialized proresolving mediators are endogenous agonists for the resolution of lung inflammation and injury in health, yet their association with acute respiratory distress syndrome severity and outcomes remains to be defined. In the current study, we investigate associations between plasma levels of specialized proresolving mediators and acute respiratory distress syndrome severity and mortality. Design: Translational pilot study nested within a large prospective cohort of patients with risk factors for acute respiratory distress syndrome. Setting: ICU from a large medical center. Patients: Twenty-six Caucasian patients with acute respiratory distress syndrome and available plasma from early in critical illness. Interventions: None. Measurements and Main Results: Here, in samples from 26 acute respiratory distress syndrome patients, we examined plasma levels of select specialized proresolving mediators that promote lung injury resolution in preclinical systems, namely lipoxin A4 and maresin 1, and select prophlogistic lipid mediators linked to acute respiratory distress syndrome pathogenesis, namely cysteinyl leukotrienes and thromboxane B2. These mediators were detected by sensitive enzyme-linked immunosorbent assay: lipoxin A4 (assay range) (8.2-5,000 pg/mL), maresin 1 (7.8-1,000 pg/mL), cysteinyl leukotrienes (7.8-1,000 pg/mL), and thromboxane B2 (15.6-2,000 pg/mL). Lower plasma levels of specialized proresolving mediators were associated with increased duration of ventilatory support and ICU length of stay. Even in this small sample size, trends were evident for increased cysteinyl leukotrienes to specialized proresolving mediator ratios (cysteinyl leukotrienes/maresin 1 and cysteinyl leukotrienes/lipoxin A4) in acute respiratory distress syndrome nonsurvivors. Conclusions: Lower specialized proresolving mediator levels in acute respiratory distress syndrome patients may disrupt timely resolution of lung inflammation and/or injury and contribute to clinical severity and mortality.

16.
Nat Commun ; 11(1): 6083, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247113

RESUMO

The evolutionary trajectories of early lung adenocarcinoma (LUAD) have not been fully elucidated. We hypothesize that genomic analysis between pre-invasive and invasive components will facilitate the description of LUAD evolutionary patterns. We micro-dissect malignant pulmonary nodules (MPNs) into paired pre-invasive and invasive components for panel-genomic sequencing and recognize three evolutionary trajectories. Evolutionary mode 1 (EM1) demonstrates none of the common driver events between paired components, but another two modes, EM2A and EM2B, exhibit critical private alterations restricted to pre-invasive and invasive components, respectively. When ancestral clones harbor EGFR mutations, truncal mutation abundance significantly decrease after the acquisition of invasiveness, which may be associated with the intratumoral accumulation of infiltrated B cells. Harboring EGFR mutations is critical to the selective pressure and further impacts the prognosis. Our findings extend the understanding of evolutionary trajectories during invasiveness acquisition in early LUAD.

17.
Occup Environ Med ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106349

RESUMO

BACKGROUND: Despite a number of known health hazards of welding fume exposure, it is unclear how exposure affects the human metabolome. OBJECTIVE: We assessed the metabolic profiles of welders before and after a 6-hour welding shift, controlling for circadian rhythm of metabolism on a non-welding day. METHODS: Welders were recruited from a training centre in Quincy, Massachusetts, in 2006 and 2010-2012 and donated blood samples on a welding shift day before and after work, as well as on a non-welding day spent in an adjacent classroom. In total, we collected 509 samples from 74 participants. Liquid chromatography-mass spectrometry quantified 665 metabolites from thawed plasmas. Metabolites with significant time (afternoon compared with morning) and day (welding/classroom) interactions were identified by two-way analysis of variance, and the overnight changes were evaluated. RESULTS: Sphingosine 1-phosphate (S1P) and sphingasine 1-phosphate (SA1P) exhibited significant interaction effects between day and time with false discovery rate-adjusted p values of 0.03 and <0.01, respectively. S1P, SA1P and sphingosine shared similar trends over time: high relative levels in the morning of a non-welding day declining by afternoon, but with lower starting levels on a welding day and no decline. There was no obvious pattern related to current smoking status. CONCLUSION: S1P and SA1P profiles were different between welding day and classroom day. The S1P pathway was disrupted on the day of welding exposure. The levels of S1P, SA1P and sphingosine were highly correlated over time. S1P is a signalling lipid with many vital roles; thus, the underlying mechanism and clinical implications of this alteration need further investigation.

18.
BMC Med Genomics ; 13(1): 162, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126877

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have proven successful in predicting genetic risk of disease using single-locus models; however, identifying single nucleotide polymorphism (SNP) interactions at the genome-wide scale is limited due to computational and statistical challenges. We addressed the computational burden encountered when detecting SNP interactions for survival analysis, such as age of disease-onset. To confront this problem, we developed a novel algorithm, called the Efficient Survival Multifactor Dimensionality Reduction (ES-MDR) method, which used Martingale Residuals as the outcome parameter to estimate survival outcomes, and implemented the Quantitative Multifactor Dimensionality Reduction method to identify significant interactions associated with age of disease-onset. METHODS: To demonstrate efficacy, we evaluated this method on two simulation data sets to estimate the type I error rate and power. Simulations showed that ES-MDR identified interactions using less computational workload and allowed for adjustment of covariates. We applied ES-MDR on the OncoArray-TRICL Consortium data with 14,935 cases and 12,787 controls for lung cancer (SNPs = 108,254) to search over all two-way interactions to identify genetic interactions associated with lung cancer age-of-onset. We tested the best model in an independent data set from the OncoArray-TRICL data. RESULTS: Our experiment on the OncoArray-TRICL data identified many one-way and two-way models with a single-base deletion in the noncoding region of BRCA1 (HR 1.24, P = 3.15 × 10-15), as the top marker to predict age of lung cancer onset. CONCLUSIONS: From the results of our extensive simulations and analysis of a large GWAS study, we demonstrated that our method is an efficient algorithm that identified genetic interactions to include in our models to predict survival outcomes.

19.
J Rural Health ; 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33040358

RESUMO

PURPOSE: The burden of chronic obstructive pulmonary disease (COPD) is high in rural America. Few studies, however, have examined urban/rural differences in health care access, or racial/ethnic and income disparities stratified by urban/rural residence, among persons with COPD. METHODS: We studied individuals age ≥ 40 years with COPD from the 2018 Behavioral Risk Factor Surveillance System. The primary exposure was "urban" or "rural" county of residence. We examined multiple health and health care access/services outcomes using logistic regressions adjusted for age and sex, and performed analyses stratified by rural/urban county that included additional adjustment for race/ethnicity or income. FINDINGS: Our sample included 34,439 individuals. COPD prevalence was 8.6% in rural counties versus 5.4% in urban counties. Rural residents with COPD were poorer, had less education, worse health, and more disability. Of the rural population with COPD, 12.6% were uninsured, versus 10.4% in urban areas (AOR 1.26; 95% CI: 1.00-1.58). Rural residents with COPD were more likely to have not seen a doctor due to cost (AOR 1.18; 95% CI: 1.02-1.36). Differences in other outcomes were mostly nonsignificant. We observed large access disparities by race/ethnicity and income among individuals in both urban and rural counties, with the highest rates of forgone care among minorities in rural counties. CONCLUSION: Patients with COPD in rural areas experience greater morbidity and obstacles to care than those in urban areas. Racial/ethnic minorities and those with low incomes-particularly in rural areas-are also at greater risk of forgoing doctor visits due to cost. Expanded access to health care could address respiratory health inequities.

20.
Med Sci Sports Exerc ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33044439

RESUMO

PURPOSE: To investigate changes in firefighter recruits' select health and fitness measurements, from academy training through the early probationary firefighter period. METHODS: Firefighter recruits from two New England fire academies were followed prospectively from enrollment at the academy, to graduation after 15-16 week training programs, and then for an average of eight months as probationary firefighters. The participants' demographic, lifestyle, and mental health information were collected using a questionnaire. Body mass index (BMI), percent body fat, blood pressure, and push-ups were also measured at each time point. Furthermore, the academies tested the recruits on selected fitness measures (push-ups, pull-ups, and 1.5-mile running time) at academy entry, mid-training, and at graduation. RESULTS: Ninety-two recruits consented and were included in the analyses. The recruits' percent body fat significantly decreased (median: 21.0% to 18.2%) from baseline to graduation and push-up capacity significantly improved (median: 34 to 53/minute) in the same period, along with pull-ups and 1.5-mile running time. However, the recruits' blood pressure, both systolic and diastolic, increased significantly by an average of 3 mmHg during the training. Those completing probationary follow-up (45 out of 92 recruits) showed that most health/fitness improvements declined after graduation. From academy graduation through probationary follow-up, recruits' physical activity decreased and TV screen time increased significantly, leading to a lower healthy lifestyle score (median: 4 to 3). After multivariate adjustments, the recruits' diastolic blood pressure increased by 2 mmHg per measuring time throughout the study period. CONCLUSION: Fire academy training improved recruits' select health and fitness measurements, but the benefits dissipated as probationary firefighters, and blood pressures increased throughout the study period. Further interventions are warranted regarding blood pressure and to maintain training benefits after joining fire departments.

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