Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study

<p>Abstract</p> <p>Background</p> <p>Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.</p> <p>Methods</p> <p>Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.</p> <p>Results</p> <p>Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1^st(7.4 μg/m³) to the 25^th(17.2 μg/m³), 50^th(33.8 μg/m³), 75^th(108.3 μg/m³), and 90^th(180.8 μg/m³) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.</p> <p>Conclusions</p> <p>The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.</p

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores

The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Abstract: Purpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making

Local influence of calcifications on the wall mechanics of abdominal aortic aneurysm

Finite element wall stress simulations on patient-specific models of abdominal aortic aneurysm (AAA) may provide a better rupture risk predictor than the currently used maximum transverse diameter. Calcifications in the wall of AAA lead to a higher maximum wall stress and thus may lead to an elevated rupture risk. The reported material, properties for calcifications and the material properties actually used for simulations show great variation. Previous studies have focussed on simplified modelling of the calcification shapes within a realistic aneurysm shape. In this study we use an accurate representation of the calcification geometry and a simplified model for the AAA. The objective of this approach is to investigate the influence of the calcification geometry, the material properties and the modelling approach for the computed peak wall stress. For four realistic calcification shapes from standard clinical CT images of AAA, we performed simulations with three distinct modelling approaches, at five distinct elasticity settings. The results show how peak wall stress is sensitive to the material properties of the calcifications. For relatively elastic calcifications, the results from the different modelling approaches agree. Also, for relatively elastic calcifications the computed wall stress in the tissue surrounding the calcifications shows to be insensitive to the exact calcification geometry. For suffer calcifications the different modelling approaches and the different geometries lead to significantly different results. We conclude that an important challenge for future research is accurately estimating the material properties and the rupture potential of the AAA wall including calcifications

Patient-specific models of wall stress in abdominal aortic aneurysm : A comparison between MR and CT

Finite element method based patient-specific wall stress in abdominal aortic: anemysm (AAA) may provide a more accurate rupture risk predictor than the currently used maximum transverse diameter. In this study, we have investigated the sensitivity of the wall stress in AAA with respect to geometrical variations. We have acquired MR and CT images for four patients with AAA. Three individual users have delineated the AAA vessel wall contours on the image slices. These contours were used to generate synthetic feature images for a cleformable model based segmentation method. We investigated the reproducibility and the influence of the user variability on the wall stress. For sufficiently smooth models of the AAA wall, the peak wall stress is reproducible for three out of the four AAA geometries. The 0.99 percentiles of the wall stress show excellent reproducibility for all four AAAs. The variations induced by user variability are larger than the errors caused by the segmentation variability. The influence of the user variability appears to be similar for MR and CT. We conclude that the peak wall stress in AAA is sensitive to small geometrical variations. To increase reproducibility it appears to be best not to allow too much geometrical detail in the simulations. This could be achieved either by using a sufficiently smooth geometry representation or by using a more robust statistical parameter derived from the wall stress distribution

Unbiased vessel-diameter quantification based on the FWHM criterion

The full-width at half-max (FWHM) criterion is often used for both manual and automatic quantification of the vessel diameter in medical images. The FWHM criterion is easy to understand and it can be implemented with low computational cost. However, it is well known that the FWHM criterion can give an over- and underestimation of the vessel diameter. In this paper, we propose a simple and original method to create an unbiased estimation of the vessel diameter based on the FWHM criterion and we compared the robustness to noise of several edge detectors. The quantitative results of our experiments show that the proposed method is accurate and precise in comparison to other (more complex) edge detectors, even for small vessels