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Background: Obesity and neurodevelopmental delay are complex traits that often co-occur and differ between boys and girls. Prenatal exposures are believed to influence children's obesity, but it is unknown whether exposures of pregnant mothers can confer a different risk of obesity between sexes, and whether they can affect neurodevelopment. Methods: We analyzed data from 1044 children from the HELIX project, comprising 93 exposures during pregnancy, and clinical, neuropsychological, and methylation data during childhood (5-11 years). Using exposome-wide interaction analyses, we identified prenatal exposures with the highest sexual dimorphism in obesity risk, which were used to create a multiexposure profile. We applied causal random forest to classify individuals into two environments: E1 and E0. E1 consists of a combination of exposure levels where girls have significantly less risk of obesity than boys, as compared to E0, which consists of the remaining combination of exposure levels. We investigated whether the association between sex and neurodevelopmental delay also differed between E0 and E1. We used methylation data to perform an epigenome-wide association study between the environments to see the effect of belonging to E1 or E0 at the molecular level. Results: We observed that E1 was defined by the combination of low dairy consumption, non-smokers' cotinine levels in blood, low facility richness, and the presence of green spaces during pregnancy (ORinteraction = 0.070, P = 2.59 × 10-5). E1 was also associated with a lower risk of neurodevelopmental delay in girls, based on neuropsychological tests of non-verbal intelligence (ORinteraction = 0.42, P = 0.047) and working memory (ORinteraction = 0.31, P = 0.02). In line with this, several neurodevelopmental functions were enriched in significant differentially methylated probes between E1 and E0. Conclusions: The risk of obesity can be different for boys and girls in certain prenatal environments. We identified an environment combining four exposure levels that protect girls from obesity and neurodevelopment delay. The combination of single exposures into multiexposure profiles using causal inference can help determine populations at risk. The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no 308333 (HELIX project); and the H2020-EU.3.1.2.—Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA-SAB data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6–04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011–2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–15). This research has received funding from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023 (CEX2018-000,806-S) program, and support from the Generalitat de Catalunya through the CERCA Program. NC and JU are supported by Spanish regional program PERIS (Ref.: SLT017/20/000061 and SLT017/20/000119, respectively), granted by Departament de Salut de la Generalitat de Catalunya. TruDiagnostics also provided funding for data analysis.

PDF file - 120K, This is a more detailed discussion of the microarray data.

Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis. This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition. The lead ERMA in this class, OSU-CG5, decreases the production of ATP and NADH in LNCaP prostate cancer cells. In this study, we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal, lateral, and anterior prostatic lobes relative to vehicle controls. The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen (PCNA) expression in the prostate. OSU-CG5 treatment was not associated with evidence of systemic toxicity. Microarray analysis indicated a central role for Akt, and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt, Src, androgen receptor, and insulin-like growth factor-1 receptor in prostate lobes. These findings support further investigation of OSU-CG5 as a potential chemopreventive agent. Cancer Prev Res; 6(3); 232–41. ©2012 AACR.

PDF file - 213K, Supplemental Table 1 is a table that lists the average sum of the adjusted lesion scores (SALS) for each lobe of the prostate, as well as the average score for the most severe and most common lesion in each lobe. Supplemental tables 2 through 5 provide detailed analysis of the microarray data.

IntroductionLiving in an area with high levels of child poverty predisposes children to poorer mental and physical health. ActEarly is a 5-year research programme that comprises a large number of interventions (>20) with citizen science and co-production embedded. It aims to improve the health and well-being of children and families living in two areas of the UK with high levels of deprivation; Bradford in West Yorkshire, and the London Borough of Tower Hamlets. This protocol outlines the meta-evaluation (an evaluation of evaluations) of the ActEarly programme from a systems perspective, where individual interventions are viewed as events in the wider policy system across the two geographical areas. It includes investigating the programme’s impact on early life health and well-being outcomes, interdisciplinary prevention research collaboration and capacity building, and local and national decision making.MethodsThe ActEarly meta-evaluation will follow and adapt the five iterative stages of the ‘Evaluation of Programmes in Complex Adaptive Systems’ (ENCOMPASS) framework for evaluation of public health programmes in complex adaptive systems. Theory-based and mixed-methods approaches will be used to investigate the fidelity of the ActEarly research programme, and whether, why and how ActEarly contributes to changes in the policy system, and whether alternative explanations can be ruled out. Ripple effects and systems mapping will be used to explore the relationships between interventions and their outcomes, and the degree to which the ActEarly programme encouraged interdisciplinary and prevention research collaboration as intended. A computer simulation model (“LifeSim”) will also be used to evaluate the scale of the potential long-term benefits of cross-sectoral action to tackle the financial, educational and health disadvantages faced by children in Bradford and Tower Hamlets. Together, these approaches will be used to evaluate ActEarly’s dynamic programme outputs at different system levels and measure the programme’s system changes on early life health and well-being.DiscussionThis meta-evaluation protocol presents our plans for using and adapting the ENCOMPASS-framework to evaluate the system-wide impact of the early life health and well-being programme, ActEarly. Due to the collaborative and non-linear nature of the work, we reserve the option to change and query some of our evaluation choices based on the feedback we receive from stakeholders to ensure that our evaluation remains relevant and fit for purpose.

Postoperative radiation therapy (RT) is an underused standard-of-care intervention for patients with prostate cancer and recurrence/adverse pathologic features after radical prostatectomy. Although stereotactic body RT (SBRT) is a well-studied and convenient option for definitive treatment, data on the postprostatectomy setting are extremely limited. The purpose of this study was to evaluate short-term physician-scored genitourinary (GU) and gastrointestinal (GI) toxicities and patient-reported outcomes after postprostatectomy SBRT.The SCIMITAR trial was a phase 2, dual-center, open-label, single-arm trial that enrolled patients with postoperative prostate-specific antigen0.03 ng/mL or adverse pathologic features. Coprimary endpoints were 4-year biochemical recurrence-free survival, physician-scored acute and late GU and GI toxicities by the Common Terminology Criteria for Adverse Events (version 4.03) scale, and patient-reported quality-of-life (QOL) outcomes, as represented by the Expanded Prostate Cancer Index-26 and the International Prostate Symptom Score. Patients received SBRT 30 to 34 Gy/5 fractions to the prostate bed ± bed boost ± pelvic nodes with computed tomography (CTgRT) or magnetic resonance imaging guidance (MRgRT) in a nonrandomized fashion. Physician-scored toxicities and patient-reported QOL outcomes were collected at baseline and at 1, 3, and 6 months of follow-up. Univariable and multivariable analyses were performed to evaluate predictors of toxicities and QOL outcomes.One hundred participants were enrolled (CTgRT, n = 69; MRgRT, n = 31). The median follow-up was 29.5 months (CTgRT: 33.3 months, MRgRT: 22.6 months). The median (range) prostate bed dose was 32 (30-34) Gy. Acute and late grade 2 GU toxicities were both 9% while acute and late grade 2 GI toxicities were 5% and 0%, respectively. Three patients had grade 3 toxicity (n = 1 GU, n = 2 GI). No patient receiving MRgRT had grade 3 GU or grade ≥2 GI toxicity. Compared with CTgRT, MRgRT was associated with a 30.5% (95% confidence interval, 11.6%-49.5%) reduction in any-grade acute GI toxicity (P = .006). MRgRT was independently associated with improved any-grade GI toxicity and improved bowel QOL.Postprostatectomy SBRT was well tolerated at short-term follow-up. MRgRT may decrease GI toxicity. Longer toxicity and/or efficacy follow-up and randomized studies are needed.

Research suggests that maternal exposure to natural environments (i.e., green and blue spaces) promotes healthy fetal growth. However, the available evidence is heterogeneous across regions, with very few studies on the effects of blue spaces. This study evaluated associations between maternal exposure to natural environments and birth outcomes in 11 birth cohorts across nine European countries. This study, part of the LifeCycle project, was based on a total sample size of 69,683 newborns with harmonised data. For each participant, we calculated seven indicators of residential exposure to natural environments: surrounding greenspace in 100m, 300m, and 500m using Normalised Difference Vegetation Index (NDVI) buffers, distance to the nearest green space, accessibility to green space, distance to the nearest blue space, and accessibility to blue space. Measures of birth weight and small for gestational age (SGA) were extracted from hospital records. We used pooled linear and logistic regression models to estimate associations between exposure to the natural environment and birth outcomes, controlling for the relevant covariates. We evaluated the potential effect modification by socioeconomic status (SES) and region of Europe and the influence of ambient air pollution on the associations. In the pooled analyses, residential surrounding greenspace in 100m, 300m, and 500m buffer was associated with increased birth weight and lower odds for SGA. Higher residential distance to green space was associated with lower birth weight and higher odds for SGA. We observed close to null associations for accessibility to green space and exposure to blue space. We found stronger estimated magnitudes for those participants with lower educational levels, from more deprived areas, and living in the northern European region. Our associations did not change notably after adjustment for air pollution. These findings may support implementing policies to promote natural environments in our cities, starting in more deprived areas. Research suggests that maternal exposure to natural environments (i.e., green and blue spaces) promotes healthy fetal growth. However, the available evidence is heterogeneous across regions, with very few studies on the effects of blue spaces. This study evaluated associations between maternal exposure to natural environments and birth outcomes in 11 birth cohorts across nine European countries. This study, part of the LifeCycle project, was based on a total sample size of 69,683 newborns with harmonised data. For each participant, we calculated seven indicators of residential exposure to natural environments: surrounding greenspace in 100m, 300m, and 500m using Normalised Difference Vegetation Index (NDVI) buffers, distance to the nearest green space, accessibility to green space, distance to the nearest blue space, and accessibility to blue space. Measures of birth weight and small for gestational age (SGA) were extracted from hospital records. We used pooled linear and logistic regression models to estimate associations between exposure to the natural environment and birth outcomes, controlling for the relevant covariates. We evaluated the potential effect modification by socioeconomic status (SES) and region of Europe and the influence of ambient air pollution on the associations. In the pooled analyses, residential surrounding greenspace in 100m, 300m, and 500m buffer was associated with increased birth weight and lower odds for SGA. Higher residential distance to green space was associated with lower birth weight and higher odds for SGA. We observed close to null associations for accessibility to green space and exposure to blue space. We found stronger estimated magnitudes for those participants with lower educational levels, from more deprived areas, and living in the northern European region. Our associations did not change notably after adjustment for air pollution. These findings may support implementing policies to promote natural environments in our cities, starting in more deprived areas.

MicroRNA-34 (miR-34) is widely studied for its role in tumor suppression, DNA regulation, and cell cycle regulation. During DNA damage, miR-34 is directly upregulated by p53, inhibiting proliferation and promoting DNA repair. Accordingly, radiation therapy induces upregulation of miR-34 expression, coordinating several downstream radiation-induced stress responses. Recent work has demonstrated the existence of a stable, unphosphorylated pool of miR-34, which is rapidly phosphorylated and activated via loading onto Argonaute after ionizing radiation, independent of de novo transcription. Since Argonaute binding to the 5’ phosphate is also important for miRNA stability, we hypothesize that a separate mechanism must exist to stabilize the unphosphorylated pool of miR-34. Mass spectrometry performed on co-precipitates of biotinylated mimics of unphosphorylated miR-34 identified predominantly nuclear proteins, with a notable enrichment for proteins localized in nuclear paraspeckles. Nuclear paraspeckles are a phase-separated nuclear subcompartment comprised of several key structural proteins and a long noncoding RNA NEAT1_2 that prevents mixing of internal contents with the rest of the nucleoplasm and are canonically implicated in regulating gene expression by sequestering inosine-modified mRNA. To further investigate the role of nuclear paraspeckles in the stability or sequestering of unphosphorylated miR-34, stable cell lines with deletion of a a motif required for stability of paraspeckles through disruption of the lncRNA NEAT1_2 were created (A549 NEAT1 dTH). Interestingly, luciferase reporter assays for miR-34 activity in the NEAT1 dTH lines showed a general loss of miR-34 activity after radiation compared to wildtype cells which exhibit radiation induced activation of miR-34. This loss of activity occurred both immediately after radiation, which is attributable to phosphorylation of the unphosphorylated pool, and at later time points after radiation, which has been attributed to de novo miRNA production. Ongoing research will monitor colocalization of proteins known to activate the unphosphorylated pool with paraspeckles to determine if paraspeckles coordinate activation of unphosphorylated miR-34, as well as will investigate the potential impact of disruption of paraspeckles on de novo miR-34 production. A better understanding of the interplay between nuclear paraspeckles and stress-responsive miRNA production may provide a means to selectively modify cancer stress responses and uncover novel mechanisms in miRNA production and coordination. Citation Format: Graham H. Read, David W. Salzman, Julian Whitelegge, Whitaker Cohn, Tiffany Yang, Cynthia Tsang, Ihsan A. Turk, Joanne B. Weidhaas. Analyzing nuclear paraspeckle-dependent protection of unphosphorylated MicroRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2815.

PurposeFor a cohort of prostate cancer patients treated on an MR-guided radiotherapy (MRgRT) system, we retrospectively analyzed urethral interfractional geometric and dosimetric variations based on onboard MRIs acquired at different timepoints and evaluated onboard prostatic urethra visualization for urethra-focused online adaptive RT.MethodsTwenty-six prostate cancer patients were prospectively scanned on a 0.35-T MRgRT system using an optimized T2-weighted HASTE sequence at simulation and final fraction. Two radiation oncologists (RO1 and RO2) contoured the urethras on all HASTE images. The simulation and final fraction HASTE images were rigidly registered, and urethral interobserver and interfractional geometric variation was evaluated using the 95th percentile Hausdorff distance (HD95), mean distance to agreement (MDA), center-of-mass shift (COMS), and DICE coefficient. For dosimetric analysis, simulation and final fraction HASTE images were registered to the 3D bSSFP planning MRI and 3D bSSFP final setup MRI, respectively. Both ROs’ urethra contours were transferred from HASTE images for initial treatment plan optimization and final fraction dose estimation separately. Stereotactic body radiotherapy (SBRT) plans, 40 Gy in 5 fractions, were optimized to meet clinical constraints, including urethral V42Gy ≤0.03 cc, on the planning MRI. The initial plan was then forward calculated on the final setup MRI to estimate urethral dose on the final fraction and evaluate urethral dosimetric impact due to anatomy change.ResultsThe average interobserver HD95, MDA, COMS, and DICE were 2.85 ± 1.34 mm, 1.02 ± 0.36 mm, 3.16 ± 1.61 mm, and 0.58 ± 0.15, respectively. The average interfractional HD95, MDA, COMS, and DICE were 3.26 ± 1.54 mm, 1.29 ± 0.54 mm, 3.34 ± 2.01 mm, and 0.49 ± 0.18, respectively. All patient simulation MRgRT plans met all clinical constraints. For RO1 and RO2, 23/26 (88%) and 21/26 (81%) patients’ final fraction estimated urethral dose did not meet the planned constraint. The average urethral V42Gy change was 0.48 ± 0.58 cc.ConclusionUrethral interfractional motion and anatomic change can result in daily treatment violating urethral constraints. Onboard MRI with good visualization of the prostatic urethra can be a valuable tool to help better protect the urethra through patient setup or online adaptive RT.

Background It has been hypothesised that greater maternal adiposity before or during pregnancy causes greater offspring adiposity in childhood and adulthood, via causal intrauterine or periconceptional mechanisms. Previous Mendelian randomization (MR) estimates were imprecise, with wide confidence intervals that included potentially important protective or adverse effects, and may have been biased by collider effects or imperfect adjustment for genetic inheritance. Here we use an improved MR approach to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal, or are instead due to confounding. Methods and findings We undertook confounder adjusted multivariable (MV) regression and Mendelian randomization (MR) using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB the outcomes were birthweight (BW; N = 9339) and BMI at age 1 (N = 8659) and 4 years (N = 7575), and in ALSPAC only we investigated BMI at 10 (N = 4476) and 15 years (N = 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10– 18 years (N = 2659 to 3855). We compared MR results from several polygenic risk scores (PRS), calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). MV and MR showed a consistent positive association of maternal BMI with BW, but for adiposity at most older ages MR estimates were weaker than MV estimates. In MV regression a one standard deviation (SD) higher maternal BMI was associated with a 0.13 (95% confidence interval [CI]: 0.10, 0.16) SD increase in offspring BW. The corresponding MR estimate from the strongest PRS (including up to 80,939 SNPs) was 0.14 (95% CI: 0.05, 0.23), with no difference between the two estimates (Pdifference = 0.84). For 15 year BMI the MV and MR estimates (80,939 SNPs) were 0.32 (95% CI: 0.29, 0.36) and 0.13 (95% CI: 0.01, 0.24) respectively (Pdifference = 1.0e-3). Results for FMI were similar to those for adolescent BMI. As the number of SNPs included in the PRS increased, the MR confidence intervals narrowed and the effect estimates for adolescent adiposity became closer to the MV estimates. Sensitivity analyses suggested the stronger effects with more SNPs were explained by horizontal pleiotropic bias away from zero. Consequently, the unbiased difference between the MV and MR estimates is probably greater than shown in our main analyses. Furthermore, MR estimates from IVs with fewer SNPs provided no strong evidence for a causal effect on adolescent adiposity. Conclusions Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.

Many women who experience gestational diabetes (GDM), gestational hypertension (GHT), pre-eclampsia (PE), have a spontaneous preterm birth (sPTB) or have an offspring born small/large for gestational age (SGA/LGA) do not meet the criteria for high-risk pregnancies based upon certain maternal risk factors. Tools that better predict these outcomes are needed to tailor antenatal care to risk. Recent studies have suggested that metabolomics may improve the prediction of these pregnancy-related disorders. These have largely been based on targeted platforms or focused on a single pregnancy outcome. The aim of this study was to assess the predictive ability of an untargeted platform of over 700 metabolites to predict the above pregnancy-related disorders in two cohorts. We used data collected from women in the Born in Bradford study (BiB, two sub-samples, n = 2000 and n = 1000) and the Pregnancy Outcome Prediction study (POPs, n = 827) to train, test and validate prediction models for GDM, PE, GHT, SGA, LGA and sPTB. We compared the predictive performance of three models: (1) risk factors (maternal age, pregnancy smoking, BMI, ethnicity and parity) (2) mass spectrometry (MS)-derived metabolites (n = 718 quantified metabolites, collected at 26–28 weeks’ gestation) and (3) combined risk factors and metabolites. We used BiB for the training and testing of the models and POPs for independent validation. In both cohorts, discrimination for GDM, PE, LGA and SGA improved with the addition of metabolites to the risk factor model. The models’ area under the curve (AUC) were similar for both cohorts, with good discrimination for GDM (AUC (95% CI) BiB 0.76 (0.71, 0.81) and POPs 0.76 (0.72, 0.81)) and LGA (BiB 0.86 (0.80, 0.91) and POPs 0.76 (0.60, 0.92)). Discrimination was improved for the combined models (compared to the risk factors models) for PE and SGA, with modest discrimination in both studies (PE-BiB 0.68 (0.58, 0.78) and POPs 0.66 (0.60, 0.71), SGA-BiB 0.68 (0.63, 0.74) and POPs 0.64 (0.59, 0.69)). Prediction for sPTB was poor in BiB and POPs for all models. In BiB, calibration for the combined models was good for GDM, LGA and SGA. Retained predictors include 4-hydroxyglutamate for GDM, LGA and PE and glycerol for GDM and PE. MS-derived metabolomics combined with maternal risk factors improves the prediction of GDM, PE, LGA and SGA, with good discrimination for GDM and LGA. Validation across two very different cohorts supports further investigation on whether the metabolites reflect novel causal paths to GDM and LGA.

BackgroundWeight perception may differ by ethnicity but is not well-understood, particularly among migrants to the United Kingdom (UK). It is also unknown whether a figure rating scale (FRS) or perceived weight question (PWQ) is more accurate for assessing body weight perception.MethodsAt 24-months postpartum, women in the Born in Bradford cohort (Bradford, UK) completed the 9-item Stunkard FRS and a 7-category PWQ. Both scales were condensed to weight categories representing the World Health Organisation cut-offs. Weighted kappa statistics assessed agreement between measured and perceived weight categories. χ2 and Fisher’s exact tests assessed categories of misperception by ethnicity and migration and logistic regression was used to examine odds of underestimation.ResultsThirty percent of white British and 23% of Pakistani-origin women had obesity. Agreement between measured and perceived weight categories were similar for white British women using either a visual scale or weight question (FRS: κ [95%CI]: 0.61 [0.56, 0.65]; PWQ: 0.61 [0.55, 0.68)]. Overall agreement was lower for Pakistani-origin women with the visual scale performing better (FRS (0.58 [0.52, 0.63]) vs PWQ (0.47 [0.40, 0.54]). Pakistani-origin women, particularly those born outside the UK, were more likely to underestimate their body weight compared to white British women; this was greater with the PWQ (18% vs 10%; pConclusionWe observed ethnic differences in weight misperception with Pakistani-origin women more likely to underestimate their weight compared to white British women. Our findings suggest visual scales, rather than perceived weight questions, are more appropriate for the self-assessment of body weight.

The impact of long COVID is increasingly recognised, but risk factors are poorly characterised. We analysed questionnaire data on symptom duration from 10 longitudinal study (LS) samples and electronic healthcare records (EHR) to investigate sociodemographic and health risk factors associated with long COVID, as part of the UK National Core Study for Longitudinal Health and Wellbeing.MethodsAnalysis was conducted on 6,899 adults self-reporting COVID-19 from 45,096 participants of the UK LS, and on 3,327 cases assigned a long COVID code in primary care EHR out of 1,199,812 adults diagnosed with acute COVID-19. In LS, we derived two outcomes: symptoms lasting 4+ weeks and symptoms lasting 12+ weeks. Associations of potential risk factors (age, sex, ethnicity, socioeconomic factors, smoking, general and mental health, overweight/obesity, diabetes, hypertension, hypercholesterolaemia, and asthma) with these two outcomes were assessed, using logistic regression, with meta-analyses of findings presented alongside equivalent results from EHR analyses.ResultsFunctionally limiting long COVID for 12+ weeks affected between 1.2% (age 20), and 4.8% (age 63) of people reporting COVID-19 in LS. The proportion reporting symptoms overall for 12+ weeks ranged from 7.8 (mean age 28) to 17% (mean age 58) and for 4+ weeks 4.2% (age 20) to 33.1% (age 56). Age was associated with a linear increase in long COVID between age 20-70. Being female (LS: OR=1.49; 95%CI:1.24-1.79; EHR: OR=1.51 [1.41-1.61]), poor pre-pandemic mental health (LS: OR=1.46 [1.17-1.83]; EHR: OR=1.57 [1.47-1.68]) and poor general health (LS: OR=1.62 [1.25-2.09]; EHR: OR=1.26; [1.18-1.35]) were associated with higher risk of long COVID. Individuals with asthma also had higher risk (LS: OR=1.32 [1.07-1.62]; EHR: OR=1.56 [1.46-1.67]), as did those categorised as overweight or obese (LS: OR=1.25 [1.01-1.55]; EHR: OR=1.31 [1.21-1.42]) though associations for symptoms lasting 12+ weeks were less pronounced. Non-white ethnic minority groups had lower 4+ week symptom risk (LS: OR=0.32 [0.22-0.47]), a finding consistent in EHR. Associations were not observed for other risk factors. Few participants in the studies had been admitted to hospital (0.8-5.2%).ConclusionsLong COVID is clearly distributed differentially according to several sociodemographic and pre-existing health factors. Establishing which of these risk factors are causal and predisposing is necessary to further inform strategies for preventing and treating long COVID.

Background Congenital heart diseases (CHDs) are the most common congenital anomaly. The causes of CHDs are largely unknown. Higher prenatal body mass index (BMI), smoking, and alcohol consumption are associated with increased risk of CHDs. Whether these are causal is unclear. Methods and Results Seven European birth cohorts, including 232 390 offspring (2469 CHD cases [1.1%]), were included. We applied negative exposure paternal control analyses to explore the intrauterine effects of maternal BMI, smoking, and alcohol consumption during pregnancy, on offspring CHDs and CHD severity. We used logistic regression, adjusting for confounders and the other parent's exposure and combined estimates using a fixed‐effects meta‐analysis. In adjusted analyses, maternal overweight (odds ratio [OR], 1.15 [95% CI, 1.01–1.31]) and obesity (OR, 1.12 [95% CI, 0.93–1.36]), compared with normal weight, were associated with higher odds of CHD, but there was no clear evidence of a linear increase in odds across the whole BMI distribution. Associations of paternal overweight, obesity, and mean BMI were similar to the maternal associations. Maternal pregnancy smoking was associated with higher odds of CHD (OR, 1.11 [95% CI, 0.97–1.25]) but paternal smoking was not (OR, 0.96 [95% CI, 0.85–1.07]). The positive association with maternal smoking appeared to be driven by nonsevere CHD cases (OR, 1.22 [95% CI, 1.04–1.44]). Associations with maternal moderate/heavy pregnancy alcohol consumption were imprecisely estimated (OR, 1.16 [95% CI, 0.52–2.58]) and similar to those for paternal consumption. Conclusions We found evidence of an intrauterine effect for maternal smoking on offspring CHDs, but no evidence for higher maternal BMI or alcohol consumption. Our findings provide further support for the importance of smoking cessation during pregnancy.

Purpose Participation in community programmes by the Roma community is low, whilst this community presents with high risk of poor health and low levels of wellbeing. To improve rates of participation in programmes, compatibility must be achieved between implementation efforts and levels of readiness in the community. The Community Readiness Model (CRM) is a widely used toolkit which provides an indication of how prepared and willing a community is to take action on specific issues. The purpose of this paper is to present findings from a CRM assessment for the Eastern European Roma community in Bradford, UK, on issues related to nutrition and obesity. Design/methodology/approach The authors interviewed key respondents identified as knowledgeable about the Roma community using the CRM. This approach applies a mixed methodology incorporating readiness scores and qualitative data. A mean community readiness score was calculated enabling researchers to place the community in one of nine possible stages of readiness. Interview transcripts were analysed using a qualitative framework analysis to generate the contextual information. Findings An overall score consistent with vague awareness was achieved, which indicates a low level of community readiness. This score suggests that there will be a low likelihood of participation in currently available nutrition and obesity programmes. Originality/value To our knowledge, this is the first study to apply the CRM in the Roma community for any issue. The authors present the findings for each of the six dimensions that make up the CRM together with salient qualitative findings.

Maternal risk factors, such as body mass index (BMI), age, smoking, parity and ethnicity, are associated with risk of pregnancy-related disorders. However, many women who experience gestational diabetes (GDM), gestational hypertension (GHT), pre-eclampsia (PE), have a spontaneous preterm birth (sPTB) or an offspring born small/large for gestational age (SGA/LGA), do not display any of these risk factors. Tools that better predict these outcomes are needed to tailor antenatal care to risk. Recent studies have suggested that metabolomics may improve the prediction of these pregnancy-related disorders. These have largely been based on targeted platforms or focused on a single pregnancy outcome. The aim of this study was to assess the predictive ability of an untargeted platform of over 700 metabolites to predict the above pregnancy-related disorders in two cohorts.We used data collected from women in the Born in Bradford study (BiB; two sub-samples, n=2,000 and n=1,000) and the Pregnancy Outcome Prediction study (POPs; n=827) to train, test and validate prediction models for GDM, PE, GHT, SGA, LGA and sPTB. We used ten-fold cross-validation and penalised regression to create prediction models. We compared the predictive performance of 3 models: 1) risk factors (maternal age, pregnancy smoking, BMI, ethnicity, and parity) 2) mass spectrometry (MS)-derived metabolites (N = 718 quantified metabolites, collected at 26-28 weeks’ gestation) and 3) combined risk factors and metabolites. We used BiB for training and testing the models and POPs for independent validation.In both cohorts, discrimination for GDM, PE, LGA and SGA improved with the addition of metabolites to the risk factor model (combined risk factor and metabolite model). The combined models’ area under the curve (AUC) were similar for both cohorts, with good discrimination for GDM (AUC (95% CI) BiB 0.76 (0.71,0.81) and POPs 0.76 (0.72,0.81)) and LGA (BiB 0.86 (0.80,0.91) and POPs 0.76 (0.60,0.92)). Discrimination was improved for the combined models (compared to the risk factors models) for PE and SGA, with modest discrimination in both studies (PE - BiB 0.68 (0.58,0.78) and POPs 0.66 (0.60,0.71); SGA - BiB 0.68 (0.63,0.74) and POPs 0.64 (0.59,0.69)). Prediction for sPTB was poor in BiB and POPs for all models, with AUC ∼0.5. In BiB, calibration for the combined models was good for GDM, LGA and SGA. Retained predictors include 4-hydroxyglutamate for GDM, LGA and PE, and glycerol for GDM and PE.MS-derived metabolomics combined with maternal risk factors improve prediction of GDM, PE, LGA and SGA, with good discrimination for GDM and LGA. Validation across two very different cohorts supports further investigation on whether the metabolites reflect novel causal paths to GDM and LGA. Developing these prediction tools could enable tailoring antenatal care to improve earlier and more accurate identification of high-risk women.

