Hypoglycemia in Type 2 Diabetes: Current Controversies and Changing Practices

Hypoglycemia is well-recognized to limit the degree of glycemic control possible for many individuals for diabetes. Although the likelihood of hypoglycemia increases as A1c levels decrease in type 1 diabetes, insulin-treated type 2 diabetic persons with higher A1c appear paradoxically to have more hypoglycemia which may explain, in part, the adverse outcome reported in the ACCORD study. Approaches to glucose-lowering that cause lesser degrees of risk for hypoglycemia, technologies to better ascertain hypoglycemic events, and better understanding of patient characteristics associated with greater likelihood of hypoglycemia will all be required to reduce this limiting factor in optimizing glycemic treatment

ThermoParser:Streamlined Analysis of Thermoelectric Properties

Thermoelectric materials, which convert heat into electricity, could be an important renewable energy source to help slow the encroaching climate crisis, not only by displacing fossil fuels, but by recycling waste heat, which makes up around 50 % of generated energy. With the growing computational capacity and development of several codes to calculate the key properties of thermoelectrics, they have become an increasingly popular area of computational materials research in recent years. Thermal transport packages include Phonopy, Phono3py, ShengBTE/ almaBTE, ALAMODE, TDEP and HiPhive; and electronic transport packages include BoltzTraP, BoltzTraP2, EPW, EPA, EPIC STAR, AMSET, Perturbo, TOSSPB and ElecTra. While separate packages are required for such different calculations, this makes data analysis complex, needing to load in different file formats, account for different data arrangements (e.g. array shapes), and convert to consistent units, even before one begins analysing anything. ThermoParser deals with these time-consuming and error-prone problems by loading data from multiple codes into a consistent data format with informative metadata, and facilitates the post-processing of thermoelectric properties by using this to accurately calculate and visualise them through an easy-to-use command-line interface (CLI) and a fully customisable Python package. Some of its utility can be seen by its use in the literature (sometimes under its former name, ThermoPlotter)

Are technicolor models compatible with a very heavy top quark?

We consider the phenomenological constraints on technicolor and extended technicolor (ETC) interactions required to give a realistic quark-lepton spectrum consistent with limits on flavor-changing neutral currents. Treating ETC interactions as higher-dimensional vertices in an effective-field theory of technicolor, we outline a phenomenologically acceptable technicolor model with a walking SU2 technicolor and a single generation of technifermions. Without fine-tuning or violating known constraints, we argue that both the strange-quark mass and a top-quark mass on the order of 100 GeV can be plausibly accommodated However, the precise ETC group and the dynamical mechanism responsible for its breaking are not determined.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30155/1/0000532.pd

A First-Quantized Formalism for Cosmological Particle Production

We show that the amount of particle production in an arbitrary cosmological background can be determined using only the late-time positive-frequency modes. We don't refer to modes at early times, so there is no need for a Bogolubov transformation. We also show that particle production can be extracted from the Feynman propagator in an auxiliary spacetime. This provides a first-quantized formalism for computing particle production which, unlike conventional Bogolubov transformations, may be amenable to a string-theoretic generalization.Comment: 18 pages, LaTeX; v2: significantly revised for clarity; conclusions unchange

Role of Fas and Treg Cells in Fracture Healing as Characterized in the Fas-Deficient (lpr) Mouse Model of Lupus

