The relationship between adiposity, bone density and microarchitecture is maintained in young women irrespective of diabetes status

Background: The relationship between bone health and adiposity and how it may be affected in people with chronic metabolic conditions is complex. Methods: 17 women with Type 1 diabetes mellitus (T1DM) and 9 age-matched healthy women with a median age of 22.6 yrs (range, 17.4, 23.8) were studied by 3T-MRI and MR spectroscopy to assess abdominal adiposity, tibial bone microarchitecture and vertebral bone marrow adiposity. Additional measures included DXA-based assessments of total body (TB), femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) and fat mass (FM). Results: Although women with T1DM had similar BMI and bone marrow adiposity to the controls, they had higher visceral and subcutaneous adiposity on MRI (p<0.05) and total body FM by DXA (p=0.03). Overall, in the whole cohort, a clear inverse association was evident between bone marrow adiposity and BMD at all sites (p<0.05). These associations remained significant after adjusting for age, BMI, FM, and abdominal adiposity. In addition, visceral adiposity, but not subcutaneous adiposity, showed a positive association with bone marrow adiposity (r,0.4, p=0.03), and a negative association with total body BMD (r,0.5, p=0.02). Apparent trabecular separation as assessed by MRI showed an inverse association to total body BMD by DXA (r,–0.4, p=0.04). Conclusion: Irrespective of the presence of an underlying metabolic condition, young women display a negative relationship between MRI-measured bone marrow adiposity and DXA-based assessment of bone mineral density. Furthermore, an association between bone marrow adiposity and visceral adiposity supports the notion of a common origin of these two fat depots

Using the inertia of spacecraft during landing to penetrate regoliths of the Solar System

The high inertia, i.e. high mass and low speed, of a landing spacecraft has the potential to drive a penetrometer into the subsurface without the need for a dedicated deployment mechanism, e.g., during Huygens landing on Titan. Such a method could complement focused subsurface exploration missions, particularly in the low gravity environments of comets and asteroids, as it is conducive to conducting surveys and to the deployment of sensor networks. We make full-scale laboratory simulations of a landing spacecraft with a penetrometer attached to its base plate. The tip design is based on that used in terrestrial Cone Penetration Testing (CPT) with a large enough shaft diameter to house instruments for analysing pristine subsurface material. Penetrometer measurements are made in a variety of regolith analogue materials and target compaction states. For comparison a copy of the ACC-E penetrometer from the Huygens mission to Titan is used. A test rig at the Open University is used and is operated over a range of speeds from 0.9 to 3 m s−1 and under two gravitational accelerations. The penetrometer was found to be sensitive to the target’s compaction state with a high degree of repeatability. The penetrometer measurements also produced unique pressure profile shapes for each material. Measurements in limestone powder produced an exponential increase in pressure with depth possibly due to increasing compaction with depth. Measurements in sand produced an almost linear increase in pressure with depth. Iron powder produced significantly higher pressures than sand presumably due to the rough surface of the grains increasing the grain-grain friction. Impacts into foamglas produced with both ACC-E and the large penetrometer produced an initial increase in pressure followed by a leveling off as expected in a consolidated material. Measurements in sand suggest that the pressure on the tip is not significantly dependent on speed over the range tested, which suggests bearing strength equations could be applied to impact penetrometry in sand-like regoliths. In terms of performance we find the inertia of a landing spacecraft, with a mass of 100 kg, is adequate to penetrate regoliths expected on the surface of Solar System bodies. Limestone powder, an analogue for a dusty surface, offered very little resistance allowing full penetration of the target container. Both iron powder, representing a stronger coarse grained regolith, and foamglas, representing a consolidated comet crust, could be penetrated to similar depths of around two to three tip diameters. Speed tests suggest a linear dependence of penetration depth on impact speed

Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

Peer reviewe

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation

The Cholecystectomy As A Day Case (CAAD) Score: A Validated Score of Preoperative Predictors of Successful Day-Case Cholecystectomy Using the CholeS Data Set

Background Day-case surgery is associated with significant patient and cost benefits. However, only 43% of cholecystectomy patients are discharged home the same day. One hypothesis is day-case cholecystectomy rates, defined as patients discharged the same day as their operation, may be improved by better assessment of patients using standard preoperative variables. Methods Data were extracted from a prospectively collected data set of cholecystectomy patients from 166 UK and Irish hospitals (CholeS). Cholecystectomies performed as elective procedures were divided into main (75%) and validation (25%) data sets. Preoperative predictors were identified, and a risk score of failed day case was devised using multivariate logistic regression. Receiver operating curve analysis was used to validate the score in the validation data set. Results Of the 7426 elective cholecystectomies performed, 49% of these were discharged home the same day. Same-day discharge following cholecystectomy was less likely with older patients (OR 0.18, 95% CI 0.15–0.23), higher ASA scores (OR 0.19, 95% CI 0.15–0.23), complicated cholelithiasis (OR 0.38, 95% CI 0.31 to 0.48), male gender (OR 0.66, 95% CI 0.58–0.74), previous acute gallstone-related admissions (OR 0.54, 95% CI 0.48–0.60) and preoperative endoscopic intervention (OR 0.40, 95% CI 0.34–0.47). The CAAD score was developed using these variables. When applied to the validation subgroup, a CAAD score of ≤5 was associated with 80.8% successful day-case cholecystectomy compared with 19.2% associated with a CAAD score >5 (p < 0.001). Conclusions The CAAD score which utilises data readily available from clinic letters and electronic sources can predict same-day discharges following cholecystectomy

Cowan, Florence H.

Florence H. Cowan - Born March 19, 1857, from Orono. Class of 1876.https://digitalcommons.library.umaine.edu/univ_photos/2138/thumbnail.jp

Dystonia, clinical lateralization and regional blood flow changes in temporal lobe seizures

We analyzed the lateralizing value of ictal dystonia and head-turning in temporal lobe epilepsy, and sought the biologic basis of these clinical signs by studying the regional changes in perfusion with ictal single-photon emission computed tomography (SPECT). We identified unilateral temporal lobe epilepsy in 40 of 42 patients undergoing evaluation for temporal lobe surgery, and with ictal SPECT all 40 showed striking hyperperfusion of the epileptogenic temporal lobe. Twenty-five of the 40 patients showed unilateral or predominantly unilateral upper limb dystonia, which was opposite the epileptic temporal lobe in all cases. Analysis of regional count ratios in cases with ictal dystonia, compared with those without, showed significant changes only in the basal ganglia. Specifically, we found that ictal dystonia was associated with a relative increase in perfusion of the basal ganglia opposite the dystonic limb. Although we found 26 cases with head-turning, the sign was of no lateralizing value, even when only those with major or "tonic" versions (n = 11) were analyzed. Slight increases in cortical blood flow on the side opposite the direction of version were associated with head-turning, irrespective of the side of seizure focus. In clinical practice, ictal SPECT is a highly accurate aid in the lateralization of temporal lobe foci, in addition to providing a new method to investigate the pathophysiology of clinical signs in focal seizures

Adaptation to Low Carbohydrate High Fat diet is rapid but impairs endurance exercise metabolism and performance despite enhanced glycogen availability