Metabolomics is the quantification of small molecules, commonly known as metabolites. Collectively, these metabolites and their interactions within a biological system are known as the metabolome. The metabolome is a unique area of study, capturing influences from both genotype and environment. The availability of high-throughput technologies for quantifying large numbers of metabolites, as well as lipids and lipoprotein particles, has enabled detailed investigation of human metabolism in large-scale epidemiological studies. The Born in Bradford (BiB) cohort includes 12,453 women who experienced 13,776 pregnancies recruited between 2007-2011, their partners and their offspring. In this data note, we describe the metabolomic data available in BiB, profiled during pregnancy, in cord blood and during early life in the offspring. These include two platforms of metabolomic profiling: nuclear magnetic resonance and mass spectrometry. The maternal measures, taken at 26-28 weeks� gestation, can provide insight into the metabolome during pregnancy and how it relates to maternal and offspring health. The offspring cord blood measurements provide information on the fetal metabolome. These measures, alongside maternal pregnancy measures, can be used to explore how they may influence outcomes. The infant measures (taken around ages 12 and 24 months) provide a snapshot of the early life metabolome during a key phase of nutrition, environmental exposures, growth, and development. These metabolomic data can be examined alongside the BiB cohorts� extensive phenotype data from questionnaires, medical, educational and social record linkage, and other �omics data.

BACKGROUND Bisphenol A (BPA) and phthalates metabolites are linked to a variety of adverse health consequences but studies have not explored their association with growth trajectories. OBJECTIVE Explore body mass index (BMI) trajectories for tertile exposures to BPA and phthalates metabolites in the third trimester of pregnancy. METHODS We constructed BMI (kg/m2 ) trajectories from birth to 14 years in a birth cohort of 249 children from Mexico City using tertiles of third trimester maternal urinary concentrations of BPA and phthalates metabolites. Fractional age polynomials and mixed effects models were fit separately by sex. Predicted models were plotted for each metabolite tertile with the covariates mother's education and BMI centered at average values. RESULTS Highest predicted BMI trajectories for female children were observed for third tertile exposure to the phthalate metabolite mono(2-ethyl-5-carboxypentyl) phthalate. In male children, first tertile exposure to mono-isobutyl phthalate and monobenzyl phthalate and second tertile exposure to mono(2-ethylhexyl) phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate predicted the highest BMI trajectory by adolescence. There was no relationshsip between BPA and child growth trajectory. CONCLUSIONS These results suggest sex-specific differences in BMI trajectories by levels of metabolite exposure. Additional studies are needed to consider growth through adolescence in assessing the association of pregnancy exposures on child's BMI.

Background: Body mass index (BMI) is commonly used as a proxy to determine excess adiposity, though this may underestimate fat mass (FM) in individuals of South Asian (SA) heritage. SA tend to have greater central adiposity than white people, which is associated with a higher risk of cardiometabolic disease. In this cross-sectional study, we aimed to determine the differences in total and regional FM using Dual-energy X-ray absorptiometry (DXA), and to see if any differences in FM varied by BMI category in UK-born white and SA children aged ~9 years. Methods: Anthropometric measurements and DXA scans were undertaken from 225 white and 269 SA children from the Born in Bradford cohort study. Linear regression was used to assess ethnic differences in total body fat percent and total and regional FM. Results: Although the mean BMI was similar, compared to white children, the proportion of SA children who were overweight or obese was ~20% higher, they had a median of 2kg more total FM, and the proportion with > 35% total body fat (TBF) was 22% and 16% higher in boys and girls respectively. Mean TBF% was greater in each BMI category, as was truncal, android and gynoid FM, with the greatest differences between ethnic groups observed in the healthy and overweight categories. Conclusions: Greater TBF% and total and regional FM in the healthy- and overweight BMI categories observed in SA children suggests they may be at greater risk of future cardiometabolic disease at a BMI level below obesity threshold. However, our sample size was small, and results may be influenced by selection bias and confounding; our findings need to be replicated in a larger study.

We documented blood biochemistry and haematology of healthy loggerhead turtles (Caretta caretta) in the Northwest (NW) Atlantic in order to establish clinical reference intervals (RIs) for this threatened population. Blood samples were analysed from migratory loggerheads captured off the Mid-Atlantic coast of the USA in 2011, 2012, 2013 and 2016 as part of a long-term research program. Blood variables were determined using a point-of-care analyser, and a veterinary diagnostic laboratory service. We calculated 95% RIs with associated 90% confidence intervals (CIs) for each blood variable. We compared results obtained from our study of migratory loggerheads with published data for similarly sized loggerheads resident at a seasonal temperate latitude foraging area. Significant differences in several blood variables between migratory and resident turtles provided insight on energetic and health status during different behavioural states. Temperature was significantly correlated with several blood variables: lactate, pCO2, sodium, haemoglobin and lactate dehydrogenase. Our assessment of blood chemistry in healthy loggerhead turtles in the NW Atlantic provides a baseline for clinical comparisons with turtles impacted by anthropogenic and environmental threats, and highlights the importance of identifying unique aspects of biochemical and haematological profiles for sea turtles at the intra-population level.

Economic, physical, built, cultural, learning, social and service environments have a profound effect on lifelong health. However, policy thinking about health research is dominated by the ‘biomedical model’ which promotes medicalisation and an emphasis on diagnosis and treatment at the expense of prevention. Prevention research has tended to focus on ‘downstream’ interventions that rely on individual behaviour change, frequently increasing inequalities. Preventive strategies often focus on isolated leverage points and are scattered across different settings. This paper describes a major new prevention research programme that aims to create City Collaboratory testbeds to support the identification, implementation and evaluation of upstream interventions within a whole system city setting. Prevention of physical and mental ill-health will come from the cumulative effect of multiple system-wide interventions. Rather than scatter these interventions across many settings and evaluate single outcomes, we will test their collective impact across multiple outcomes with the goal of achieving a tipping point for better health. Our focus is on early life (ActEarly) in recognition of childhood and adolescence being such critical periods for influencing lifelong health and wellbeing.