Previous studies showed that loss of tumor necrosis factor α (TNFα) signaling delayed fracture healing by delaying chondrocyte apoptosis and cartilage resorption. Mechanistic studies showed that TNFα induced Fas expression within chondrocytes; however, the degree to which chondrocyte apoptosis is mediated by TNFα alone or dependent on the induction of Fas is unclear. This question was addressed by assessing fracture healing in Fas-deficient B6.MRL/Faslpr/J mice. Loss of Fas delayed cartilage resorption but also lowered bone fraction in the calluses. The reduced bone fraction was related to elevated rates of coupled bone turnover in the B6.MRL/Faslpr/J calluses, as evidenced by higher osteoclast numbers and increased osteogenesis. Analysis of the apoptotic marker caspase 3 showed fewer positive chondrocytes and osteoclasts in calluses of B6.MRL/Faslpr/J mice. To determine if an active autoimmune state contributed to increased bone turnover, the levels of activated T cells and Treg cells were assessed. B6.MRL/Faslpr/J mice had elevated Treg cells in both spleens and bones of B6.MRL/Faslpr/J but decreased percentage of activated T cells in bone tissues. Fracture led to ∼30% to 60% systemic increase in Treg cells in both wild-type and B6.MRL/Faslpr/J bone tissues during the period of cartilage formation and resorption but either decreased (wild type) or left unchanged (B6.MRL/Faslpr/J) the numbers of activated T cells in bone. These results show that an active autoimmune state is inhibited during the period of cartilage resorption and suggest that iTreg cells play a functional role in this process. These data show that loss of Fas activity specifically in chondrocytes prolonged the life span of chondrocytes and that Fas synergized with TNFα signaling to mediate chondrocyte apoptosis. Conversely, loss of Fas systemically led to increased osteoclast numbers during later periods of fracture healing and increased osteogenesis. These findings suggest that retention of viable chondrocytes locally inhibits osteoclast activity or matrix proteolysis during cartilage resorption

TNFα Contributes to Diabetes Impaired Angiogenesis in Fracture Healing

Diabetes increases the likelihood of fracture, interferes with fracture healing and impairs angiogenesis. The latter may be significant due to the critical nature of angiogenesis in fracture healing. Although it is known that diabetes interferes with angiogenesis the mechanisms remain poorly defined. We examined fracture healing in normoglycemic and streptozotocin-induced diabetic mice and quantified the degree of angiogenesis with antibodies to three different vascular markers, CD34, CD31 and Factor VIII. The role of diabetes-enhanced inflammation was investigated by treatment of the TNFα-specific inhibitor, pegsunercept starting 10 days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression by chondrocytes. The reduced angiogenesis and VEGFA expression in diabetic fractures was rescued by specific inhibition of TNF in vivo. In addition, the TNF inhibitor rescued the negative effect of diabetes on endothelial cell proliferation and endothelial cell apoptosis. The effect of TNFα in vitro was enhanced by high glucose and an advanced glycation endproduct to impair microvascular endothelial cell proliferation and tube formation and to stimulate apoptosis. The effect of TNF, high glucose and an AGE was mediated by the transcription factor FOXO1, which increased expression of p21 and caspase-3. These studies indicate that inflammation plays a major role in diabetes-impaired angiogenesis in endochondral bone formation through its effect on microvascular endothelial cells and FOXO1

The Relativistic Bound State Problem in QCD: Transverse Lattice Methods

The formalism for describing hadrons using a light-cone Hamiltonian of SU(N) gauge theory on a coarse transverse lattice is reviewed. Physical gauge degrees of freedom are represented by disordered flux fields on the links of the lattice. A renormalised light-cone Hamiltonian is obtained by making a colour-dielectric expansion for the link-field interactions. Parameters in the Hamiltonian are renormalised non-perturbatively by seeking regions in parameter space with enhanced Lorentz symmetry. In the case of pure gauge theories to lowest non-trivial order of the colour-dielectric expansion, this is sufficient to determine accurately all parameters in the large-N limit. We summarize results from applications to glueballs. After quarks are added, the Hamiltonian and Hilbert space are expanded in both dynamical fermion and link fields. Lorentz and chiral symmetry are not sufficient to accurately determine all parameters to lowest non-trivial order of these expansions. However, Lorentz symmetry and one phenomenological input, a chiral symmetry breaking scale, are enough to fix all parameters unambiguously. Applications to light-light and heavy-light mesons are described.Comment: 55 pp, revised version, to appear in `Progress in Particle and Nuclear Physics

Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers

Patients and methods: Patients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS. Results: From April 2014-October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84). Conclusion: Patients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy