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1.
BMC Cardiovasc Disord ; 19(1): 240, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664920

RESUMO

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

2.
Environ Health Perspect ; 127(10): 107005, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31617753

RESUMO

BACKGROUND: Pregnant women and children are especially vulnerable to exposures to food contaminants, and a balanced diet during these periods is critical for optimal nutritional status. OBJECTIVES: Our objective was to study the association between diet and measured blood and urinary levels of environmental contaminants in mother-child pairs from six European birth cohorts (n=818 mothers and 1,288 children). METHODS: We assessed the consumption of seven food groups and the blood levels of organochlorine pesticides, polybrominated diphenyl ethers, polychlorinated biphenyls (PCBs), per- and polyfluoroalkyl substances (PFAS), and heavy metals and urinary levels of phthalate metabolites, phenolic compounds, and organophosphate pesticide (OP) metabolites. Organic food consumption during childhood was also studied. We applied multivariable linear regressions and targeted maximum likelihood based estimation (TMLE). RESULTS: Maternal high (≥4 times/week) versus low (<2 times/week) fish consumption was associated with 15% higher PCBs [geometric mean (GM) ratio=1.15; 95% confidence interval (CI): 1.02, 1.29], 42% higher perfluoroundecanoate (PFUnDA) (GM ratio=1.42; 95% CI: 1.20, 1.68), 89% higher mercury (Hg) (GM ratio=1.89; 95% CI: 1.47, 2.41) and a 487% increase in arsenic (As) (GM ratio=4.87; 95% CI: 2.57, 9.23) levels. In children, high (≥3 times/week) versus low (<1.5 times/week) fish consumption was associated with 23% higher perfluorononanoate (PFNA) (GM ratio=1.23; 95% CI: 1.08, 1.40), 36% higher PFUnDA (GM ratio=1.36; 95% CI: 1.12, 1.64), 37% higher perfluorooctane sulfonate (PFOS) (GM ratio=1.37; 95% CI: 1.22, 1.54), and >200% higher Hg and As [GM ratio=3.87 (95% CI: 1.91, 4.31) and GM ratio=2.68 (95% CI: 2.23, 3.21)] concentrations. Using TMLE analysis, we estimated that fish consumption within the recommended 2-3 times/week resulted in lower PFAS, Hg, and As compared with higher consumption. Fruit consumption was positively associated with OP metabolites. Organic food consumption was negatively associated with OP metabolites. DISCUSSION: Fish consumption is related to higher PFAS, Hg, and As exposures. In addition, fruit consumption is a source of exposure to OPs. https://doi.org/10.1289/EHP5324.

3.
MBio ; 10(5)2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31662453

RESUMO

Sporadic literature reports describe isolates of pathogenic bacteria that harbor an antibiotic resistance determinant but remain susceptible to the corresponding antibiotic as a consequence of a genetic defect. Such strains represent a source from which antibiotic resistance may reemerge to cause treatment failure in patients. Here, we report a systematic investigation into the prevalence and nature of this phenomenon, which we term silencing of antibiotic resistance by mutation (SARM). Instances of SARM were detected among 1,470 Staphylococcus aureus isolates through side-by-side comparison of antibiotic resistance genotype (as determined by whole-genome sequencing) versus phenotype (as assessed through susceptibility testing). Of the isolates analyzed, 152 (10.3%) harbored a silenced resistance gene, including 46 (3.1%) that exhibited SARM to currently deployed antistaphylococcal drugs. SARM resulted from diverse mutational events but most commonly through frameshift mutation of resistance determinants as a result of point deletion in poly(A) tracts. The majority (∼90%) of SARM strains reverted to antibiotic resistance at frequencies of ≥10-9; thus, while appearing antibiotic sensitive in the clinical microbiology laboratory, most S. aureus isolates exhibiting SARM will revert to antibiotic resistance at frequencies achievable in patients. In view of its prevalence in a major pathogen, SARM represents a significant potential threat to the therapeutic efficacy of antibiotics.IMPORTANCE Antibiotic resistance hinders the treatment of bacterial infection. To guide effective therapy, clinical microbiology laboratories routinely perform susceptibility testing to determine the antibiotic sensitivity of an infecting pathogen. This approach relies on the assumption that it can reliably distinguish bacteria capable of expressing antibiotic resistance in patients, an idea challenged by the present study. We report that the important human pathogen Staphylococcus aureus frequently carries antibiotic resistance genes that have become inactivated ("silenced") by mutation, leading strains to appear antibiotic sensitive. However, resistance can rapidly reemerge in most such cases, at frequencies readily achievable in infected patients. Silent antibiotic resistance is therefore prevalent, transient, and evades routine detection, rendering it a significant potential threat to antibacterial chemotherapy.

4.
J Nucl Med ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562220

RESUMO

Preclinical Positron Emission Tomography/Computed Tomography (PET/CT) is a well-established non-invasive imaging tool for studying disease development/progression and the development of novel radiotracers and pharmaceuticals for clinical applications. Despite this pivotal role, standardization of preclinical PET/CT protocols, including CT absorbed dose guidelines, is essentially non-existent. This study: (1) quantitatively assesses the variability of current preclinical PET/CT acquisition and reconstruction protocols routinely used across multiple centers and scanners; and (2) proposes acquisition and reconstruction PET/CT protocols for standardization of multi-center data, optimized for routine scanning in preclinical PET/CT laboratory. Methods: Five different commercial preclinical PET/CT scanners in Europe and USA were enrolled. Seven different PET/CT phantoms were used for evaluating biases on default/general scanner protocols; followed by developing standardized protocols. PET, CT and absorbed dose biases were assessed. Results: Site default CT protocols: Greatest extracted Hounsfield Units (HU) for water was 133HU and -967HU for air, significant differences in all tissue equivalent material (TEM) groups were measured. Average CT absorbed dose for mouse and rat was 72mGy and 40mGy, respectively. Standardized CT protocol: Greatest extracted HU for water was -77HU and -990HU for air, TEM precision improved with a reduction in variability for each tissue group. Average CT absorbed dose for mouse and rat was reduced to 37mGy and 24mGy, respectively. Site default PET protocols: Uniformity was substandard in one scanner, Recovery Coefficients (RCs) were either over or under estimated (maximum of 43%), standard uptake values (SUVs) were biased by a maximum of 44%. Standardized PET protocol: Scanner with substandard uniformity improved by 36%, RC variability was reduced by 13% points and SUV accuracy improved to 10%. Conclusion: Data revealed important quantitative bias in preclinical PET/CT and absorbed doses with default protocols. Standardized protocols showed improvements in measured PET/CT accuracy and precision with reduced CT absorbed dose across sites. Adhering to standardized protocols generates reproducible and consistent preclinical imaging datasets, thus augmenting translation of research findings to the clinic.

6.
Sports Med ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31559566

RESUMO

OBJECTIVE: Physical activity is advocated for a range of benefits to the uncomplicated pregnancy. We investigated associations of mid-pregnancy physical activity with maternal and neonatal health in white British and Pakistani-origin women from a deprived urban setting. METHODS: The study was performed in 6921 pregnant women (53% Pakistani-origin) who contributed data for 7305 singleton births. At 26-28 weeks gestation, women were grouped into four activity levels (inactive/somewhat active/moderately active/active) based on their self-reported physical activity. Linear regression with robust standard errors was used to calculate adjusted mean differences in health markers between the four groups of physical activity (reference group: inactive). RESULTS: Three-quarters (74%) of Pakistani-origin women and 39% of white British women were inactive. Trend-tests revealed that more active white British women tended to be less adipose, had lower fasting and postload glucose levels, lower triglyceride concentrations, and their babies were less adipose (smaller triceps and subscapular skinfolds) than less active white British women. Somewhat active Pakistani-origin women exhibited lower triglyceride concentrations and systolic blood pressure, higher high-density lipoprotein cholesterol levels, and their babies were less adipose (smaller mid-upper arm and abdominal circumferences; lower cord-blood leptin concentration) compared to inactive Pakistani-origin women. No associations were observed for gestational age or birth weight. CONCLUSIONS: Physical activity performed mid-pregnancy was beneficially associated with maternal cardiometabolic health and neonatal adiposity, without influencing gestational age or birth weight. Associations were dose-dependent in white British women, and even a small amount of mid-pregnancy physical activity appeared to benefit some health markers in Pakistani-origin women.

7.
Rev Sci Instrum ; 90(8): 083702, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472628

RESUMO

This article describes a home-built scanning electrochemical microscope capable of achieving high areal imaging rates through the use of continuous line probes (CLPs) and compressed sensing (CS) image reconstruction. The CLP is a nonlocal probe consisting of a band electrode, where the achievable spatial resolution is set by the thickness of the band and the achievable imaging rate is largely determined by its width. A combination of linear and rotational motors allows for CLP scanning at different angles over areas up to 25 cm2 to generate the raw signal necessary to reconstruct the desired electrochemical image using CS signal analysis algorithms. Herein, we provide detailed descriptions of CLP fabrication, microscope design, and the procedures used to carry out scanning electrochemical microscopy imaging with CLPs. In order to illustrate the basic operating procedures for the microscope, line scans and images measured in the substrate generation-probe-collection mode for flat samples containing platinum disk electrodes are presented. These exemplary measurements illustrate methods for calibrating the positioning system, positioning and cleaning the CLP, and verifying proper positioning/probe sensitivity along its length.

8.
Mol Genet Genomic Med ; 7(10): e00928, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31478359

RESUMO

BACKGROUND: ENAM mutations cause autosomal dominant or recessive amelogenesis imperfecta (AI) and show a dose effect: enamel malformations are more severe or only penetrant when both ENAM alleles are defective. METHODS: Whole exome sequences of recruited AI probands were initially screened for mutations in known AI candidate genes. Sanger sequencing was used to confirm sequence variations and their segregation with the disease phenotype. The co-occurrence of ENAM and LAMA3 mutations in one family raised the possibility of digenic inheritance. Enamel formed in Enam+/+ Ambn+/+ , Enam+/- , Ambn+/- , and Enam+/- Ambn+/- mice was characterized by dissection and backscattered scanning electron microscopy (bSEM). RESULTS: ENAM mutations segregating with AI in five families were identified. Two novel ENAM frameshift mutations were identified. A single-nucleotide duplication (c.395dupA/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous LAMA3 mutation (c.1559G>A/p.Cys520Tyr) that cosegregated with both the AI phenotype and the ENAM mutation. In mice, Ambn+/- maxillary incisors were normal. Ambn+/- molars were also normal, except for minor surface roughness. Ambn+/- mandibular incisors were sometimes chalky and showed minor chipping. Enam+/- incisor enamel was thinner than normal with ectopic mineral deposited laterally. Enam+/- molars were sometimes chalky and rough surfaced. Enam+/- Ambn+/- enamel was thin and rough, in part due to ectopic mineralization, but also underwent accelerated attrition. CONCLUSION: Novel ENAM mutations causing AI were identified, raising to 22 the number of ENAM variations known to cause AI. The severity of the enamel phenotype in Enam+/- Ambn+/- double heterozygous mice is caused by composite digenic effects. Digenic inheritance should be explored as a cause of AI in humans.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31494544

RESUMO

Blind deconvolution is the problem of recovering a convolutional kernel a0 and an activation signal x0 from their convolution . This problem is ill-posed without further constraints or priors. This paper studies the situation where the nonzero entries in the activation signal are sparsely and randomly populated. We normalize the convolution kernel to have unit Frobenius norm and cast the sparse blind deconvolution problem as a nonconvex optimization problem over the sphere. With this spherical constraint, every spurious local minimum turns out to be close to some signed shift truncation of the ground truth, under certain hypotheses. This benign property motivates an effective two stage algorithm that recovers the ground truth from the partial information offered by a suboptimal local minimum. This geometry-inspired algorithm recovers the ground truth for certain microscopy problems, also exhibits promising performance in the more challenging image deblurring problem. Our insights into the global geometry and the two stage algorithm extend to the convolutional dictionary learning problem, where a superposition of multiple convolution signals is observed.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31550496

RESUMO

FLT3-ITD-mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant that was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peritransplant. Sorafenib dosing was individualized, starting at 200 mg twice a day (BID), and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52 years, undergoing allogeneic transplant were started on sorafenib in the peritransplant period (21 pretransplant). The median duration of post-transplant follow-up was 27.6 months (range, 5.2 to 60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with 6 deaths due to relapsed leukemia and 4 from transplant-associated toxicity. Tolerable doses ranged from 200 mg every other day to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peritransplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31537614

RESUMO

Progress in developing new reversible male contraception has been slow. While the hormonal approach has been clearly shown to be capable of providing effective and reversible contraception, there remains no product available. Currently, trials of a self-administered gel combination of testosterone and the progestogen Nestorone® are under way, complementing the largely injectable methods previously investigated. Novel long-acting steroids with both androgenic and progestogenic activity are also in early clinical trials. The non-hormonal approach offers potential advantages, with potential sites of action on spermatogenesis, and sperm maturation in the epididymis or at the vas, but remains in preclinical testing. Surveys indicate the willingness of men, and their partners, to use a new male method, but they continue to lack that opportunity.

12.
J Am Coll Cardiol ; 74(10): 1317-1328, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31488269

RESUMO

BACKGROUND: Growing evidence exists about the fetal and environmental origins of hypertension, but mainly limited to single-exposure studies. The exposome has been proposed as a more holistic approach by studying many exposures simultaneously. OBJECTIVES: This study aims to evaluate the association between a wide range of prenatal and postnatal exposures and blood pressure (BP) in children. METHODS: Systolic and diastolic BP were measured among 1,277 children from the European HELIX (Human Early-Life Exposome) cohort aged 6 to 11 years. Prenatal (n = 89) and postnatal (n = 128) exposures include air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals, and lifestyles. Two methods adjusted for confounders were applied: an exposome-wide association study considering the exposures independently, and the deletion-substitution-addition algorithm considering all the exposures simultaneously. RESULTS: Decreases in systolic BP were observed with facility density (ß change for an interquartile-range increase in exposure: -1.7 mm Hg [95% confidence interval (CI): -2.5 to -0.8 mm Hg]), maternal concentrations of polychlorinated biphenyl 118 (-1.4 mm Hg [95% CI: -2.6 to -0.2 mm Hg]) and child concentrations of dichlorodiphenyldichloroethylene (DDE: -1.6 mm Hg [95% CI: -2.4 to -0.7 mm Hg]), hexachlorobenzene (-1.5 mm Hg [95% CI: -2.4 to -0.6 mm Hg]), and mono-benzyl phthalate (-0.7 mm Hg [95% CI: -1.3 to -0.1 mm Hg]), whereas increases in systolic BP were observed with outdoor temperature during pregnancy (1.6 mm Hg [95% CI: 0.2 to 2.9 mm Hg]), high fish intake during pregnancy (2.0 mm Hg [95% CI: 0.4 to 3.5 mm Hg]), maternal cotinine concentrations (1.2 mm Hg [95% CI: -0.3 to 2.8 mm Hg]), and child perfluorooctanoate concentrations (0.9 mm Hg [95% CI: 0.1 to 1.6 mm Hg]). Decreases in diastolic BP were observed with outdoor temperature at examination (-1.4 mm Hg [95% CI: -2.3 to -0.5 mm Hg]) and child DDE concentrations (-1.1 mm Hg [95% CI: -1.9 to -0.3 mm Hg]), whereas increases in diastolic BP were observed with maternal bisphenol-A concentrations (0.7 mm Hg [95% CI: 0.1 to 1.4 mm Hg]), high fish intake during pregnancy (1.2 mm Hg [95% CI: -0.2 to 2.7 mm Hg]), and child copper concentrations (0.9 mm Hg [95% CI: 0.3 to 1.6 mm Hg]). CONCLUSIONS: This study suggests that early-life exposure to several chemicals, as well as built environment and meteorological factors, may affect BP in children.

13.
Prev Vet Med ; 171: 104767, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518830

RESUMO

Foot lesions causing lameness in dairy cows have been demonstrated to adversely affect milk yield, reproductive performance and longevity, resulting in significant economic burden to individual dairy farmers and the dairy industry. Further, foot lesions compromise dairy cow welfare. Despite this knowledge, foot lesions remain a large problem in many dairy herds woldwide. Therefore, there is potential for dairy farmers to make changes to their current management practices of foot lesions. This study used the social-psychology framework, the Theory of Planned Behavior (TPB), to explore dairy farmers' intentions to make improvements to their current management practices of foot lesions in their dairy cows and to identify the underlying behavioral, normative and control beliefs facilitating and constraining this behavior. In accordance with the theoretical framework, Australian dairy farmers were invited to participate in an online questionnaire which included questions regarding intentions, attitudes, subjective norms and perceived behavioral control. Fifty-six dairy farmers completed the questionnaire. The overall intention of these dairy farmers to make improvements to their management practices of foot lesions in the next year was moderate. Dairy farmers believed improving their current management practices of foot lesions would improve animal welfare, increase milk production and was worth the cost involved (behavioral beliefs). They indicated that the opinions of consumers, staff, and animal welfare groups were important in their decision to make improvements (normative beliefs). Better equipment and facilities, improved knowledge and training, and a favorable cost-benefit ratio were perceived as factors that would enable dairy farmers to improve their management practices (control beliefs). While all of these beliefs may be considered as potential drivers to facilitate dairy farmers to change their management practices, the behavioral beliefs were identified as the priority beliefs that industry should target in the development of strategies to increase dairy farmer intentions to make improvements to their management practices of foot lesions.

14.
Arch Dis Child ; 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409594

RESUMO

OBJECTIVE: To estimate the impact on early development of prematurity and summer birth and the potential 'double disadvantage' created by starting school a year earlier than anticipated during pregnancy, due to being born preterm. DESIGN, SETTING AND PATIENTS: We investigated the impact of gestational and school-entry age on the likelihood of failing to achieve a 'Good Level of Development' (GLD) on the Early Years Foundation Stage Profile in 5-year-old children born moderate-to-late preterm using data from the Born in Bradford longitudinal birth cohort. We used hierarchical logistic regression to control for chronological maturity, and perinatal and socioeconomic factors. RESULTS: Gestational age and school-entry age were significant predictors of attaining a GLD in the 10 337 children who entered school in the correct academic year given their estimated date of delivery. The odds of not attaining a GLD increased by 1.09 (95% CI 1.06 to 1.11) for each successive week born early and by 1.17 for each month younger within the year group (95% CI 1.16 to 1.18). There was no interaction between these two effects. Children starting school a year earlier than anticipated during pregnancy were less likely to achieve a GLD compared with (1) other children born preterm (fully adjusted OR 5.51 (2.85-14.25)); (2) term summer births (3.02 (1.49-6.79)); and (3) preterm summer births who remained within their anticipated school-entry year (3.64 (1.27-11.48)). CONCLUSIONS: These results confirm the developmental risks faced by children born moderate-to-late preterm, and-for the first time-illustrate the increased risk associated with 'double disadvantage'.

15.
Environ Health Perspect ; 127(8): 87001, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393792

RESUMO

BACKGROUND: Telomere length is a molecular marker of biological aging. OBJECTIVE: Here we investigated whether early-life exposure to residential air pollution was associated with leukocyte telomere length (LTL) at 8 y of age. METHODS: In a multicenter European birth cohort study, HELIX (Human Early Life Exposome) ([Formula: see text]), we estimated prenatal and 1-y childhood exposure to nitrogen dioxide ([Formula: see text]), particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]), and proximity to major roads. Average relative LTL was measured using quantitative real-time polymerase chain reaction (qPCR). Effect estimates of the association between LTL and prenatal, 1-y childhood air pollution, and proximity to major roads were calculated using multiple linear mixed models with a random cohort effect and adjusted for relevant covariates. RESULTS: LTL was inversely associated with prenatal and 1-y childhood [Formula: see text] and [Formula: see text] exposures levels. Each standard deviation (SD) increase in prenatal [Formula: see text] was associated with a [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]) change in LTL. Prenatal [Formula: see text] was nonsignificantly associated with LTL ([Formula: see text] per SD increase; 95% CI: [Formula: see text], 0.6). For each SD increment in 1-y childhood [Formula: see text] and [Formula: see text] exposure, LTL shortened by [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]) and [Formula: see text] (95% CI: [Formula: see text], 0.1), respectively. Each doubling in residential distance to nearest major road during childhood was associated with a 1.6% (95% CI: 0.02, 3.1) lengthening in LTL. CONCLUSION: Lower exposures to air pollution during pregnancy and childhood were associated with longer telomeres in European children at 8 y of age. These results suggest that reductions in traffic-related air pollution may promote molecular longevity, as exemplified by telomere length, from early life onward. https://doi.org/10.1289/EHP4148.

16.
BMC Public Health ; 19(1): 939, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300003

RESUMO

BACKGROUND: Born in Bradford (BiB) is a prospective multi-ethnic pregnancy and birth cohort study that was established to examine determinants of health and development during childhood and, subsequently, adult life in a deprived multi-ethnic population in the north of England. Between 2007 and 2010, the BiB cohort recruited 12,453 women who experienced 13,776 pregnancies and 13,858 births, along with 3353 of their partners. Forty five percent of the cohort are of Pakistani origin. Now that children are at primary school, the first full follow-up of the cohort is taking place. The aims of the follow-up are to investigate the determinants of children's pre-pubertal health and development, including through understanding parents' health and wellbeing, and to obtain data on exposures in childhood that might influence future health. METHODS: We are employing a multi-method approach across three data collection arms (community-based family visits, school based physical assessment, and whole classroom cognitive, motor function and wellbeing measures) to follow-up over 9000 BiB children aged 7-11 years and their families between 2017 and 2021. We are collecting detailed parent and child questionnaires, cognitive and sensorimotor assessments, blood pressure, anthropometry and blood samples from parents and children. Dual x-ray absorptiometry body scans, accelerometry and urine samples are collected on subsamples. Informed consent is collected for continued routine data linkage to health, social care and education records. A range of engagement activities are being used to raise the profile of BiB and to disseminate findings. DISCUSSION: Our multi-method approach to recruitment and assessment provides an efficient method of collecting rich data on all family members. Data collected will enhance BiB as a resource for the international research community to study the interplay between ethnicity, socioeconomic circumstances and biology in relation to cardiometabolic health, mental health, education, cognitive and sensorimotor development and wellbeing.


Assuntos
Grupos Étnicos/estatística & dados numéricos , Pobreza/etnologia , Determinantes Sociais da Saúde/etnologia , Criança , Inglaterra , Feminino , Seguimentos , Humanos , Masculino , Gravidez , Estudos Prospectivos , Inquéritos e Questionários
18.
Pediatr Allergy Immunol ; 30(6): 604-613, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31188509