In a large cohort of older women, we investigated the relationships that different forms of vitamin E may have with bone turnover markers and bone mineral density (BMD). We found a suggestive positive association between serum alpha-tocopherol and BMD at the femoral neck, but no other clinically relevant observations. Vitamin E has anti-oxidant and anti-inflammatory properties hypothesized to benefit bone, but limited studies exist regarding its homologues. We examined circulating and dietary α- and γ-tocopherols with bone turnover markers (BTMs) and bone mineral density (BMD), and the role of inflammation in this relationship. We performed two cross-sectional analyses from two visits (V2, 1997–1999, n = 3883; V3, 2007–2011, n = 2130) of the Aberdeen Prospective Osteoporosis Screening Study. Dietary and supplement intakes by food frequency questionnaire were assessed at both visits. V2 BTMs (urinary free pyridinoline and deoxypyridinoline, serum N-terminal propeptide of type 1 collagen) and V3 serum α- and γ-tocopherols, inflammatory markers (interleukin-6 [IL-6], serum amyloid A [SAA], high-sensitivity C-reactive protein [hs-CRP], E-selectin) and dual X-ray absorptiometry BMD at the femoral neck and lumbar spine were collected. Food sources of tocopherol homologues and diet-serum correlations were determined. The relationships between dietary tocopherols and BTMs (V2), and dietary and serum tocopherols with BMD (V3) were examined by multivariable regression (adjusting for age, cholesterol, inflammatory markers, carotenoids, body mass index, physical activity level, alcohol intake, smoking status and national deprivation category). Serum γ-tocopherol was associated with increasing concentrations of hs-CRP, SAA and E-selectin (P-trend all

Microwaves, which have a ∼10-cm wavelength, can penetrate deeper into tissue than photons, heralding exciting deep tissue applications such as modulation or imaging via the thermoacoustic effect. Thermoacoustic conversion efficiency is however very low, even with an exogenous contrast agent. We break this low-conversion limit, using a split ring resonator to effectively collect and confine the microwaves into a submillimeter hot spot for ultrasound emission and achieve a conversion efficiency over 2000 times higher than other reported thermoacoustic contrast agents. Importantly, the frequency of emitted ultrasound can be precisely tuned and multiplexed by modulation of the microwave pulses. Such performance is inaccessible by a piezoelectric-based transducer or a photoacoustic emitter and, therefore, split ring resonators open up new opportunities to study the frequency response of cells in ultrasonic biomodulation. For applications in deep tissue localization, a split ring resonator can be used as a wireless, battery-free ultrasound beacon placed under a breast phantom.

Telomere length and mitochondrial DNA content are considered biomarkers of cellular aging, oxidative stress, and inflammation, but there is almost no information on their association with tobacco smoke exposure in fetal and early life. The aim of this study was to assess whether prenatal and childhood tobacco exposure were associated with leukocyte telomere length (LTL) and mitochondrial DNA (mtDNA) content in children. As part of a multi-centre European birth cohort study HELIX (Human Early-Life Exposome) (n = 1396) we assessed maternal smoking status during pregnancy through questionnaires, and through urinary cotinine levels that were then used to classify women as not exposed to smoking (50 mu g/L). When the children were around 8 years of age (range: 5.4-12.0 years), childhood SHS tobacco smoke exposure was assessed through an extensive questionnaire and through measurements of urinary cotinine (3.03 mu g/L detected). Leukocyte mtDNA content and LTL were measured in the children at 8 years employing real time polymerase chain reaction (qPCR). Effect estimates were calculated using multivariate linear regression models for prenatal and childhood exposures adjusted for potential confounders. Maternal cotinine levels indicative of SHS exposure during pregnancy were associated with a decrease of 3.90% in LTL in children (95% CI: -6.68, -0.91), compared with nonsmoking, whereas the association for maternal cotinine levels indicative of active smoking did not reach statistical significance (-3.24%; 95% CI: -6.59, 0.21). Childhood SHS tobacco exposure was not associated with LTL in children. Global SHS exposure during childhood was associated with an increase of 3.51% (95% CI: 0.78, 6.27) in mtDNA content. Our findings suggest that tobacco smoke exposure during pregnancy, even at SHS levels, may accelerate telomere shortening in children and thus induce biological aging from an early age. (C) 2019 Elsevier B.V. All rights reserved.

We established reference intervals for blood biochemistry and haematology of loggerhead turtles captured off the Mid-Atlantic coast of the USA. This assessment of blood variables in healthy, wild loggerhead turtles allows for comparisons with turtles impacted by anthropogenic and environmental threats, as well as turtles sampled in different habitats and life stages., We documented blood biochemistry and haematology of healthy loggerhead turtles (Caretta caretta) in the Northwest (NW) Atlantic in order to establish clinical reference intervals (RIs) for this threatened population. Blood samples were analysed from migratory loggerheads captured off the Mid-Atlantic coast of the USA in 2011, 2012, 2013 and 2016 as part of a long-term research program. Blood variables were determined using a point-of-care analyser, and a veterinary diagnostic laboratory service. We calculated 95% RIs with associated 90% confidence intervals (CIs) for each blood variable. We compared results obtained from our study of migratory loggerheads with published data for similarly sized loggerheads resident at a seasonal temperate latitude foraging area. Significant differences in several blood variables between migratory and resident turtles provided insight on energetic and health status during different behavioural states. Temperature was significantly correlated with several blood variables: lactate, pCO2, sodium, haemoglobin and lactate dehydrogenase. Our assessment of blood chemistry in healthy loggerhead turtles in the NW Atlantic provides a baseline for clinical comparisons with turtles impacted by anthropogenic and environmental threats, and highlights the importance of identifying unique aspects of biochemical and haematological profiles for sea turtles at the intra-population level.

Current diagnosis of prostate cancer relies on histological analysis of tissue samples acquired by biopsy, which could benefit from real-time identification of suspicious lesions. Photoacoustic tomography has the potential to provide real-time targets for prostate biopsy guidance with chemical selectivity, but light delivered from the rectal cavity has been unable to penetrate to the anterior prostate. To overcome this barrier, a urethral device with cylindrical illumination is developed for whole-prostate imaging, and its performance as a function of angular light coupling is evaluated with a prostate-mimicking phantom.

Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis. This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition. The lead ERMA in this class, OSU-CG5, decreases the production of ATP and NADH in LNCaP prostate cancer cells. In this study, we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal, lateral, and anterior prostatic lobes relative to vehicle controls. The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen (PCNA) expression in the prostate. OSU-CG5 treatment was not associated with evidence of systemic toxicity. Microarray analysis indicated a central role for Akt, and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt, Src, androgen receptor, and insulin-like growth factor-1 receptor in prostate lobes. These findings support further investigation of OSU-CG5 as a potential chemopreventive agent. Cancer Prev Res; 6(3); 232–41. ©2012 AACR.

Background The perimenopausal and postmenopausal periods are times of pronounced physiological change in body mass index (BMI), physical activity and energy intake. Understanding these changes in middle age could contribute to formation of potential public health targets. Method A longitudinal cohort of 5119 perimenopausal women from the Aberdeen Prospective Osteoporosis Screening Study (APOSS) recruited between 1990 and 1994, with follow-up visits at 1997–1999 and 2009–2011. At each visit, participants were weighed, measured and completed socioeconomic and demographic questionnaires. Participants at the first visit were asked to recall body weights at 20, 30 and 40 years of age. We assessed trends in BMI, physical activity and energy intake across and within visits. Results Over 2 decades, obesity prevalence doubled from 14% to 28% of the participants, with 69% of participants being categorised as overweight or obese. Greater than 70% of participants gained >5% of their baseline BMI with weight gain occurring across all weight categories. Energy intake and physical activity levels (PALs) did not change during the 2 decades after menopause (p trend=0.06 and 0.11, respectively), but, within the second visit, energy intake increased concomitantly with a decrease in physical activity across increasing quartiles of BMI (p trend Conclusions Overweight and obesity increased by over 50% over the course of 20 years. Weight gain occurred across the adult life course regardless of starting weight. The marked increase in dietary intake and decrease in PALs in middle age suggest a potential critical period for intervention to curb excess weight gain.

Public health approaches to chronic disease prevention often advocates a healthy lifestyle, including a healthy dietary pattern and exercise regimen. Consumption of fruits, vegetables, and whole grains are promoted for their nutrient content and bioactive compounds such as carotenoids, polyphenols, and tocopherols. These compounds exhibit antioxidant and inflammatory properties and may therefore by beneficial to chronic diseases associated with low-grade chronic inflammation such as osteoporosis in postmenopausal women. The vitamin E homologue, α-tocopherol, has had significant interest due to its potent lipoperoxyl radical-scavenging capacity, leading to its use in food processing and supplementation. However, recent evidence has suggested that vitamin E homologues may have potentially different impact on bone indices and, though studies purport that vitamin E benefits bone through its anti-inflammatory properties, this relationship has not been shown in humans. In this chapter, we evaluate the current evidence on the two most prevalent vitamin E homologues, α- and γ-tocopherol, with bone indicators in peri-menopausal and postmenopausal women. We then present data on dietary sources of α- and γ-tocopherol in a population of postmenopausal women in northeast Scotland and examine whether there is a relationship between these homologues and four inflammatory markers.

Background: Exposures to the endocrine disrupting compounds (EDCs) bisphenol A (BPA) and phthalates have been linked to measures of child weight status in cross-sectional studies, but these do not ...

Parabens are esters of 4-hydroxybenzoic acid that are commonly used as antimicrobial preservatives in cosmetics, pharmaceuticals, and food or beverage processing (Andersen 2008). It is likely that repeated contact with products or foods containing parabens leads to widespread human exposure through ingestion, inhalation, or dermal contact. Methyl paraben (MP), ethyl paraben (EP), propyl paraben (PP), and butyl paraben (BP) have recently been detected in a high proportion of urine samples collected as part of a national U.S. survey of exposure to environmental chemicals (Calafat et al. 2010). Parabens are thought to possess low toxicity (Golden et al. 2005; Soni et al. 2005). However, some parabens may be estrogenic in vitro (Routledge et al. 1998), although with activity levels several orders of magnitude lower than that of estrogen. Recent experimental studies have reported that certain parabens may also act as antiandrogens (Chen et al. 2007; Darbre and Harvey 2008; Satoh et al. 2005), and there is limited evidence that parabens may affect thyroid function (Rousset 1981; Taxvig et al. 2008; Vo et al. 2010). Several animal studies have explored the impacts of parabens on male reproductive effects, with some reporting that exposure to BP and PP, but not MP, adversely affects spermatogenesis and endocrine function in rats or mice (Kang et al. 2002; Oishi 2001, 2002a; 2002b; 2004). Conversely, in another recent study, Hoberman et al. (2008) found no association between MP or BP and reproductive markers in rats. Based on these limited animal studies, in addition to the observation that paraben estrogenicity depends on the length of the alkyl side chain (Darbre and Harvey 2008), the reproductive toxicity potential of parabens for which widespread human exposure has been documented is thought to be BP > PP > EP > MP. To our knowledge, no human studies have investigated the association between paraben exposure and measures of male reproduction. In the present study we assessed relationships between urinary concentrations of several parabens and a range of male reproductive health markers in an ongoing study of environmental determinants of reproductive health. We also considered the potential for interactions between parabens and another estrogenic xenobiotic, bisphenol A (BPA), for which we recently reported associations with reproductive measures in this population (Meeker et al. 2010a, 2010b).

Cardiac ventricular myocytes possess an extensive t-tubule system which plays a number of important roles including facilitation of membrane potential propagation across the cell body. It has been shown that ion fluxes at a highly restricted t-tubular space may lead to significant accumulation/depletion of specific ions which in turn may affect t-tubular, as well as whole-cell, membrane potential. The extent of ion accumulation/depletion depends on the current densities and the volume/structure of t-tubules. In this study we used the whole-cell patch-clamp technique to monitor t-tubular accumulation of potassium (caused by outward potassium currents in response to 400 ms voltage step to +50 mV) by measuring inward rectifier IK1 tail currents (Itail) at −75 mV. At room temperatures of ∼21-23 °C the amplitude of Itail current measured 9-10 minutes after the establishment of whole-cell configuration was essentially unchanged (93.6% of initial value), but declined to 53.5% upon application (within 2-5 minutes after the beginning of cell dialysis ) of 1 mM cyanide, a blocker of oxidative phosphorylation (n=9 and 6, respectively; p