Cis-eQTL-Based Trans-Ethnic Meta-Analysis Reveals Novel Genes Associated with Breast Cancer Risk

Breast cancer is the most common solid organ malignancy and the most frequent cause of cancer death among women worldwide. Previous research has yielded insights into its genetic etiology, but there remains a gap in the understanding of genetic factors that contribute to risk, and particularly in the biological mechanisms by which genetic variation modulates risk. The National Cancer Institute\u27s Up for a Challenge (U4C) competition provided an opportunity to further elucidate the genetic basis of the disease. Our group leveraged the seven datasets made available by the U4C organizers and data from the publicly available UK Biobank cohort to examine associations between imputed gene expression and breast cancer risk. In particular, we used reference datasets describing the breast tissue and whole blood transcriptomes to impute expression levels in breast cancer cases and controls. In trans-ethnic meta-analyses of U4C and UK Biobank data, we found significant associations between breast cancer risk and the expression of RCCD1 (joint p-value: 3.6x10-06) and DHODH (p-value: 7.1x10-06) in breast tissue, as well as a suggestive association for ANKLE1 (p-value: 9.3x10-05). Expression of RCCD1 in whole blood was also suggestively associated with disease risk (p-value: 1.2x10-05), as were expression of ACAP1 (p-value: 1.9x10-05) and LRRC25 (p-value: 5.2x10-05). While genome-wide association studies (GWAS) have implicated RCCD1 and ANKLE1 in breast cancer risk, they have not identified the remaining three genes. Among the genetic variants that contributed to the predicted expression of the five genes, we found 23 nominally (p-value \u3c 0.05) associated with breast cancer risk, among which 15 are not in high linkage disequilibrium with risk variants previously identified by GWAS. In summary, we used a transcriptome-based approach to investigate the genetic underpinnings of breast carcinogenesis. This approach provided an avenue for deciphering the functional relevance of genes and genetic variants involved in breast cancer

Brain abscess as a manifestation of spinal dermal sinus

Dermal sinuses have been associated with a wide spectrum of clinical manifestations ranging from asymptomatic to drainage of purulent material from the sinus tract, inclusion tumors, meningitis, and spinal abscess. To date, there has been no documented report of brain abscess as a complication of spinal dermal sinus. Here, we report an 8-month-old girl who was presented initially with a brain abscess at early infancy but lumbar dermal sinus and associated spinal abscess were discovered afterwards. The probable mechanisms of this rare association have been discussed

Association between Thyroid Hormones and Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis in Obese Individuals Undergoing Bariatric Surgery

Background: Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatic fibrosis have emerged as one of the leading causes of chronic liver disease. The prevalence of the NAFLD spectrum has increased, which can be attributed to the rise in obesity. As NAFLD can ultimately lead to liver cirrhosis, it is imperative to identify modifiable risk factors associated with its onset and progression to provide timely intervention to prevent potentially disastrous consequences. Considering the pivotal role of the endocrine axis in several metabolic pathways such as obesity and insulin resistance, thyroid hormones are crucial in the pathophysiology of NAFLD. The study is focused on the identification of an association between thyroid function and radiographic and histological parameters of NAFLD in patients with severe obesity. Methods: Ninety patients were recruited for this study and underwent initial assessments, including demographic profiles, anthropometric measurements, hepatic biopsy, and basic laboratory tests. Liver stiffness was evaluated using two-dimensional shear wave elastography (2D-SWE) at least 2 weeks before liver biopsy. Results: Among the 90 participants, 80% were women. The mean age was 38.5 ± 11.1 years, and the mean body mass index (BMI) was 45.46 ± 6.26 kg/m2. The mean levels of serum T3 and free T4 in patients with positive histology were not statistically significant compared with patients with negative histology. Furthermore, there was no statistical significance in the mean T3 and free T4 levels between patients diagnosed with hepatic steatosis or fibrosis (on ultrasonography and elastography) and those with negative hepatic imaging. Serum levels of thyroid-stimulating hormone (TSH) were negatively correlated with ultrasonography (P = 0.007). Binary logistic regression analysis revealed that none of the thyroid hormones was a predictive factor for liver histology in both adjusted and crude models. Conclusion: The results from our analysis did not suggest an association between thyroid hormones and NAFLD, which is in line with several previously published studies. However, the authors note that there are published data that do propose a link between the two entities. Therefore, well-designed large-scale clinical studies are required to clarify this discrepancy

Exploring the Correlation between Hα\rm{H}\alpha-to-UV Ratio and Burstiness for Typical Star-forming Galaxies at z∼2z\sim2

The $\rm{H}\alpha$-to-UV luminosity ratio ($L(\rm H\alpha)/L(\rm UV)$) is often used to probe SFHs of star-forming galaxies and it is important to validate it against other proxies for burstiness. To address this issue, we present a statistical analysis of the resolved distribution of $\Sigma_{\rm{SFR}}$ as well as stellar age and their correlations with the globally measured $L(\rm H\alpha)/L(\rm UV)$ for a sample of 310 star-forming galaxies in two redshift bins of $1.37 < z < 1.70$ and $2.09 < z < 2.61$ observed by the MOSDEF survey. We use the multi-waveband CANDELS/3D-HST imaging of MOSDEF galaxies to construct $\Sigma_{\rm{SFR}}$ and stellar age maps. We analyze the composite rest-frame far-UV spectra of a subsample of MOSDEF targets obtained by the Keck/LRIS, which includes 124 star-forming galaxies (MOSDEF-LRIS) at redshifts $1.4 < z < 2.6$, to examine the average stellar population properties, and the strength of age-sensitive FUV spectral features in bins of $L(\rm H\alpha)/L(\rm UV)$. Our results show no significant evidence that individual galaxies with higher $L(\rm H\alpha)/L(\rm UV)$ are undergoing a burst of star formation based on the resolved distribution of $\Sigma_{\rm{SFR}}$ of individual star-forming galaxies. We segregate the sample into subsets with low and high $L(\rm H\alpha)/L(\rm UV)$. The high-$L(\rm H\alpha)/L(\rm UV)$ subset exhibits, on average, an age of $\log[\rm{Age/yr}]$ = 8.0, compared to $\log[\rm{Age/yr}]$ = 8.4 for the low-$L(\rm H\alpha)/L(\rm UV)$ galaxies, though the difference in age is significant at only the $2\sigma$ level. Furthermore, we find no variation in the strengths of Siiv$\lambda\lambda1393, 1402$ and Civ$\lambda\lambda1548, 1550$ P-Cygni features from massive stars between the two subsamples.Comment: 16 pages, 10 figures, published by the Monthly Notices of the Royal Astronomical Societ

The Immune Epitope Database 2.0

The Immune Epitope Database (IEDB, www.iedb.org) provides a catalog of experimentally characterized B and T cell epitopes, as well as data on Major Histocompatibility Complex (MHC) binding and MHC ligand elution experiments. The database represents the molecular structures recognized by adaptive immune receptors and the experimental contexts in which these molecules were determined to be immune epitopes. Epitopes recognized in humans, nonhuman primates, rodents, pigs, cats and all other tested species are included. Both positive and negative experimental results are captured. Over the course of 4 years, the data from 180 978 experiments were curated manually from the literature, which covers ∼99% of all publicly available information on peptide epitopes mapped in infectious agents (excluding HIV) and 93% of those mapped in allergens. In addition, data that would otherwise be unavailable to the public from 129 186 experiments were submitted directly by investigators. The curation of epitopes related to autoimmunity is expected to be completed by the end of 2010. The database can be queried by epitope structure, source organism, MHC restriction, assay type or host organism, among other criteria. The database structure, as well as its querying, browsing and reporting interfaces, was completely redesigned for the IEDB 2.0 release, which became publicly available in early 2009

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: r(g) = 0.098, p = 2.3 x 10(-8)) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: r(g) = 0.137, p = 2.0 x 10(-12)). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis

The Lyman Continuum Escape Fraction of Star-forming Galaxies at 2.4≲z≲3.72.4\lesssim z\lesssim3.7 from UVCANDELS