RESUMO

BACKGROUND: The prevalence of allergic diseases has increased in recent decades, but the causes remain unclear. Changes in the epidemiology of childhood infections could have contributed, but the current evidence is inconclusive. This study aims to investigate whether age at cytomegalovirus (CMV), Epstein-Barr virus (EBV) or varicella zoster virus (VZV) infection is associated with the development of atopy. METHODS: A total of 2559 children were enrolled in the Born in Bradford Allergy and Infection Study. Serum samples collected at 12 and 24 months were tested for CMV-IgG, EBV-IgG and VZV-IgG for 1000 children to establish age at infection. Skin prick testing (SPT) was conducted at age 4 years. RESULTS: Serology and SPT results were available for 740 children. Of these, 135 (18%) were atopic. In girls, there was a strong association of CMV infection in the second year with increased odds of atopy (adjusted OR 4.38, 95% CI 1.87-10.29) but this was not observed in boys. Age at EBV or VZV infection was not associated with risk of atopy in unadjusted analysis, but there was effect modification by sex; girls infected with VZV in the second year of life had increased odds of atopy (adjusted OR 2.85, 95% CI 1.29-6.30). CONCLUSIONS: Our results highlight potential sex-specific effects of age at CMV infection and age at VZV infection on risk of atopy, which provide insight into the mechanisms involved in the development of atopy.

19.
Anesthesiology ; 131(3): 477-491, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31166241

RESUMO

BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. The authors hypothesized that delirium would be a significant risk factor for postoperative cognitive dysfunction during follow-up. METHODS: This study used data from an observational study of cognitive outcomes after major noncardiac surgery, the Successful Aging after Elective Surgery study. Postoperative delirium was evaluated each hospital day with confusion assessment method-based interviews supplemented by chart reviews. Postoperative cognitive dysfunction was determined using methods adapted from the International Study of Postoperative Cognitive Dysfunction. Associations between delirium and postoperative cognitive dysfunction were examined at 1, 2, and 6 months. RESULTS: One hundred thirty-four of 560 participants (24%) developed delirium during hospitalization. Slightly fewer than half (47%, 256 of 548) met the International Study of Postoperative Cognitive Dysfunction-defined threshold for postoperative cognitive dysfunction at 1 month, but this proportion decreased at 2 months (23%, 123 of 536) and 6 months (16%, 85 of 528). At each follow-up, the level of agreement between delirium and postoperative cognitive dysfunction was poor (kappa less than .08) and correlations were small (r less than .16). The relative risk of postoperative cognitive dysfunction was significantly elevated for patients with a history of postoperative delirium at 1 month (relative risk = 1.34; 95% CI, 1.07-1.67), but not 2 months (relative risk = 1.08; 95% CI, 0.72-1.64), or 6 months (relative risk = 1.21; 95% CI, 0.71-2.09). CONCLUSIONS: Delirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.

20.
Biol Sex Differ ; 10(1): 23, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060622

RESUMO

BACKGROUND: Knee osteoarthritis (OA) is among the most common and disabling persistent pain conditions, with increasing prevalence in the developed world, and affects women to a greater degree than men. In the USA, the growth of knee OA has been paralleled by an increase in rates of total knee arthroplasty (TKA), a surgical treatment option for late-stage knee OA. While TKA outcomes are generally good, postoperative trajectories of pain vary widely, with some patients reporting a complete absence of pain, but with a significant minority reporting worsening pain. Biopsychosocial factors, including anxiety and depression, are known to contribute importantly to the experience of joint pain, with women reporting a higher degree of negative affective symptoms. METHODS: This study investigated sex differences in TKA outcomes in age-matched groups of men and women at two academic medical centers. Pain and physical function were assessed in 100 patients (50 men and 50 women) during the perioperative period (preoperative visit-6 weeks postsurgical). The association of preoperative negative affect (anxiety and depression scores) to postoperative pain and function was evaluated, with specific attention to sex differences in this relationship. RESULTS: Overall, women reported more baseline pain-related physical dysfunction (although not higher baseline pain scores), as well as higher acute postoperative pain scores during the 2 weeks following TKA than their male counterparts. By 6 weeks postoperatively, sex differences in reported pain were no longer evident. Interestingly, although women reported higher preoperative levels of emotional distress than men, preoperative anxiety and depression scores were better predictors of severe postoperative pain among men than women, throughout the postoperative test period. CONCLUSIONS: This study underlines the importance of considering sex and psychosocial factors, as well as their interaction, in understanding postsurgical pain trajectories.

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