Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, ...and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders.
Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios ORs = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR 95% CI per 1-kg increase in predicted VAT mass = 1.32 1.06-1.64, P = 0.0130), PCOS (OR 95% CI = 1.15 1.08-1.23, P = 3.24 × 10-05), and pre-eclampsia (OR 95% CI = 3.08 1.98-4.79, P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy.
We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.
ABSTRACT The Atacama Cosmology Telescope (ACT) makes high angular resolution measurements of anisotropies in the Cosmic Microwave Background (CMB) at millimeter wavelengths. We describe ACTPol, an ...upgraded receiver for ACT, which uses feedhorn-coupled, polarization-sensitive detector arrays, a 3° field of view, 100 mK cryogenics with continuous cooling, and meta material antireflection coatings. ACTPol comprises three arrays with separate cryogenic optics: two arrays at a central frequency of 148 GHz and one array operating simultaneously at both 97 GHz and 148 GHz. The combined instrument sensitivity, angular resolution, and sky coverage are optimized for measuring angular power spectra, clusters via the thermal Sunyaev-Zel'dovich (SZ) and kinetic SZ signals, and CMB lensing due to large-scale structure. The receiver was commissioned with its first 148 GHz array in 2013, observed with both 148 GHz arrays in 2014, and has recently completed its first full season of operations with the full suite of three arrays. This paper provides an overview of the design and initial performance of the receiver and related systems.
Advanced ACTPol is a polarization-sensitive upgrade for the 6 m aperture Atacama Cosmology Telescope, adding new frequencies and increasing sensitivity over the previous ACTPol receiver. In 2016, ...Advanced ACTPol will begin to map approximately half the sky in five frequency bands (28-230 GHz). Its maps of primary and secondary cosmic microwave background anisotropies-imaged in intensity and polarization at few arcminute-scale resolution-will enable precision cosmological constraints and also awide array of cross-correlation science that probes the expansion history of the universe and the growth of structure via gravitational collapse. To accomplish these scientific goals, the AdvancedACTPol receiver will be a significant upgrade to the ACTPol receiver, including four new multichroic arrays of cryogenic, feedhorn-coupled AlMn transition edge sensor polarimeters (fabricated on 150 mm diameter wafers); a system of continuously rotating meta-material silicon half-wave plates; and a new multiplexing readout architecture which uses superconducting quantum interference devices and time division to achieve a 64-row multiplexing factor. Here we present the status and scientific goals of the Advanced ACTPol instrument, emphasizing the design and implementation of the AdvancedACTPol cryogenic detector arrays.
Drug resistance is a major hurdle in oncology. Responses of acute myeloid leukaemia (AML) patients to cytarabine (Ara-C)-based therapies are often short lived with a median overall survival of ...months. Therapies are under development to improve outcomes and include targeting the eukaryotic translation initiation factor (eIF4E) with its inhibitor ribavirin. In a Phase II clinical trial in poor prognosis AML, ribavirin monotherapy yielded promising responses including remissions; however, all patients relapsed. Here we identify a novel form of drug resistance to ribavirin and Ara-C. We observe that the sonic hedgehog transcription factor glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes are elevated in resistant cells. UGT1As add glucuronic acid to many drugs, modifying their activity in diverse tissues. GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and Ara-C, and thus drug resistance. Resistance is overcome by genetic or pharmacological inhibition of GLI1, revealing a potential strategy to overcome drug resistance in some patients.
The objectives of this paper are twofold: first, to report our estimates of the meter‐to‐decameter‐scale topography and slopes of candidate landing sites for the Phoenix mission, based on analysis of ...Mars Global Surveyor (MGS) Mars Orbiter Camera (MOC) images with a typical pixel scale of 3 m and Mars Reconnaissance Orbiter (MRO) High Resolution Imaging Science Experiment (HiRISE) images at 0.3 m pixel−1 and, second, to document in detail the geometric calibration, software, and procedures on which the photogrammetric analysis of HiRISE data is based. A combination of optical design modeling, laboratory observations, star images, and Mars images form the basis for software in the U.S. Geological Survey Integrated Software for Imagers and Spectrometers (ISIS) 3 system that corrects the images for a variety of distortions with single‐pixel or subpixel accuracy. Corrected images are analyzed in the commercial photogrammetric software SOCET SET (® BAE Systems), yielding digital topographic models (DTMs) with a grid spacing of 1 m (3–4 pixels) that require minimal interactive editing. Photoclinometry yields DTMs with single‐pixel grid spacing. Slopes from MOC and HiRISE are comparable throughout the latitude zone of interest and compare favorably with those where past missions have landed successfully; only the Mars Exploration Rover (MER) B site in Meridiani Planum is smoother. MOC results at multiple locations have root‐mean‐square (RMS) bidirectional slopes of 0.8–4.5° at baselines of 3–10 m. HiRISE stereopairs (one per final candidate site and one in the former site) yield 1.8–2.8° slopes at 1‐m baseline. Slopes at 1 m from photoclinometry are also in the range 2–3° after correction for image blur. Slopes exceeding the 16° Phoenix safety limit are extremely rare.
Background and aims: Fatty liver is a common histological finding in human liver biopsy specimens. It affects 10–24% of the general population and is believed to be a marker of risk of later chronic ...liver disease. The present study examined the risk of development of cirrhotic liver disease and the risk of death in a cohort diagnosed with pure fatty liver without inflammation. Methods: A total of 215 patients who had a liver biopsy performed during the period 1976–1987 were included in the study. The population consisted of 109 non-alcoholic and 106 alcoholic fatty liver patients. Median follow up time was 16.7 (0.2–21.9) years in the non-alcoholic and 9.2 (0.6–23.1) years in the alcoholic group. Systematic data collection was carried out by review of all medical records. All members of the study cohort were linked through their unique personal identification number to the National Registry of Patients and the nationwide Registry of Causes of Death, and all admissions, discharge diagnoses, and causes of death were obtained. Results: In the non-alcoholic fatty liver group, one patient developed cirrhosis during the follow up period compared with 22 patients in the alcoholic group. Survival estimates were significantly (p<0.01) different between the two groups, for men as well as for women, with a higher death rate in the alcoholic fatty liver group. Survival estimates in the non-alcoholic fatty liver group were not different from the Danish population. Conclusions: This study revealed that patients with type 1 non-alcoholic fatty liver disease have a benign clinical course without excess mortality.
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