The UltraViolet Imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) survey is a Hubble Space Telescope (HST) Cycle-26 Treasury Program, allocated in total 164 orbits of primary Wide-Field Camera 3 Ultraviolet and Visible light F275W imaging with coordinated parallel Advanced Camera for Surveys F435W imaging, on four of the five premier extragalactic survey fields: GOODS-N, GOODS-S, EGS, and COSMOS. We introduce this survey by presenting a thorough search for galaxies at $z\gtrsim2.4$ that leak significant Lyman continuum (LyC) radiation, as well as a stringent constraint on the LyC escape fraction ($f_{\rm esc}$) from stacking the UV images of a population of star-forming galaxies with secure redshifts. Our extensive search for LyC emission and stacking analysis benefit from the catalogs of high-quality spectroscopic redshifts compiled from archival ground-based data and HST slitless spectroscopy, carefully vetted by dedicated visual inspection efforts. We report a sample of five galaxies as individual LyC leaker candidates, showing $f_{\rm esc}^{\rm rel}\gtrsim60\%$ estimated using detailed Monte Carlo analysis of intergalactic medium attenuation. We develop a robust stacking method to apply to five samples of in total 85 non-detection galaxies in the redshift range of $z\in[2.4,3.7]$. Most stacks give tight 2-$\sigma$ upper limits below $f_{\rm esc}^{\rm rel}<6\%$. A stack for a subset of 32 emission-line galaxies shows tentative LyC leakage detected at 2.9-$\sigma$, indicating $f_{\rm esc}^{\rm rel}=5.7\%$ at $z\sim2.65$, supporting the key role of such galaxies in contributing to the cosmic reionization and maintaining the UV ionization background. These new F275W and F435W imaging mosaics from UVCANDELS have been made publicly available on the Barbara A. Mikulski Archive for Space Telescopes.Comment: 33 pages, 21 figures, and 5 tables. Resubmitted after addressing the referee repor

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BACKGROUND: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. METHODS: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. FINDINGS: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. INTERPRETATION: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic. FUNDING: Bill & Melinda Gates Foundation

The Ultraviolet Luminosity Function at 0.6 < z < 1 from UVCANDELS

UVCANDELS is a Hubble Space Telescope Cycle-26 Treasury Program awarded 164 orbits of primary ultraviolet (UV) F275W imaging and coordinated parallel optical F435W imaging in four CANDELS fields—GOODS-N, GOODS-S, EGS, and COSMOS—covering a total area of ∼426 arcmin2. This is ∼2.7 times larger than the area covered by previous deep-field space UV data combined, reaching a depth of about 27 and 28 ABmag (5σ in 0.”2 apertures) for F275W and F435W, respectively. Along with new photometric catalogs, we present an analysis of the rest-frame UV luminosity function (LF), relying on our UV-optimized aperture photometry method, yielding a factor of 1.5 increase over H-isophot aperture photometry in the signal-to-noise ratios of galaxies in our F275W imaging. Using well-tested photometric redshift measurements, we identify 5810 galaxies at redshifts 0.6 &lt; z &lt; 1, down to an absolute magnitude of M UV = −14.2. In order to minimize the effect of uncertainties in estimating the completeness function, especially at the faint end, we restrict our analysis to sources above 30% completeness, which provides a final sample of 4726 galaxies at −21.5 &lt; M UV &lt; −15.5. We performed a maximum likelihood estimate to derive the best-fit parameters of the UV LF. We report a best-fit faint-end slope of α=−1.359−0.041+0.041 at z ∼ 0.8. Creating subsamples at z ∼ 0.7 and z ∼ 0.9, we observe a possible evolution of α with redshift. The unobscured UV luminosity density at M UV &lt; −10 is derived as ρUV=1.339−0.030+0.027(×1026ergs−1Hz−1Mpc−3) using our best-fit LF parameters. The new F275W and F435 photometric catalogs from UVCANDELS have been made publicly available on the Barbara A. Mikulski Archive for Space Telescopes