Publications by authors named "Mary Ward"

293 Publications

Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts.

Int J Epidemiol 2021 Sep 14. Epub 2021 Sep 14.

Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.

Background: Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data.

Methods: Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models.

Results: Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10-2.58)] and subtypes ALL [1.49 (0.87-2.56)] and AML [2.70 ([0.93-7.86)], but not with any cancer [1.13 (0.85-1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06-2.34)], ALL [1.43 (0.94-2.19)], AML [2.37 (1.10-5.12)] and any cancer [1.33 (1.09-1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes.

Conclusions: Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.
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http://dx.doi.org/10.1093/ije/dyab199DOI Listing
September 2021

Glycated haemoglobin (HbA ), diabetes and neuropsychological performance in community-dwelling older adults.

Diabet Med 2021 Aug 3:e14668. Epub 2021 Aug 3.

Mercer's Institute for Successful Ageing, St James's Hospital, Dublin, Ireland.

Aims: Given that diabetes is associated with cognitive impairment and dementia in later life, we aimed to investigate the relationship between glycated haemoglobin (HbA ), diabetes and domain-specific neuropsychological performance in older adults.

Methods: Cross-sectional cohort study using data from the Trinity-Ulster-Department of Agriculture (TUDA) study. Participants underwent detailed cognitive and neuropsychological assessment using the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Repeatable Assessment for Neuropsychological Status (RBANS). Linear regression was used to assess associations between HbA , diabetes status and neuropsychological performance, with adjustment for important clinical covariates.

Results: Of 4938 older adults (74.1 ± 8.3 years; 66.9% female), 16.3% (n = 803) had diabetes (HbA  ≥ 6.5%; 48 mmol/mol), with prediabetes (HbA  ≥ 5.7%-6.4%; 39-47 mmol/mol) present in 28.3% (n = 1395). Increasing HbA concentration was associated with poorer overall performance on the FAB [β: -0.01 (-0.02, -0.00); p = 0.04 per % increase] and RBANS [β = -0.66 (-1.19, -0.13); p = 0.02 per % increase]. Increasing HbA was also associated with poorer performance on immediate memory, visuo-spatial, language and attention RBANS domains. Diabetes was associated poorer performance on neuropsychological tests of immediate memory, language, visual-spatial and attention.

Conclusions: Both increasing HbA and the presence of diabetes were associated with poorer cognitive and domain-specific performance in older adults. HbA , and not just diabetes status per se, may represent an important target in the promotion of optimal brain health in older adults.
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http://dx.doi.org/10.1111/dme.14668DOI Listing
August 2021

Long-term anticholinergic, benzodiazepine and Z-drug use in community-dwelling older adults: What is the impact on cognitive and neuropsychological performance?

Int J Geriatr Psychiatry 2021 Jul 6. Epub 2021 Jul 6.

Mercer's Institute for Successful Ageing, St James's Hospital, Dublin, Ireland.

Background: Long-term use of anticholinergics, benzodiazepines and related drugs (or "Z-drugs") have been associated with cognitive impairment and dementia. However, the relationship of these medications with cognitive function and domain-specific neuropsychological performance in older adults without dementia, is unclear.

Methods: 5135 older adults (74.0 ± 8.3 years; 67.4% female) without a diagnosis of dementia were recruited in Ireland to the Trinity-Ulster-Department of Agriculture (TUDA) study. Detailed cognitive and neuropsychological assessment was conducted using the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Repeatable Battery for Assessment of Neuropsychological Status (RBANS).

Results: A total of 44% (2259 of 5153) used either a potential or definite anticholinergic medication. Overall, 9.7% (n = 500) used a definite anticholinergic medication. Regular benzodiazepine use was reported by 7% (n = 363), whilst 7.5% (n = 387) used a "Z-drug". Use of definite, but not potential anticholinergic medication was associated with poorer performance on all three assessments (β: -0.09; 95% CI: -0.14, -0.03, p = 0.002 for MMSE; β: -0.04; 95% CI: -0.06, -0.02; p < 0.001 for FAB; β: -4.15; 95% CI: -5.64, -2.66; p < 0.001 for RBANS) in addition to all domains of the RBANS. Regular benzodiazepine use was also associated with poorer neuropsychological test performance, especially in Immediate Memory (β: -4.98; 95% CI: -6.81, -3.15; p < 0.001) and Attention (β: -6.81; 95% CI: -8.60, -5.03; p < 0.001) RBANS domains.

Conclusions: Regular use of definite anticholinergic medications and benzodiazepines, but not potential anticholinergics or "Z-drugs", was associated with poorer overall and domain-specific neuropsychological performance in older adults.
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http://dx.doi.org/10.1002/gps.5598DOI Listing
July 2021

Ingestion of Nitrate and Nitrite and Risk of Stomach and Other Digestive System Cancers in the Iowa Women's Health Study.

Int J Environ Res Public Health 2021 06 25;18(13). Epub 2021 Jun 25.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.

Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC) which are potent animal carcinogens for the organs of the digestive system. We evaluated dietary intakes of nitrate and nitrite, as well as nitrate ingestion from drinking water (public drinking water supplies (PWS)), in relation to the incidence (1986-2014) of cancers of the esophagus (n = 36), stomach (n = 84), small intestine (n = 32), liver (n = 31), gallbladder (n = 66), and bile duct (n = 58) in the Iowa Women's Health Study (42,000 women aged from 50 to 75 in 1986). Dietary nitrate and nitrite were estimated using a food frequency questionnaire and a database of nitrate and nitrite levels in foods. Historical nitrate measurements from PWS were linked to the enrollment address by duration. We used Cox regression to compute hazard ratios (HR) and 95% confidence intervals (CI) for exposure quartiles (Q), tertiles (T), or medians, depending on the number of cancer cases. In adjusted models, nitrite intake from processed meats was associated with an increased risk of stomach cancer (HR = 2.2, CI: 1.2-4.3). A high intake of total dietary nitrite was inversely associated with gallbladder cancer (HR = 0.3, CI: 0.1-0.96), driven by an inverse association with plant sources of nitrite (HR = 0.3, CI: 0.1-0.9). Additionally, small intestine cancer was inversely associated with a high intake of animal nitrite (HR = 0.2, CI: 0.1-0.7). There were no other dietary associations. Nitrate concentrations in PWS (average, years ≥ 1/2 the maximum contaminant level) were not associated with cancer incidence. Our findings for stomach cancer are consistent with prior dietary studies, and we are the first to evaluate nitrate and nitrite ingestion for certain gastrointestinal cancers.
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http://dx.doi.org/10.3390/ijerph18136822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297261PMC
June 2021

Residential exposure to carbamate, organophosphate, and pyrethroid insecticides in house dust and risk of childhood acute lymphoblastic leukemia.

Environ Res 2021 Jun 15;201:111501. Epub 2021 Jun 15.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 9609 Medical Center Dr., Rockville, MD, 20850, USA.

Background: Self-reported residential use of pesticides has consistently been associated with increased risk of childhood leukemia. However, these studies were limited in their ability to identify specific insecticide active ingredients that were associated with risk.

Objective: We used household carpet dust measurements of 20 insecticides (two carbamate, 10 organophosphate, two organochlorine, and six pyrethroid) as indicators of exposure and evaluated associations with the risk of childhood acute lymphoblastic leukemia (ALL).

Methods: We conducted a population-based case-control study of 252 ALL cases diagnosed from 1999 to 2007 and 306 birth certificate controls from 35 counties in Central and Northern California. Carpet dust was collected at a second interview (2001-2007) for cases who had not moved since diagnosis (comparable reference date for controls) using a specialized vacuum cleaner in the room where the child spent most of their time or from the household vacuum. Insecticides were categorized as detected (yes/no), or as tertiles or quartiles of their distributions among controls. We calculated odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression adjusting for demographic characteristics, interview year, and season of dust collection.

Results: Permethrin, chlorpyrifos, diazinon, and carbaryl were the most frequently detected insecticide active ingredients. When we compared the highest quartile to the lowest or to non-detections, there was no association with ALL for permethrin (OR Q4 vs. Q1 = 0.81; 95% CI 0.50-1.31), carbaryl (OR Q4 vs. non-detects = 0.61, 95% CI 0.34-1.08) or chlorpyrifos (OR Q4 vs. Q1 = 0.60; 95% CI 0.36-1.00). The highest quartile of diazinon concentration was inversely associated with risk in the single pesticide model but without a monotonic exposure-response (p-trend = 0.14). After adjusting for other common insecticides, the OR was not significant (OR Q4 vs. Q1 = 0.58; 95% CI 0.33-1.05). None of the other insecticides were associated with risk.

Conclusion: Our results should be interpreted within the limitations of the case-control study design including the use of a single post-diagnosis dust sample and restriction to residentially stable participants, which may have resulted in selection bias. Although difficult to implement, additional studies with assessment of exposure to insecticide active and non-active ingredients are necessary to elucidate the role of these common exposures in childhood leukemia risk.
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http://dx.doi.org/10.1016/j.envres.2021.111501DOI Listing
June 2021

Associations of atrophic gastritis and proton-pump inhibitor drug use with vitamin B-12 status, and the impact of fortified foods, in older adults.

Am J Clin Nutr 2021 Jun 16. Epub 2021 Jun 16.

Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom.

Background: Atrophic gastritis (AG) and use of proton pump inhibitors (PPIs) result in gastric acid suppression that can impair the absorption of vitamin B-12 from foods. The crystalline vitamin B-12 form, found in fortified foods, does not require gastric acid for its absorption and could thus be beneficial for older adults with hypochlorhydria, but evidence is lacking.

Objectives: To investigate associations of AG and PPI use with vitamin B-12 status, and the potential protective role of fortified foods, in older adults.

Methods: Eligible participants (n = 3299) not using vitamin B-12 supplements were drawn from the Trinity-Ulster and Department of Agriculture cohort, a study of noninstitutionalized adults aged ≥60 y and recruited in 2008-2012. Vitamin B-12 status was measured using 4 biomarkers, and vitamin B-12 deficiency was defined as a combined indicator value < -0.5. A pepsinogen I:II ratio <3 was considered indicative of AG.

Results: AG was identified in 15% of participants and associated with significantly lower serum total vitamin B-12 (P < 0.001) and plasma holotranscobalamin (holoTC; P < 0.001), and higher prevalence of vitamin B-12 deficiency (38%), compared with PPI users (21%) and controls (without AG and nonusers of PPIs; 15%; P < 0.001). PPI drugs were used (≥6 mo) by 37% of participants and were associated with lower holoTC concentrations, but only in participants taking higher doses (≥30 mg/d). Regular, compared with nonregular, consumption of fortified foods (i.e., ≥5 and 0-4 portions/wk, respectively) was associated with higher vitamin B-12 biomarkers in all participants, but inadequate to restore normal vitamin B-12 status in those with AG.

Conclusions: Older adults who have AG and/or use higher doses of PPIs are more likely to have indicators of vitamin B-12 deficiency. Fortified foods, if consumed regularly, were associated with enhanced vitamin B-12 status, but higher levels of added vitamin B-12 than currently provided could be warranted to optimize status in people with AG.
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http://dx.doi.org/10.1093/ajcn/nqab193DOI Listing
June 2021

Does Parenting Style Affect Adolescent IBD Transition Readiness and Self-Efficacy Scores?

Children (Basel) 2021 May 4;8(5). Epub 2021 May 4.

Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Background: Transition to adult-centered care requires adolescents with inflammatory bowel disease (IBD) to acquire a set of independent self-management skills. Transition success can be affected by maturity, cognitive development, and many other factors. Our hypothesis was that parenting style would be associated with increased self-efficacy and therefore transitions readiness.

Methods: A prospective cohort survey study of adolescents with IBD and their parents from October 2018 to October 2019 was performed. Participants completed the IBD-Self-Efficacy Scale- Adolescent questionnaire (IBD-SES-A) and the Transition Readiness Assessment Questionnaire (TRAQ). Parents completed the Parent Styles and Dimensions Questionnaire (PSDQ-short form). Demographic and disease information were also collected.

Results: Sixty-nine participants were included for full analysis (36 males and 33 females); mean age was 18.2 years, and average age of IBD diagnosis 13 years. Overall, 83% of participants were non-Hispanic Caucasian, and 84% reported parental annual income over USD 100,000. All 69 parents reported an authoritative parenting style. Females have significantly higher TRAQ scores than males ( = 0.0004). TRAQ scores differed significantly between age groups, with 20 to 22 years old having higher scores ( ≤ 0.0001). TRAQ and IBD-SES-A scores did not differ by parental education or parenting style.

Conclusion: Given the inability to delineate different parenting, this study was unable to demonstrate a protective parenting style associated with better transitions readiness and self-efficacy scores in adolescents with IBD. Within the context of authoritative parenting, we did find that females and older adolescents had higher transition readiness scores. Additional research into psychosocial determinants of transition readiness, and the importance of multidisciplinary management with an integrated team including psychologist and social workers, can help improve IBD transition outcomes.
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http://dx.doi.org/10.3390/children8050367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147961PMC
May 2021

Simulation-Based Discharge Education Program for Caregivers of Children With Tracheostomies.

Hosp Pediatr 2021 Jun 12;11(6):571-578. Epub 2021 May 12.

Department of Pediatrics, Weill Cornell Medicine and.

Objectives: To design, implement, and evaluate a simulation-based education (SBE) program for caregivers of children with tracheostomy.

Methods: Self-reported comfort and confidence in knowledge as well as tracheostomy care skills were assessed before and after a single SBE session for 24 consecutively enrolled caregivers of children with tracheostomies aged <21 years who were hospitalized at an academic medical center from August 2018 to September 2019 by using a survey and checklist, respectively. Mean individual and aggregated scores were compared by using a paired samples t-test, and association between instruments was determined with Spearman correlation.

Results: Post-SBE, there was a significant improvement in both self-reported comfort and confidence ( < .001) and checklist assessment of most tracheostomy care skills ( < .001). There were no significant correlations between caregivers' self-reported comfort and confidence and skills pre-SBE (ρ = 0.13) or post-SBE (ρ = 0.14). Cronbach's α coefficients for the survey ranged from 0.93 to 0.95 and for the checklist from 0.58 to 0.67. Seventeen percent of caregivers competently completed the entire checklist post-SBE, with most caregivers missing 1 or 2 critical skills such as obturator removal after tracheostomy insertion.

Conclusions: In this pilot study, we demonstrated successful design and implementation of an SBE program for caregivers of children with tracheostomies, revealing improvements in self-reported comfort and confidence as well as in their performance of tracheostomy care skills. Further optimization is needed, and caregivers may benefit from additional SBE sessions to achieve complete skills competency. Future research on the long-term impact of SBE and the peer-to-peer support element of the program is needed.
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http://dx.doi.org/10.1542/hpeds.2020-000984DOI Listing
June 2021

Exposure to nitrate from drinking water and the risk of childhood cancer in Denmark.

Environ Int 2021 10 6;155:106613. Epub 2021 May 6.

Department of Public Health, Aarhus University, Aarhus, Denmark.

Background: There is limited evidence that nitrate, a common contaminant in drinking water, increases the risk of childhood cancers. Our objective was to examine this association in Denmark.

Methods: We conducted a nationwide case-control study based on all singletons liveborn to Danish-born parents from 1991 to 2015 (N = 1,219,140) that included 596 leukemias, 180 lymphomas, and 310 central nervous system cancers (CNC) who were ≤15 years of age at diagnosis and were identified from the Danish Cancer Registry. Approximately 100 controls were randomly selected and matched to each case on date of birth and sex. Nitrate measurements in public water systems were linked with an address registry to estimate individual average nitrate concentrations during preconception, prenatal, and postnatal periods. Odd ratios (OR) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression controlling for the matching variables, and birth order, birthweight, urbanicity, maternal education, employment, income and smoking, and parental age.

Results: There was no evidence of an association of nitrate with leukemia or lymphoma. An association between CNC and the highest category of nitrate exposure (>25 mg/L nitrate) was observed for preconception (OR = 1.82, 95%CI:1.09 to 3.04), prenatal (OR = 1.65, 95%CI:0.97 to 2.81), and postnatal exposure (OR = 1.48, 95%CI:0.82 to 2.68) in fully adjusted models. There was also some evidence of an exposure-response in models of continuous nitrate exposure and CNC.

Conclusions: Our findings provide some evidence that exposure to nitrate from drinking water may increase the risk of childhood CNC cancer, but not leukemia or lymphoma.
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http://dx.doi.org/10.1016/j.envint.2021.106613DOI Listing
October 2021

Bayesian Group Index Regression for Modeling Chemical Mixtures and Cancer Risk.

Int J Environ Res Public Health 2021 03 27;18(7). Epub 2021 Mar 27.

UC Berkeley School of Public Health, University of California, Berkeley, CA 94704-7394, USA.

There has been a growing interest in the literature on multiple environmental risk factors for diseases and an increasing emphasis on assessing multiple environmental exposures simultaneously in epidemiologic studies of cancer. One method used to analyze exposure to multiple chemical exposures is weighted quantile sum (WQS) regression. While WQS regression has been demonstrated to have good sensitivity and specificity when identifying important exposures, it has limitations including a two-step model fitting process that decreases power and model stability and a requirement that all exposures in the weighted index have associations in the same direction with the outcome, which is not realistic when chemicals in different classes have different directions and magnitude of association with a health outcome. Grouped WQS (GWQS) was proposed to allow for multiple groups of chemicals in the model where different magnitude and direction of associations are possible for each group. However, GWQS shares the limitation of WQS of a two-step estimation process and splitting of data into training and validation sets. In this paper, we propose a Bayesian group index model to avoid the estimation limitation of GWQS while having multiple exposure indices in the model. To evaluate the performance of the Bayesian group index model, we conducted a simulation study with several different exposure scenarios. We also applied the Bayesian group index method to analyze childhood leukemia risk in the California Childhood Leukemia Study (CCLS). The results showed that the Bayesian group index model had slightly better power for exposure effects and specificity and sensitivity in identifying important chemical exposure components compared with the existing frequentist method, particularly for small sample sizes. In the application to the CCLS, we found a significant negative association for insecticides, with the most important chemical being carbaryl. In addition, for children who were born and raised in the home where dust samples were taken, there was a significant positive association for herbicides with dacthal being the most important exposure. In conclusion, our approach of the Bayesian group index model appears able to make a substantial contribution to the field of environmental epidemiology.
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http://dx.doi.org/10.3390/ijerph18073486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037139PMC
March 2021

Effects of processed meat and drinking water nitrate on oral and fecal microbial populations in a controlled feeding study.

Environ Res 2021 06 27;197:111084. Epub 2021 Mar 27.

Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: One mechanism that can explain the link between processed meat consumption and colorectal cancer (CRC) is the production of carcinogenic N-nitroso compounds (NOCs) in the gastrointestinal tract. Oral and gut microbes metabolize ingested proteins (a source of secondary and tertiary amines and amides) and can reduce nitrate to nitrite, generating potentially carcinogenic NOCs.

Objective: We evaluated whether nitrate/nitrite in processed meat or water influences the fecal or salivary microbiota.

Design: In this dietary intervention study, 63 volunteers consumed diets high in conventional processed meats for two weeks, switched to diets high in poultry for two weeks, and then consumed phytochemical-enriched conventional processed or low-nitrite processed meat diets for two weeks. During the intervention, they drank water with low nitrate concentrations and consumed a healthy diet with low antioxidants. Then the volunteers drank nitrate-enriched water for 1 week, in combination with one of the four different diets. We measured creatinine-adjusted urinary nitrate levels and characterized the oral and fecal microbiota using 16S rRNA amplicon sequencing.

Results: Using linear mixed models, we found that, compared to baseline, urinary nitrate levels were reduced during the phytochemical-enriched low-nitrite meat diet (p-value = 0.009) and modestly during the poultry diet (p-value = 0.048). In contrast, urinary nitrate increased after 1-week of drinking nitrate-enriched water (p-value<10). Nitrate-enriched water, but not processed meats with or without phytochemicals, altered the saliva microbial population (p-value ≤0.001), and significantly increased abundance of 8 bacterial taxa, especially genus Neisseria and other nitrate-reducing taxa. Meats, phytochemicals and nitrate-enriched water had no significant effects on saliva alpha diversity or any diversity parameter measured for the fecal microbiota.

Conclusion: These findings support the hypothesis that drinking high nitrate water increases oral nitrate-reducing bacteria, which likely results in increased NOC. However, meat nitrate/nitrite at the levels tested had no effect on either the gut or oral bacteria. CLINICALTRIALS.

Gov Identifier: NCT04138654.
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http://dx.doi.org/10.1016/j.envres.2021.111084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388086PMC
June 2021

New insights into modeling exposure measurements below the limit of detection.

Environ Epidemiol 2021 Feb 16;5(1):e116. Epub 2020 Dec 16.

Biostatistics Branch, Division Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.

In environmental epidemiology, it is of interest to assess the health effects of environmental exposures. Some exposure analytes present values that are below the laboratory limit of detection (LOD). There have been many methods proposed for handling this issue to incorporate exposures subject to LOD in risk modeling using logistic regression. We present a fresh look at proposed methods to handle exposure analytes that present values that are below the LOD.

Methods: We performed comparisons through an extensive simulation study and a cancer epidemiology example. The methods we considered were a maximum-likelihood approach, multiple imputation, Cox regression, complete case analysis, filling in values below the LOD with , and a missing indicator method.

Results: We found that the logistic regression coefficient associated with the exposure (subject to LOD) can be severely biased when underlying assumptions are not met, even with a relatively small proportion (under 20%) of measurements below the LOD.

Conclusions: We propose the use of a simple method where the relationship between the analyte and disease risk is modeled only above the detection limit with an intercept term at the LOD and a slope parameter, which makes no assumptions about what happens below the LOD. In most practical situations, our results suggest that this simple method may be the best choice for analyzing analytes with detection limits.
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http://dx.doi.org/10.1097/EE9.0000000000000116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939440PMC
February 2021

Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial.

BMC Med 2021 Mar 10;19(1):73. Epub 2021 Mar 10.

Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, BT52 1SA, Northern Ireland, UK.

Background: Maternal folic acid (FA) supplementation before and in early pregnancy prevents neural tube defects (NTD), but it is uncertain whether continuing FA after the first trimester has benefits on offspring health. We aimed to evaluate the effect of FA supplementation throughout pregnancy on cognitive performance and brain function in the child.

Methods: Follow-up investigation of 11-year-old children, residing in Northern Ireland, whose mothers had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) in pregnancy and received 400 μg/day FA or placebo from the 14th gestational week. Cognitive performance (Full Scale Intelligence Quotient, Verbal Comprehension, Working Memory, Perceptual Reasoning, and Processing Speed) was assessed using the Wechsler Intelligence Scale for Children. Neuronal function was assessed using magnetoencephalographic (MEG) brain imaging.

Results: Of 119 mother-child pairs in the FASSTT trial, 68 children were assessed for neurocognitive performance at 11-year follow-up (Dec 2017 to Nov 2018). Children of mothers randomised to FA compared with placebo scored significantly higher in two Processing Speed tests, i.e. symbol search (mean difference 2.9 points, 95% CI 0.3 to 5.5, p = 0.03) and cancellation (11.3 points, 2.5 to 20.1, p = 0.04), whereas the positive effect on Verbal Comprehension was significant in girls only (6.5 points, 1.2 to 11.8, p = 0.03). MEG assessment of neuronal responses to a language task showed increased power at the Beta (13-30 Hz, p = 0.01) and High Gamma (49-70 Hz, p = 0.04) bands in children from FA-supplemented mothers, suggesting more efficient semantic processing of language.

Conclusions: Continued FA supplementation in pregnancy beyond the early period currently recommended to prevent NTD can benefit neurocognitive development of the child. MEG provides a non-invasive tool in paediatric research to objectively assess functional brain activity in response to nutrition and other interventions.

Trial Registration: ISRCTN ISRCTN19917787 . Registered on 15 May 2013.
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http://dx.doi.org/10.1186/s12916-021-01914-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945668PMC
March 2021

Evaluation of a commercial database to estimate residence histories in the los angeles ultrafines study.

Environ Res 2021 06 6;197:110986. Epub 2021 Mar 6.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Background: Commercial databases can be used to identify participant addresses over time, but their quality and impact on environmental exposure assessment is uncertain.

Objective: To evaluate the performance of a commercial database to find residences and estimate environmental exposures for study participants.

Methods: We searched LexisNexis® for participant addresses in the Los Angeles Ultrafines Study, a prospective cohort of men and women aged 50-71 years. At enrollment (1995-1996) and follow-up (2004-2005), we evaluated attainment (address found for the corresponding time period) and match rates to survey addresses by participant characteristics. We compared geographically-referenced predictors and estimates of ultrafine particulate matter (UFP) exposure from a land use regression model using LexisNexis and survey addresses at enrollment.

Results: LexisNexis identified an address for 69% of participants at enrollment (N = 50,320) and 95% of participants at follow-up (N = 24,432). Attainment rate at enrollment modestly differed (≥5%) by age, smoking status, education, and residential mobility between surveys. The match rate at both survey periods was high (82-86%) and similar across characteristics. When using LexisNexis versus survey addresses, correlations were high for continuous values of UFP exposure and its predictors (rho = 0.86-0.92).

Significance: Time period and population characteristics influenced the attainment of addresses from a commercial database, but accuracy and subsequent estimation of specific air pollution exposures were high in our older study population.
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http://dx.doi.org/10.1016/j.envres.2021.110986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187285PMC
June 2021

Vitamin D and Hospital Admission in Older Adults: A Prospective Association.

Nutrients 2021 Feb 14;13(2). Epub 2021 Feb 14.

Department of Gerontology, St James's Hospital, D08 NYH1 Dublin, Ireland.

The health effects of vitamin D are well documented, with increasing evidence of its roles beyond bone. There is, however, little evidence of the effects of vitamin D on hospitalisation among older adults. This study aimed to prospectively determine the relationship of vitamin D status in older adults with hospital admission and emergency department (ED) attendance. Trinity University of Ulster Department of Agriculture (TUDA) is a large cross-sectional study of older adults with a community population from three disease-defined cohorts (cognitive dysfunction, hypertension, and osteoporosis). Participants included in this analysis were recruited between 2008 and 2012. ED and hospital admission data were gathered from the date of TUDA participation until June 2013, with a mean follow up of 3.6 years. Of the 3093 participants, 1577 (50.9%) attended the ED during the period of follow-up. Attendees had lower mean serum 25(OH)D concentrations than non-attendees (59.1 vs. 70.6 nmol/L). Fully adjusted models showed an inverse association between vitamin D and ED attendance (Hazard Ratio (HR) 0.996; 95% Confidence Interval (CI) 0.995-0.998; < 0.001). A total of 1269 participants (41%) were admitted to hospital during the follow-up. Those admitted had lower mean vitamin D concentrations (58.4 vs. 69.3 nmol/L, < 0.001). In fully adjusted models, higher vitamin D was inversely associated with hospital admission (HR 0.996; 95% CI 0.994-0.998; < 0.001) and length of stay (LOS) (β = -0.95, = 0.006). This study showed independent prospective associations between vitamin D deficiency and increased hospitalisation by older adults. The need for further evaluation of current recommendations in relation to vitamin D supplementation, with consideration beyond bone health, is warranted and should focus on randomised controlled trials.
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http://dx.doi.org/10.3390/nu13020616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918803PMC
February 2021

Spatial Heterogeneity in Positional Errors: A Comparison of Two Residential Geocoding Efforts in the Agricultural Health Study.

Int J Environ Res Public Health 2021 02 9;18(4). Epub 2021 Feb 9.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Geocoding is a powerful tool for environmental exposure assessments that rely on spatial databases. Geocoding processes, locators, and reference datasets have improved over time; however, improvements have not been well-characterized. Enrollment addresses for the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa (IA) and North Carolina (NC), were geocoded in 2012-2016 and then again in 2019. We calculated distances between geocodes in the two periods. For a subset, we computed positional errors using "gold standard" rooftop coordinates (IA; N = 3566) or Global Positioning Systems (GPS) (IA and NC; N = 1258) and compared errors between periods. We used linear regression to model the change in positional error between time periods (improvement) by rural status and population density, and we used spatial relative risk functions to identify areas with significant improvement. Median improvement between time periods in IA was 41 m (interquartile range, IQR: -2 to 168) and 9 m (IQR: -80 to 133) based on rooftop coordinates and GPS, respectively. Median improvement in NC was 42 m (IQR: -1 to 109 m) based on GPS. Positional error was greater in rural and low-density areas compared to in towns and more densely populated areas. Areas of significant improvement in accuracy were identified and mapped across both states. Our findings underscore the importance of evaluating determinants and spatial distributions of errors in geocodes used in environmental epidemiology studies.
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http://dx.doi.org/10.3390/ijerph18041637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915413PMC
February 2021

Assessment of Grouped Weighted Quantile Sum Regression for Modeling Chemical Mixtures and Cancer Risk.

Int J Environ Res Public Health 2021 01 9;18(2). Epub 2021 Jan 9.

Division of Epidemiology/Biostatistics, University of California, Berkeley School of Public Health, Berkeley, CA 94704-7394, USA.

Individuals are exposed to a large number of diverse environmental chemicals simultaneously and the evaluation of multiple chemical exposures is important for identifying cancer risk factors. The measurement of a large number of chemicals (the exposome) in epidemiologic studies is allowing for a more comprehensive assessment of cancer risk factors than was done in earlier studies that focused on only a few chemicals. Empirical evidence from epidemiologic studies shows that chemicals from different chemical classes have different magnitudes and directions of association with cancers. Given increasing data availability, there is a need for the development and assessment of statistical methods to model environmental cancer risk that considers a large number of diverse chemicals with different effects for different chemical classes. The method of grouped weighted quantile sum (GWQS) regression allows for multiple groups of chemicals to be considered in the model such that different magnitudes and directions of associations are possible for each group of chemicals. In this paper, we assessed the ability of GWQS regression to estimate exposure effects for multiple chemical groups and correctly identify important chemicals in each group using a simulation study. We compared the performance of GWQS regression with WQS regression, the least absolute shrinkage and selection operator (lasso), and the group lasso in estimating exposure effects and identifying important chemicals. The simulation study results demonstrate that GWQS is an effective method for modeling exposure to multiple groups of chemicals and compares favorably with other methods used in mixture analysis. As an application, we used GWQS regression in the California Childhood Leukemia Study (CCLS), a population-based case-control study of childhood leukemia in California to estimate exposure effects for many chemical classes while also adjusting for demographic factors. The CCLS analysis found evidence of a positive association between exposure to the herbicide dacthal and an increased risk of childhood leukemia.
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http://dx.doi.org/10.3390/ijerph18020504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827322PMC
January 2021

An Experimental Simulation of Heat Effects on Cognition and Workload of Surgical Team Members.

Ann Surg 2020 Nov 13. Epub 2020 Nov 13.

Curtin University, Perth, Australia, Faculty of Business and Law, Future of Work Institute.

Objective: To isolate heat exposure as a cause of cognitive impairment and increased subjective workload in burns surgical teams.

Summary Background Data: Raising ambient temperature of the operating room can improve burns patient outcomes, but risks increased cognitive impairment and workload of surgical team members. Prior research indicates ambient heat exposure depletes physiological and cognitive resources, but these findings have not been studied in the context of burns surgical teams.

Methods: Seventeen surgical team members completed two surgery simulations of similar complexities in a hot and in a normothermic operating room. During each simulation, participants completed multiple cognitive tests to assess cognitive functioning and the SURG-TLX to self-assess workload. Order effects, core body temperature changes due to menstruation, and circadian rhythms were controlled for in the experimental design. Descriptive statistics, correlations, and mixed ANOVAs were performed to assess relationships between ambient heat exposure with cognitive functioning and perceived workload.

Results: Heat had a main effect on executive functioning and verbal reasoning. Duration of heat exposure (heat*time) increased response times and negatively impacted executive functioning, spatial planning and mental rotation. Perceived workload was higher in the hot condition.

Conclusions: We provide causal evidence that over time, heat exposure impairs cognitive speed and accuracy, and increases subjective workload. We recommend building on this study to drive best-practices for acute burns surgery and design work to enable burns teams to maintain their cognitive stamina, lower their workload, and improve outcomes for patients and surgeons.
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http://dx.doi.org/10.1097/SLA.0000000000004598DOI Listing
November 2020

Impact of the common MTHFR 677C→T polymorphism on blood pressure in adulthood and role of riboflavin in modifying the genetic risk of hypertension: evidence from the JINGO project.

BMC Med 2020 11 11;18(1):318. Epub 2020 Nov 11.

The Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK.

Background: Genome-wide and clinical studies have linked the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension.

Methods: Observational data on 6076 adults of 18-102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008-2012 using standardised methods.

Results: The variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34-6.68; P = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes (P < 0.027).

Conclusions: The MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.
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http://dx.doi.org/10.1186/s12916-020-01780-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656675PMC
November 2020

Impact of residential mobility on estimated environmental exposures in a prospective cohort of older women.

Environ Epidemiol 2020 Oct 24;4(5):e110. Epub 2020 Aug 24.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Longitudinal studies of environmental hazards often rely on exposure estimated at the participant's enrollment residence. This could lead to exposure misclassification if participants move over time.

Methods: We evaluated residential mobility in the Iowa Women's Health Study (age 55-69 years) over 19 years of follow-up (1986-2004). We assessed several environmental exposures of varying spatial scales at enrollment and follow-up addresses. Exposures included average nitrate concentrations in public water supplies, percent of agricultural land (row crops and pasture/hay) within 750 m, and the presence of concentrated animal feeding operations within 5 km. In comparison to gold standard duration-based exposures averaged across all residences, we evaluated the sensitivity and specificity of exposure metrics and attenuation bias for a hypothetical nested case-control study of cancer, which assumed participants did not move from their enrollment residence.

Results: Among 41,650 participants, 32% moved at least once during follow-up. Mobility was predicted by working outside the home, being a former/current smoker, having a higher education level, using a public drinking water supply, and town size of previous residence. Compared with duration-based exposures, the sensitivity and specificity of exposures at enrollment ranged from 94% to 99% and 97% to 99%, respectively. A hypothetical true odds ratio of 2.0 was attenuated 8% for nitrate, 9%-10% for agricultural land, and 6% for concentrated animal feeding operation exposures.

Conclusions: Overall, we found low rates of mobility and mobility-related exposure misclassification in the Iowa Women's Health Study. Misclassification and attenuation of hypothetical risk estimates differed by spatial variability and exposure prevalence.
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http://dx.doi.org/10.1097/EE9.0000000000000110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595244PMC
October 2020

Pesticide exposure and incident thyroid cancer among male pesticide applicators in agricultural health study.

Environ Int 2021 01 27;146:106187. Epub 2020 Oct 27.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Many pesticides are known to have thyroid-disrupting properties. However, few studies have evaluated the association between specific pesticide ingredients and risk of thyroid cancer. We investigated self-reported pesticide use and incident thyroid cancer in the Agricultural Health Study (AHS), a large cohort of occupationally-exposed male pesticide applicators.

Methods: The AHS is a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. At enrollment (1993-1997) and follow-up (1999-2005), participants reported use of 50 pesticides. We characterized exposure as ever use (44 pesticides with ≥5 exposed cases) and by cumulative intensity-weighted lifetime days (22 pesticides with ≥10 exposed cases), a metric that accounts for factors that influence exposure. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression for incident thyroid (n = 85 cases) cancer among male participants using follow-up through 2014/2015.

Results: Use of the fungicide metalaxyl (HR = 2.03, CI:1.16-3.52) and the organochlorine insecticide lindane (HR = 1.74, CI:1.06-2.84) was associated with increased risk of thyroid cancer. The herbicide chlorimuron-ethyl was inversely associated with risk when we restricted to papillary thyroid cancer, the most common subtype (HR = 0.52, CI:0.28-0.96). High use of the insecticide carbaryl (>median intensity-weighted days) was inversely associated with thyroid cancer (HR = 0.20, CI:0.08-0.53, p = 0.001).

Conclusions: In this large cohort study, we observed increased risk of thyroid cancer associated with use of metalaxyl and lindane, and an inverse association with carbaryl. More work is needed to understand the potential role of these chemicals in thyroid carcinogenesis.
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http://dx.doi.org/10.1016/j.envint.2020.106187DOI Listing
January 2021

Polyphenol Intake and Gastric Cancer Risk: Findings from the Stomach Cancer Pooling Project (StoP).

Cancers (Basel) 2020 Oct 20;12(10). Epub 2020 Oct 20.

Research Group in Gene-Environment Interactions and Health, Instituto de Biomedicina (IBIOMED), University of León, 24071 León, Spain.

Phenolic compounds may exert a favorable effect on the risk of several cancer types, including gastric cancer (GC). However, selected polyphenol classes have not been adequately investigated in relation to GC. The aim of this study is to evaluate the association between the intake of polyphenols in relation to GC risk. We used data from the Stomach cancer Pooling (StoP) Project, including 10 studies from six countries (3471 GC cases and 8344 controls). We carried out an individual participant data pooled analysis using a two-stage approach. The summary odds ratios (ORs) of GC for each compound, and the corresponding 95% confidence intervals (95% CI), were computed by pooling study specific ORs obtained through multivariate logistic regression, using random effect models. Inverse associations with GC emerged for total polyphenols (OR = 0.67, 95% CI = 0.54-0.81, for the highest versus lowest quartile of intake), total flavonoids (OR = 0.73, 95% CI = 0.55-0.90), anthocyanidins (OR = 0.74, 95% CI = 0.56-0.92), flavanols (OR = 0.77, 95% CI = 0.66-0.88), flavanones (OR = 0.57, 95%CI = 0.44-0.69), total phenolic acids (OR = 0.75, 95%CI = 0.55-0.94), and hydroxybenzoic acids (OR = 0.73, 95%CI = 0.57-0.89). Results were consistent across strata of age, sex, social class, and smoking habit. Suggestive inverse associations were also found for flavonols (OR = 0.76, 95%CI = 0.51-1.01) and hydroxycinnamic acids (OR = 0.82, 95%CI = 0.58-1.06). Further investigations from longitudinal data are needed to confirm this association.
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http://dx.doi.org/10.3390/cancers12103064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588964PMC
October 2020

DNA methylation of hypertension-related genes and effect of riboflavin supplementation in adults stratified by genotype for the MTHFR C677T polymorphism.

Int J Cardiol 2021 01 10;322:233-239. Epub 2020 Sep 10.

Genomic Medicine Research Group, Ulster University, Coleraine BT52 1SA, N. Ireland, UK. Electronic address:

Background: The interaction between genetic, epigenetic and environmental factors plays an important role in the aetiology of hypertension. GWAS and observational studies link the C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) with hypertension, while riboflavin, the MTHFR cofactor, has been shown to reduce blood pressure and global DNA methylation in homozygous (TT genotype) individuals. It is currently unclear whether riboflavin modulates DNA methylation of other hypertension-related genes.

Objectives: To compare DNA methylation of hypertension-related genes in adults stratified by MTHFR genotype and effect of riboflavin intervention in adults with the variant MTHFR 677TT genotype.

Method: Pyrosequencing was carried out for hypertension-related genes (ACE, AGTR1, GCK, GNA12, IGF2, MMP9 and NOS3) in blood samples from participants in previous trials (CC, n = 40; TT, n = 40). The effect of intervention with riboflavin (1.6 mg/d for16 weeks) or placebo on DNA methylation was investigated in adults with the variant MTHFR 677TT genotype (n = 80).

Results: Individuals with the MTHFR 677TT v CC genotype had significantly higher average DNA methylation at NOS3 (+1.66%, P = 0.044). In response to riboflavin supplementation in TT individuals, there was an increase in average DNA methylation at IGF2 (+1.09%, P = 0.019) and a decrease at ACE (-0.44%, P = 0.021) in females only. Specific CpG sites were hypomethylated in GNA12 and hypermethylated in AGTR1.

Conclusion: This study provides the first RCT evidence that riboflavin alters DNA methylation of hypertension-related genes in adults with the MTHFR 677TT genotype, providing some insight into mechanisms linking hypertension with the genotype-specific response of BP to riboflavin.
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http://dx.doi.org/10.1016/j.ijcard.2020.09.011DOI Listing
January 2021

Riboflavin Is an Important Determinant of Vitamin B-6 Status in Healthy Adults.

J Nutr 2020 10;150(10):2699-2706

Nutrition Innovation Centre for food and Health (NICHE), Ulster University, Coleraine, United Kingdom.

Background: Riboflavin is required to generate the active form of vitamin B-6 (pyridoxal 5'-phosphate; PLP) in tissues, but the relevance of this metabolic interaction for nutritional status of vitamin B-6 is unclear because riboflavin biomarkers are rarely measured in human studies.

Objectives: The purpose of this study was to identify the determinants of biomarkers of vitamin B-6 and riboflavin status and to examine the relationship between these nutrients in healthy adults.

Methods: Multiple linear regression was performed on observational data in 407 healthy adults aged 18-92 y who did not use B-vitamin supplements. Vitamin B-6 status was assessed by plasma PLP concentrations and erythrocyte glutathione reductase activation coefficient (EGRac) was used as a functional indicator of riboflavin status.

Results: Dietary intakes of vitamin B-6 and riboflavin were below the average requirements in 10% and 29% of participants, respectively. Suboptimal status of vitamin B-6 (PLP ≤30.0 nmol/L) was more prevalent in adults aged ≥60 y than in younger participants (i.e., 14% compared with 5%), whereas a high proportion (i.e., overall 37%) of both age groups had deficient riboflavin status (EGRac ≥1.40). In multiple regression analysis, EGRac (P = 0.019) was a significant determinant of plasma PLP, along with dietary vitamin B-6 intake (P = 0.003), age (P < 0.001), BMI (kg/m2) (P = 0.031), and methylenetetrahydrofolate reductase gene (MTHFR) genotype (P < 0.001). Significant determinants of EGRac were dietary riboflavin intake (P < 0.001), age (P < 0.001) and MTHFR genotype (P = 0.020). Plasma PLP showed a stepwise decrease across riboflavin status categories from optimal (EGRac ≤1.26) to low (EGRac 1.27-1.39) to deficient status (P = 0.001), independent of dietary vitamin B-6 intake.

Conclusions: The findings are consistent with the known metabolic dependency of vitamin B-6 on riboflavin status and indicate that riboflavin may be the limiting nutrient, particularly in older people, for maintaining adequate vitamin B-6 status.
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http://dx.doi.org/10.1093/jn/nxaa225DOI Listing
October 2020

Residential proximity to agriculture and risk of childhood leukemia and central nervous system tumors in the Danish national birth cohort.

Environ Int 2020 10 22;143:105955. Epub 2020 Jul 22.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr., Rockville, MD 20850, USA. Electronic address:

Background: Living in an agricultural area or on farms has been associated with increased risk of childhood cancer but few studies have evaluated specific agricultural exposures. We prospectively examined residential proximity to crops and animals during pregnancy and risk of childhood leukemia and central nervous system (CNS) tumors in Denmark.

Methods: The Danish National Birth Cohort (DNBC) consists of 91,769 pregnant women (96,841 live-born children) enrolled in 1996-2003. For 61 childhood leukemias and 59 CNS tumors <15 years of age that were diagnosed through 2014 and a ~10% random sample of the live births (N = 9394) with geocoded addresses, we linked pregnancy addresses to crop fields and animal farm locations and estimated the crop area (hectares [ha]) and number of animals (standardized by their nitrogen emissions) by type within 250 meters (m), 500 m, 1000 m, and 2000 m of the home. We also estimated pesticide applications (grams, active ingredient) based on annual sales data for nine herbicides and one fungicide that were estimated to have been applied to >30% of the area of one or more crop. We used Cox proportional hazard models (weighted to the full cohort) to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of childhood leukemia and CNS tumors with crop area, animals, and pesticide applications adjusted for gender and maternal age.

Results: Sixty-three percent of mothers had crops within 500 m of their homes during pregnancy; winter and spring cereals were the major crop types. Compared to mothers with no crops <500 m, we found increasing risk of childhood leukemia among offspring of mothers with increasing crop area near their home (highest tertile >24 ha HR: 2.0, CI:1.02-3.8), which was stronger after adjustment for animals (within 1000 m) (HR: 2.6, CI:1.02-6.8). We also observed increased risk for grass/clover (highest tertile >1.1 ha HR: 3.1, CI:1.2-7.7), peas (>0 HR: 2.4, CI: 1.02-5.4), and maize (>0 HR: 2.8, CI: 1.1-6.9) in animal-adjusted models. We found no association between number of animals near homes and leukemia risk. Crops, total number of animals, and hogs within 500 m of the home were not associated with CNS tumors but we observed an increased risk with >median cattle compared with no animals in crop-adjusted models (HR = 2.2, CI: 1.02-4.9). In models adjusted for total animals, the highest tertiles of use of three herbicides and one fungicide were associated with elevated risk of leukemia but no associations were statistically significant; there were no associations with CNS tumors.

Conclusions: Risk of childhood leukemia was associated with higher crop area near mothers' homes during pregnancy; CNS tumors were associated with higher cattle density. Quantitative estimates of crop pesticides and other agricultural exposures are needed to clarify possible reasons for these increased risks.
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http://dx.doi.org/10.1016/j.envint.2020.105955DOI Listing
October 2020

Nutritional Epigenomics and Age-Related Disease.

Curr Dev Nutr 2020 Jul 6;4(7):nzaa097. Epub 2020 Jun 6.

Genomic Medicine Research Group , School of Biomedical Sciences, Ulster University, Northern Ireland, United Kingdom. BT52 1SA.

Recent advances in epigenetic research have enabled the development of epigenetic clocks, which have greatly enhanced our ability to investigate molecular processes that contribute to aging and age-related disease. These biomarkers offer the potential to measure the effect of environmental exposures linked to dynamic changes in DNA methylation, including nutrients, as factors in age-related disease. They also offer a compelling insight into how imbalances in the supply of nutrients, particularly B-vitamins, or polymorphisms in regulatory enzymes involved in 1-carbon metabolism, the key pathway that supplies methyl groups for epigenetic reactions, may influence epigenetic age and interindividual disease susceptibility. Evidence from recent studies is critically reviewed, focusing on the significant contribution of the epigenetic clock to nutritional epigenomics and its impact on health outcomes and age-related disease. Further longitudinal studies and randomized nutritional interventions are required to advance the field.
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http://dx.doi.org/10.1093/cdn/nzaa097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335360PMC
July 2020

Fruits and vegetables intake and gastric cancer risk: A pooled analysis within the Stomach cancer Pooling Project.

Int J Cancer 2020 12 29;147(11):3090-3101. Epub 2020 Jun 29.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

A low intake of fruits and vegetables is a risk factor for gastric cancer, although there is uncertainty regarding the magnitude of the associations. In our study, the relationship between fruits and vegetables intake and gastric cancer was assessed, complementing a previous work on the association betweenconsumption of citrus fruits and gastric cancer. Data from 25 studies (8456 cases and 21 133 controls) with information on fruits and/or vegetables intake were used. A two-stage approach based on random-effects models was used to pool study-specific adjusted (sex, age and the main known risk factors for gastric cancer) odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Exposure-response relations, including linear and nonlinear associations, were modeled using one- and two-order fractional polynomials. Gastric cancer risk was lower for a higher intake of fruits (OR: 0.76, 95% CI: 0.64-0.90), noncitrus fruits (OR: 0.86, 95% CI: 0.73-1.02), vegetables (OR: 0.68, 95% CI: 0.56-0.84), and fruits and vegetables (OR: 0.61, 95% CI: 0.49-0.75); results were consistent across sociodemographic and lifestyles categories, as well as study characteristics. Exposure-response analyses showed an increasingly protective effect of portions/day of fruits (OR: 0.64, 95% CI: 0.57-0.73 for six portions), noncitrus fruits (OR: 0.71, 95% CI: 0.61-0.83 for six portions) and vegetables (OR: 0.51, 95% CI: 0.43-0.60 for 10 portions). A protective effect of all fruits, noncitrus fruits and vegetables was confirmed, supporting further dietary recommendations to decrease the burden of gastric cancer.
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http://dx.doi.org/10.1002/ijc.33134DOI Listing
December 2020

Outdoor light at night and postmenopausal breast cancer risk in the NIH-AARP diet and health study.

Int J Cancer 2020 11 2;147(9):2363-2372. Epub 2020 Jun 2.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.

Circadian disruption may play a role in breast carcinogenesis. Previous studies reported relationships between outdoor light at night (LAN) and the breast cancer risk, but their findings are mixed. There is also a need to examine LAN and breast cancer incidence according to different individual and environmental characteristics to identify subpopulations at greater risk associated with LAN exposure. We studied residential outdoor LAN estimated from satellite imagery at baseline (1996) in relation to postmenopausal breast cancer incidence over ~16 years of follow-up in 186 981 postmenopausal women including 12 318 incident postmenopausal breast cancer cases in the NIH-AARP Diet and Health Study. We used Cox proportional hazards models to estimate hazard ratios (HR) and two-sided 95% confidence intervals (CI) of the relationship between quintiles of LAN and postmenopausal breast cancer risk, overall and by hormone receptor status and cancer stage. We found that when compared to women in the lowest quintile of baseline LAN, those in the highest quintile had a 10% increase in postmenopausal breast cancer risk (HR (95% CI), 1.10 (1.02, 1.18), P-trend, .002). The association appeared to be stronger for estrogen receptor (ER) positive breast cancer (1.12 [1.02, 1.24], .007) than for ER-negative cancer (1.07 [0.85, 1.34], .66). Our findings also suggested that the relationship between LAN and breast cancer risk may differ by individual characteristics, such as smoking, alcohol drinking, sleep duration and BMI, and neighborhood environment. In conclusion, our study suggests that higher outdoor LAN exposure may be a risk factor for postmenopausal breast cancer.
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http://dx.doi.org/10.1002/ijc.33016DOI Listing
November 2020

The Homozygous Hemoglobin EE Variant Is Associated with Poorer Riboflavin Status in Cambodian Women of Reproductive Age.

J Nutr 2020 07;150(7):1943-1950

Department of Food, Nutrition and Health, the University of British Columbia, Vancouver, Canada.

Background: Riboflavin is required for erythropoiesis, which is increased in people with hemoglobinopathies due to increased hemolysis and erythrocyte turnover. Dietary intake and status of riboflavin is poor in Cambodia, where hemoglobinopathies are common.

Objective: We assessed the association between genetic hemoglobin disorders and riboflavin status in women of reproductive age in Cambodia.

Methods: Venous blood samples from 515 Cambodian women of reproductive age, 18-45 y, were analyzed for biomarker status of riboflavin [erythrocyte glutathione reductase activation coefficient (EGRac)], genetic hemoglobin (Hb) disorders, and hematological indices. Linear regression analysis was used to estimate the association between EGRac with Hb, ferritin, and Hb genotypes. EGRac was log transformed in the analyses, and the regression coefficients represent the geometric mean differences.

Results: Genetic Hb disorders were present in 57% of the population, with the homozygous hemoglobin E variant (Hb EE) occurring in ∼10% of women (n = 53). Deficient (EGRac ≥1.40) or marginal riboflavin status (EGRac ≥1.30 and <1.40) was observed in 92% (n = 475) of women. The variant Hb EE genotype was associated with 18% (95% CI: 9%, 28%) higher geometric mean EGRac values than the normal Hb AA genotype (P < 0.001).

Conclusions: Although riboflavin biomarker deficiency or marginal status is widely prevalent in Cambodian women, lower riboflavin status was observed more frequently in women with the Hb EE genotype than in women with normal Hb AA. The relation between genetic Hb disorders and riboflavin warrants further investigation. This trial was registered at clinicaltrials.gov as NCT01593423 and NCT02481375.
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http://dx.doi.org/10.1093/jn/nxaa119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330481PMC
July 2020

Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype.

Biochimie 2020 Jun 22;173:17-26. Epub 2020 Apr 22.

Genomic Medicine Research Group, Ulster University, Coleraine, Northern Ireland, United Kingdom. Electronic address:

DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p < 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (-1.2%, p < 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.
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http://dx.doi.org/10.1016/j.biochi.2020.04.007DOI Listing
June 2020
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