Key points: Brief (5–6 days) adaptation to a low carbohydrate high fat diet in elite athletes increased exercise fat oxidation to rates previously observed with medium (3–4 weeks) or chronic (>12 months) adherence to this diet, with metabolic changes being washed out in a similar time frame. Increased fat utilisation during exercise was associated with a 5–8% increase in oxygen cost at speeds related to Olympic Programme races. Acute restoration of endogenous carbohydrate (CHO) availability (24 h high CHO diet, pre-race CHO) only partially restored substrate utilisation during a race warm-up. Fat oxidation continued to be elevated above baseline values although it was lower than achieved by 5–6 days’ keto adaptation; CHO oxidation only reached 61% and 78% of values previously seen at exercise intensities related to race events. Acute restoration of CHO availability failed to overturn the impairment of high-intensity endurance performance previously associated with low carbohydrate high fat adaptation, potentially due to the blunted capacity for CHO oxidation. Abstract: We investigated substrate utilisation during exercise after brief (5–6 days) adaptation to a ketogenic low-carbohydrate (CHO), high-fat (LCHF) diet and similar washout period. Thirteen world-class male race walkers completed economy testing, 25 km training and a 10,000 m race (Baseline), with high CHO availability (HCHO), repeating this (Adaptation) after 5–6 days’ LCHF (n = 7; CHO: 200%) increases in exercise fat oxidation occurred in the LCHF Adaptation economy and 25 km tests, reaching mean rates of ∼1.43 g min−1. However, relative (Formula presented.) (ml min−1 kg−1) was higher (P < 0.0001), by ∼8% and 5% at speeds related to 50 km and 20 km events. During Adaptation race warm-up in the LCHF group, rates of fat and CHO oxidation at these speeds were decreased and increased, respectively (P < 0.001), compared with the previous day, but were not restored to Baseline values. Performance changes differed between groups (P = 0.009), with all HCHO athletes improving in the Adaptation race (5.7 (5.6)%), while 6/7 LCHF athletes were slower (2.2 (3.4)%). Substrate utilisation returned to Baseline values after 5–6 days of HCHO diet. In summary, robust changes in exercise substrate use occurred in 5–6 days of extreme changes in CHO intake. However, adaptation to a LCHF diet plus acute restoration of endogenous CHO availability failed to restore high-intensity endurance performance, with CHO oxidation rates remaining blunted. © 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Societ

A phase 2 trial of abiraterone acetate without glucocorticoids for men with metastatic castration-resistant prostate cancer

BACKGROUND:Abiraterone acetate suppresses adrenal androgens and glucocorticoids through the inhibition of CYP17; however, given the risk of mineralocorticoid excess, it is administered with glucocorticoids. Herein, the authors performed a phase 2, single-arm study that was designed to assess the safety of abiraterone acetate without steroids in patients with castration-resistant prostate cancer. METHODS:Eligible patients had castration-resistant prostate cancer with controlled blood pressure and normal potassium. Patients initially received abiraterone acetate at a dose of 1000 mg daily alone. Those with persistent or severe mineralocorticoid toxicity received treatment with prednisone initiated at a dose of 5 mg twice daily. Therapy was continued until radiographic progression, toxicity, or withdrawal. The primary objective of the current study was to determine the percentage of men requiring prednisone to manage mineralocorticoid toxicity. Toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0. RESULTS:A total of 58 patients received at least 1 dose of abiraterone acetate; the majority had metastases (53 patients; 91.4%). Sixteen patients (27.6%) received prior chemotherapy, 6 patients (10.3%) received prior enzalutamide, and 4 patients (7%) received prior ketoconazole. Grade 3 to 4 adverse events of interest included hypertension (9 patients; 15.5%) and hypokalemia (4 patients; 7%). There was no grade ≥3 edema. Seven patients (12%) initiated prednisone therapy for mineralocorticoid toxicity, 3 patients for hypertension (5%), and 4 patients for hypokalemia (7%). Two patients initiated prednisone therapy for fatigue (3%). Forty patients (68%) experienced a decline in prostate-specific antigen of ≥50% with the use of abiraterone acetate alone. Patients with lower baseline levels of androstenedione (P = .04), androsterone (P = .01), dehydroepiandrosterone (P = .03), and 17-hydroxyprogesterone (P = .03) were found to be more likely to develop mineralocorticoid toxicity. CONCLUSIONS:Treatment with abiraterone acetate without steroids is feasible, although clinically significant adverse events can occur in a minority of patients. The use of abiraterone acetate without prednisone should be balanced with the potential for toxicity and requires close monitoring.Rana R. McKay, Lillian Werner, Susanna J. Jacobus, Alexandra Jones, Elahe A. Mostaghel, Brett T. Marck ... et al