Fetal hemoglobin levels and morbidity in untransfused patients with β-thalassemia intermedia

To evaluate the association between fetal hemoglobin (HbF) levels and morbidity in \u3b2-thalassemia intermedia (TI), we analyzed data from 63 untransfused patients who had also never received HbF induction therapy. Patient records were reviewed for any history of 10 predefined morbidities. Laboratory measurements for markers of ineffective erythropoiesis were also obtained. The mean age of patients was 32.1 years, 47.6% were males, and the median HbF level was 37.2%. HbF levels correlated positively with total hemoglobin, yet negatively with growth differentiation factor-15 and non-transferrin-bound iron levels. Median HbF levels were significantly lower in patients with the majority of evaluated morbidities than in those without. There was a strong negative adjusted linear correlation between the HbF level and the total number of morbidities (R(2) = 0.825, P < .001). The HbF threshold of 63.7% had 95.5% sensitivity and 100% specificity for ensuring absence of morbidity. There exists a strong association between HbF levels and morbidity in the subset of untransfused patients with T

Stress Transmission through Three-Dimensional Ordered Granular Arrays

We measure the local contact forces at both the top and bottom boundaries of three-dimensional face-centered-cubic and hexagonal-close-packed granular crystals in response to an external force applied to a small area at the top surface. Depending on the crystal structure, we find markedly different results which can be understood in terms of force balance considerations in the specific geometry of the crystal. Small amounts of disorder are found to create additional structure at both the top and bottom surfaces.Comment: 9 pages including 9 figures (many in color) submitted to PR

Synthesis of 3-D coronal-solar wind energetic particle acceleration modules

1. Introduction Acute space radiation hazards pose one of the most serious risks to future human and robotic exploration. Large solar energetic particle (SEP) events are dangerous to astronauts and equipment. The ability to predict when and where large SEPs will occur is necessary in order to mitigate their hazards. The Coronal-Solar Wind Energetic Particle Acceleration (C-SWEPA) modeling effort in the NASA/NSF Space Weather Modeling Collaborative [Schunk, 2014] combines two successful Living With a Star (LWS) (http://lws. gsfc.nasa.gov/) strategic capabilities: the Earth-Moon-Mars Radiation Environment Modules (EMMREM) [Schwadron et al., 2010] that describe energetic particles and their effects, with the Next Generation Model for the Corona and Solar Wind developed by the Predictive Science, Inc. (PSI) group. The goal of the C-SWEPA effort is to develop a coupled model that describes the conditions of the corona, solar wind, coronal mass ejections (CMEs) and associated shocks, particle acceleration, and propagation via physics-based modules. Assessing the threat of SEPs is a difficult problem. The largest SEPs typically arise in conjunction with X class flares and very fast (\u3e1000 km/s) CMEs. These events are usually associated with complex sunspot groups (also known as active regions) that harbor strong, stressed magnetic fields. Highly energetic protons generated in these events travel near the speed of light and can arrive at Earth minutes after the eruptive event. The generation of these particles is, in turn, believed to be primarily associated with the shock wave formed very low in the corona by the passage of the CME (injection of particles from the flare site may also play a role). Whether these particles actually reach Earth (or any other point) depends on their transport in the interplanetary magnetic field and their magnetic connection to the shock

Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes

There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80–90 g [300–400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances

Coherent π0 photoproduction on the deuteron up to 4 GeV

The differential cross section for 2H(γ,d)π0 has been measured at deuteron center-of-mass angles of 90° and 136°. This work reports the first data for this reaction above a photon energy of 1 GeV, and permits a test of the apparent constituent counting rule and reduced nuclear amplitude behavior as observed in elastic ed scattering. Measurements were performed up to a photon energy of 4.0 GeV, and are in good agreement with previous lower energy measurements. Overall, the data are inconsistent with both constituent-counting rule and reduced nuclear amplitude predictions

Measurements of Deuteron Photodisintegration up to 4.0 GeV

The first measurements of the differential cross section for the d(γ,p)n reaction up to 4.0 GeV were performed at the Continuous Electron Beam Accelerator Facility (CEBAF) at Thomas Jefferson Laboratory. We report the cross sections at the proton center-of-mass angles of 36°, 52°, 69°, and 89°. These results are in reasonable agreement with previous measurements at lower energy. The 89° and 69° data show constituent-counting-rule behavior up to 4.0 GeV photon energy. The 52° and 36° data disagree with the counting-rule behavior. The quantum chromodynamics (QCD) model of nuclear reactions involving reduced amplitudes disagrees with the present data.U.S. Department of Energy, National Science Foundatio

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries