denosumab in postmenopausal women with osteoporosis and diabetes subgroup analysis of freedom and freedom extension

Abstract Purpose Diabetes and osteoporosis occur frequently in older adults and are both associated with increased fracture risk. Denosumab treatment reduced new vertebral, nonvertebral, and hip fractures over 3 years, with continued low fracture incidence for up to 10 years in postmenopausal women with osteoporosis. However, its effects in diabetic subjects with osteoporosis have not yet been investigated. Methods Post hoc analysis of the 3-year, placebo-controlled FREEDOM study and 7-year Extension included postmenopausal women with osteoporosis and diabetes. Effects on BMD, vertebral, and nonvertebral fracture incidence were evaluated. Results Of 7808 subjects in FREEDOM, 508 with diabetes received denosumab (n = 266) or placebo (n = 242). Among those, BMD increased significantly with denosumab versus placebo in FREEDOM, and continued to increase during the Extension in long-term (continuing denosumab) and crossover (placebo to denosumab) denosumab subjects. In FREEDOM, denosumab-treated subjects with diabetes had significantly lower new vertebral fracture rates (1.6%) versus placebo (8.0%) (RR: 0.20 [95% CI 0.07–0.61]; p = .001). Nonvertebral fracture incidence was higher with denosumab (11.7%) versus placebo (5.9%) (HR: 1.94 [95% CI 1.00–3.77]; p = .046), although there were fewer hip fractures with denosumab (World Health Organization, 2017 [ 1 ]) than placebo (4; nonsignificant). During the first 3 years in FREEDOM Extension, new vertebral and nonvertebral fracture incidences were low in long-term and crossover denosumab diabetic groups (≤6%), consistent with the overall Extension population; yearly nonvertebral fracture incidence was comparable to the FREEDOM placebo group. Conclusion Denosumab significantly increased BMD and decreased vertebral fracture risk in subjects with osteoporosis and diabetes. No reduction in nonvertebral fractures was observed

Bone Mass and Strength in Older Men With Type 2 Diabetes: The Osteoporotic Fractures in Men Study

The effects of type 2 diabetes mellitus (T2DM) on bone volumetric density, bone geometry, and estimates of bone strength are not well established. We used peripheral quantitative computed tomography (pQCT) to compare tibial and radial bone volumetric density (vBMD, mg/cm3), total (ToA, mm2) and cortical (CoA, mm2) bone area and estimates of bone compressive and bending strength in a subset (n = 1171) of men (≥65 years of age) who participated in the multisite Osteoporotic Fractures in Men (MrOS) study. Analysis of covariance–adjusted bone data for clinic site, age, and limb length (model 1) and further adjusted for body weight (model 2) were used to compare data between participants with (n = 190) and without (n = 981) T2DM. At both the distal tibia and radius, patients with T2DM had greater bone vBMD (+2% to +4%, model 1, p < .05) and a smaller bone area (ToA −1% to −4%, model 2, p < .05). The higher vBMD compensated for lower bone area, resulting in no differences in estimated compressive bone strength at the distal trabecular bone regions. At the mostly cortical bone midshaft sites of the radius and tibia, men with T2DM had lower ToA (−1% to −3%, p < .05), resulting in lower bone bending strength at both sites after adjusting for body weight (−2% to −5%, p < .05) despite the lack of difference in cortical vBMD at these sites. These data demonstrate that older men with T2DM have bone strength that is low relative to body weight at the cortical-rich midshaft of the radius despite no difference in cortical vBMD. © 2010 American Society for Bone and Mineral Researc

Tobacco smoking as a risk factor of bronchioloalveolar carcinoma of the lung: pooled analysis of seven case–control studies in the International Lung Cancer Consortium (ILCCO)

Background: The International Lung Cancer Consortium (ILCCO) was established in 2004, based on the collaboration of research groups leading large molecular epidemiology studies of lung cancer that are ongoing or have been recently completed. This framework offered the opportunity to investigate the role of tobacco smoking in the development of bronchioloalveolar carcinoma (BAC), a rare form of lung cancer. Methods: Our pooled data comprised seven case–control studies from the United States, with detailed information on tobacco smoking and histology, which contributed 799 cases of BAC and 15,859 controls. We estimated the odds ratio of BAC for tobacco smoking, using never smokers as a referent category, after adjustment for age, sex, race, and study center. Results: The odds ratio of BAC for ever smoking was 2.47 (95% confidence interval [CI] 2.08, 2.93); the risk increased linearly with duration, amount, and cumulative cigarette smoking and persisted long after smoking cessation. The proportion of BAC cases attributable to smoking was 0.47 (95% CI 0.39, 0.54). Conclusions: This analysis provides a precise estimate of the risk of BAC for tobacco smoking

Breast-Cancer-Specific Mortality in Patients Treated Based on the 21-Gene Assay: A SEER Population-Based Study

The 21-gene Recurrence Score assay is validated to predict recurrence risk and chemotherapy benefit in hormone-receptor-positive (HR+) invasive breast cancer. To determine prospective breast-cancer-specific mortality (BCSM) outcomes by baseline Recurrence Score results and clinical covariates, the National Cancer Institute collaborated with Genomic Health and 14 population-based registries in the the Surveillance, Epidemiology, and End Results (SEER) Program to electronically supplement cancer surveillance data with Recurrence Score results. The prespecified primary analysis cohort was 40–84 years of age, and had node-negative, HR+, HER2-negative, nonmetastatic disease diagnosed between January 2004 and December 2011 in the entire SEER population, and Recurrence Score results (N = 38,568). Unadjusted 5-year BCSM were 0.4% (n = 21,023; 95% confidence interval (CI), 0.3–0.6%), 1.4% (n = 14,494; 95% CI, 1.1–1.7%), and 4.4% (n = 3,051; 95% CI, 3.4–5.6%) for Recurrence Score \u3c 18, 18–30, and ≥ 31 groups, respectively (P \u3c 0.001). In multivariable analysis adjusted for age, tumor size, grade, and race, the Recurrence Score result predicted BCSM (P \u3c 0.001). Among patients with node-positive disease (micrometastases and up to three positive nodes; N = 4,691), 5-year BCSM (unadjusted) was 1.0% (n = 2,694; 95% CI, 0.5–2.0%), 2.3% (n = 1,669; 95% CI, 1.3–4.1%), and 14.3% (n = 328; 95% CI, 8.4–23.8%) for Recurrence Score \u3c 18, 18–30, ≥ 31 groups, respectively (P \u3c 0.001). Five-year BCSM by Recurrence Score group are reported for important patient subgroups, including age, race, tumor size, grade, and socioeconomic status. This SEER study represents the largest report of prospective BCSM outcomes based on Recurrence Score results for patients with HR+, HER2-negative, node-negative, or node-positive breast cancer, including subgroups often under-represented in clinical trials

Electromagnetic Wave Theory and Applications

Contains reports on twelve research projects.Joint Services Electronics Program (Contract DAALO3-86-K-0002)National Science Foundation (Grant ECS 85-04381)National Aeronautics and Space Administration/Goddard Space Flight Center (Contract NAG5-270)National Aeronautics and Space Administration/Goddard Space Flight Center (Contract NAG5-725)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0258)U.S. Navy - Office of Naval Research (Contract N00014-86-K-0533)U.S. Army - Research Office Durham (Contract DAAG29-85-K-0079)International Business Machines, Inc.National Aeronautics and Space Administration/Goddard Space Flight Center (Contract NAG5-269)Simulation TechnologiesSchlumberger-Doll Researc

Tackling barriers to COVID-19 vaccine uptake in London: a mixed-methods evaluation

BACKGROUND: In response to the COVID-19 pandemic, the first vaccine was administered in December 2020 in England. However, vaccination uptake has historically been lower in London than in other English regions. METHODS: Mixed-methods: This comprised an analysis of cumulative percentage uptake across London between 8 December 2020 and 6 June 2021 by vaccine priority cohorts and ethnicity. We also undertook thematic analyses of uptake barriers, interventions to tackle these and key learning from a qualitative survey of 27 London local authority representatives, vaccine plans from London's five Integrated Care Systems and interviews with 38 London system representatives. RESULTS: Vaccine uptake was lower in Black ethnic (57-65% uptake) compared with the White British group (90% uptake). Trust was a critical issue, including mistrust in the vaccine itself and in authorities administering or promoting it. The balance between putative costs and benefits of vaccination created uptake barriers for zero-hour and shift workers. Intensive, targeted and 'hyper-local' initiatives, which sustained community relationships and were not constrained by administrative boundaries, helped tackle these barriers. CONCLUSIONS: The success of the national vaccination programme depended on conceding local autonomy, investing in responsive and long-term partnerships to engender trust through in-depth understanding of communities' beliefs

THE IMPACT OF GEL ELECTROPHORESIS UPON OUR UNDERSTANDING OF THE ESTERASES *

The impact of gel electrophoresis upon our understanding of the esterases has been formidable in that it has provided us with new insights and understanding concerning the number and biochemical characteristics of the many esterase-active proteins found in biological material. The relationships between the esterases within a species and among species still remains largely to be determined. With regard to the function of esterases it is to be expected that there will be several. One promising possibility is suggested by the work of Allen and Hunter, which illustrated a dependent relationship between male sex hormone and the esterases in the mouse epididymis. Supporting this work is the observation by Shaw and Koen (1963) demonstrating the presence of an esterase in the mouse kidney, which also was dependent on male sex hormone. The change observed in the serum esterase of the pregnant rabbit reported here and in women by Friedman and Lapman (1961) may also relate to hormone changes associated with pregnancy, although this relationship remains to be demonstrated. A second area where the esterases are likely to be functioning is in relation to protein synthetic activity of the endoplasmic reticulum. The only evidence supporting this suggestion is the abundant presence of esterases found in this location. The seven experiments described and discussed here along with those included in the references may serve as illustrations of the kind of work that can be accomplished by the use of these methods.*Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75632/1/j.1749-6632.1964.tb14224.x.pd

Simplified Models for LHC New Physics Searches

This document proposes a collection of simplified models relevant to the design of new-physics searches at the LHC and the characterization of their results. Both ATLAS and CMS have already presented some results in terms of simplified models, and we encourage them to continue and expand this effort, which supplements both signature-based results and benchmark model interpretations. A simplified model is defined by an effective Lagrangian describing the interactions of a small number of new particles. Simplified models can equally well be described by a small number of masses and cross-sections. These parameters are directly related to collider physics observables, making simplified models a particularly effective framework for evaluating searches and a useful starting point for characterizing positive signals of new physics. This document serves as an official summary of the results from the "Topologies for Early LHC Searches" workshop, held at SLAC in September of 2010, the purpose of which was to develop a set of representative models that can be used to cover all relevant phase space in experimental searches. Particular emphasis is placed on searches relevant for the first ~50-500 pb-1 of data and those motivated by supersymmetric models. This note largely summarizes material posted at http://lhcnewphysics.org/, which includes simplified model definitions, Monte Carlo material, and supporting contacts within the theory community. We also comment on future developments that may be useful as more data is gathered and analyzed by the experiments.Comment: 40 pages, 2 figures. This document is the official summary of results from "Topologies for Early LHC Searches" workshop (SLAC, September 2010). Supplementary material can be found at http://lhcnewphysics.or

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD