Strategy for Mitigating DKA Risk in Patients with Type 1 Diabetes on Adjunctive Treatment with SGLT Inhibitors: A STICH Protocol

Diabetic ketoacidosis (DKA) is a serious complication of diabetes that occurs primarily in type 1 diabetes (T1D), although it may also affect patients with other forms of insulin-dependent diabetes and may occur in new-onset type 2 diabetes. Insulin deficiency is associated with an increase in glucagon and excessive lipolysis with increased oxidation of fatty acids to ketone bodies in the liver and ketonemia. Ketosis may advance to metabolic acidosis. For DKA to be diagnosed, both ketosis and acidosis must be present. If not recognized and/or treated early, it can become serious and life-threatening; 168,000 patients were admitted to U.S. hospitals for DKA in 2014

Excitation Spectrum of One-dimensional Extended Ionic Hubbard Model

We use Perturbative Continuous Unitary Transformations (PCUT) to study the one dimensional Extended Ionic Hubbard Model (EIHM) at half-filling in the band insulator region. The extended ionic Hubbard model, in addition to the usual ionic Hubbard model, includes an inter-site nearest-neighbor (n.n.) repulsion, $V$. We consider the ionic potential as unperturbed part of the Hamiltonian, while the hopping and interaction (quartic) terms are treated as perturbation. We calculate total energy and ionicity in the ground state. Above the ground state, (i) we calculate the single particle excitation spectrum by adding an electron or a hole to the system. (ii) the coherence-length and spectrum of electron-hole excitation are obtained. Our calculations reveal that for V=0, there are two triplet bound state modes and three singlet modes, two anti-bound states and one bound state, while for finite values of $V$ there are four excitonic bound states corresponding to two singlet and two triplet modes. The major role of on-site Coulomb repulsion $U$ is to split singlet and triplet collective excitation branches, while $V$ tends to pull the singlet branches below the continuum to make them bound states.Comment: 10 eps figure

Incretin-based therapies and diabetic retinopathy: Real-world evidence in older U.S. adults

OBJECTIVE: Recent large trials yield conflicting results on the association between incretin-based therapies (IBTs) and diabetic retinopathy (DR). We examined whether IBTs increase DR risk compared with other antihyperglycemics. RESEARCH DESIGN AND METHODS: We implementedan active comparator, new-user cohort design using anationwide 20% random sample of fee-for-service U.S. Medicare beneficiaries aged 65 years or older with Parts A, B, and D coverage between 2007 and 2015. We identified the following cohorts without prior treatment for retinopathy: dipeptidyl peptidase 4 inhibitors (DPP4i) versus sulfonylureas (SU), DPP4i versus thiazolidinediones (TZD), glucagon-like peptide-1receptor agonists (GLP1RA)versus long-acting insulin (LAI), and GLP1RA versus TZD. Primary outcome was advanced diabetic retinopathy requiring treatment (ADRRT), defined as a procedure code for retinopathy treatment. Incident diabetic retinopathy (IDR), identified by a diagnosis code, was a secondary outcome. We estimated propensity scores to balance confounders and adjusted hazard ratios (95% CI) using weighted Cox proportional hazards models. RESULTS: We identified 213, 652 eligible patients. During a median duration of 0.58 to 0.87 years across comparisons, with a rate from 6.0 to 12.8 per 1,000 person-years, IBTs were not associated with increased ADRRT or IDR risk. The adjusted hazard ratios (95% CI) for ADRRT were 0.91 (0.79-1.04) by comparing DPP4i to SU (n = 39,292 and 87,073); 0.91 (0.75-1.11), DPP4i to TZD (n = 51, 410 and 22, 231); 0.50 (0.39-0.65), GLP1RA to LAI (n = 9, 561 and 82, 849); and 0.75 (0.53-1.06), GLP1RA to TZD (n = 10, 355 and 27, 345). CONCLUSIONS: Our population-based cohort study of older U.S. adults with diabetes suggests that IBTs used for approximately 1 year do not increase the DR risk

From Gapped Excitons to Gapless Triplons in One Dimension

Often, exotic phases appear in the phase diagrams between conventional phases. Their elementary excitations are of particular interest. Here, we consider the example of the ionic Hubbard model in one dimension. This model is a band insulator (BI) for weak interaction and a Mott insulator (MI) for strong interaction. Inbetween, a spontaneously dimerized insulator (SDI) occurs which is governed by energetically low-lying charge and spin degrees of freedom. Applying a systematically controlled version of the continuous unitary transformations (CUTs) we are able to determine the dispersions of the elementary charge and spin excitations and of their most relevant bound states on equal footing. The key idea is to start from an externally dimerized system using the relative weak interdimer coupling as small expansion parameter which finally is set to unity to recover the original model.Comment: 18 pages, 10 figure

Improved time in range and glycemic variability with sotagliflozin in combination with insulin in adults with type 1 diabetes: A pooled analysis of 24-week continuous glucose monitoring data from the IntanDEM program

OBJECTIVE To evaluate effects of the dual sodium–glucose cotransporter (SGLT) 1 and SGLT2 inhibitor sotagliflozin in combination with insulin on glucose time in range (TIR) and glucose excursions, postprandial glucose (PPG), and other glycemic metrics in adults with type 1 diabetes using masked continuous glucose monitoring (CGM). RESEARCH DESIGN AND METHODS Data sets from the inTandem1 (clinical trial reg. no. NCT02384941) and inTandem2 (clinical trial reg. no. NCT02421510) double-blind randomized trials evaluating sotagliflozin versus placebo in adults with type 1 diabetes treated with optimized insulin were pooled for analyses of masked CGM data from a subset of participants in each trial. The pooled cohort included patients randomized to receive placebo (n = 93), sotagliflozin 200 mg (n = 89), or sotagliflozin 400 mg (n = 96). The primary outcome was change from baseline to week 24 in glucose TIR (3.9–10.0 mmol/L [70–180 mg/dL]). Secondary end points included time below and above the target range and 2-h PPG level assessed after a standardized mixed meal. RESULTS Mean percentage of glucose TIR/percentage time spent at <3.9 mmol/L (<70 mg/dL) during week 24 was 51.6%/5.9%, 57.8%/5.5%, and 64.2%/5.5% with placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively, which corresponded to a placebo-adjusted change from a baseline of +5.4%/20.3% (P = 0.026; +1.3/20.1 h/day) for sotagliflozin 200 mg and +11.7%/20.1% (P < 0.001; +2.8/20.02 h/day) for sotagliflozin 400 mg. Placebo-adjusted PPG reductions were 1.9 6 0.7 mmol/L (35 6 13 mg/dL; P = 0.004) and 2.8 6 0.7 mmol/L (50 6 13 mg/dL; P < 0.001) with sotagliflozin 200 and 400 mg, respectively. CONCLUSIONS Combined with optimized insulin in type 1 diabetes, sotagliflozin significantly increased glucose TIR without increasing time spent at <3.9 mmol/L and reduced PPG, thereby improving glycemic control

Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: The North American in Tandem1 study

OBJECTIVE: Evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with optimized insulin in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: The in Tandem1 trial, a double-blind, 52-week phase 3 trial, randomized North American adults with T1D to placebo (n = 268), sotagliflozin 200 mg (n = 263), or sotagliflozin 400mg(n =262) after6 weeks ofinsulin optimization. The primary end point was HbA1c change from baseline at 24 weeks. HbA1c, weight, and safety were also assessed through 52 weeks. RESULTS: From a mean baseline of 7.57%, placebo-adjusted HbA1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P &lt; 0.001). Among patients with a baseline HbA1c ≥7.0%, an HbA1c &lt;7% was achieved by 15.7%, 27.2%, and 40.3% of patients receiving placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively (P ≤ 0.003 vs. placebo) at 24 weeks. At 52 weeks, mean treatment differences between sotagliflozin 400 mg and placebo were 21.08 mmol/L for fasting plasma glucose, 24.32 kg for weight, and 215.63% for bolus insulin dose and 211.87% for basal insulin dose (all P &lt; 0.001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly by 2.5 points with sotagliflozin versus placebo (P &lt; 0.001) at 24 weeks. Genital mycotic infections and diarrhea occurred more frequently with sotagliflozin. Adjudicated diabetic ketoacidosis (DKA) occurred in 9 (3.4%) and 11 (4.2%) patients receiving sotagliflozin 200 and 400 mg, respectively, and in 1 (0.4%) receiving placebo. Severe hypoglycemia occurred in 17 (6.5%) patients from each sotagliflozin group and 26 (9.7%) patients receiving placebo. CONCLUSIONS: In a 1-year T1D study, sotagliflozin combined with optimized insulin therapy was associated with sustained HbA1c reduction, weight loss, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo (ClinicalTrials.gov, NCT02384941)

Myocardial inflammation and energetics by cardiac MRI : a review of emerging techniques

The role of inflammation in cardiovascular pathophysiology has gained a lot of research interest in recent years. Cardiovascular Magnetic Resonance has been a powerful tool in the non-invasive assessment of inflammation in several conditions. More recently, Ultrasmall superparamagnetic particles of iron oxide have been successfully used to evaluate macrophage activity and subsequently inflammation on a cellular level. Current evidence from research studies provides encouraging data and confirms that this evolving method can potentially have a huge impact on clinical practice as it can be used in the diagnosis and management of very common conditions such as coronary artery disease, ischaemic and non-ischaemic cardiomyopathy, myocarditis and atherosclerosis. Another important emerging concept is that of myocardial energetics. With the use of phosphorus magnetic resonance spectroscopy, myocardial energetic compromise has been proved to be an important feature in the pathophysiological process of several conditions including diabetic cardiomyopathy, inherited cardiomyopathies, valvular heart disease and cardiac transplant rejection. This unique tool is therefore being utilized to assess metabolic alterations in a wide range of cardiovascular diseases. This review systematically examines these state-of-the-art methods in detail and provides an insight into the mechanisms of action and the clinical implications of their use

Indistinguishability Obfuscation and UCEs : The Case of Computationally Unpredictable Sources

Random oracles are powerful cryptographic objects. They facilitate the security proofs of an impressive number of practical cryptosystems ranging from KDM-secure and deterministic encryption to point-function obfuscation and many more. However, due to an uninstantiability result of Canetti, Goldreich, and Halevi (STOC 1998) random oracles have become somewhat controversial. Recently, Bellare, Hoang, and Keelveedhi (BHK; CRYPTO 2013 and ePrint 2013/424, August 2013) introduced a new abstraction called Universal Computational Extractors (UCEs), and showed that they suffice to securely replace random oracles in a number of prominent applications, including all those mentioned above, without suffering from the aforementioned uninstantiability result. This, however, leaves open the question of constructing UCEs in the standard model. We show that the existence of indistinguishability obfuscation (iO) implies (non-black-box) attacks on all the definitions that BHK proposed within their UCE framework in the original version of their paper, in the sense that no concrete hash function can satisfy them. We also show that this limitation can be overcome, to some extent, by restraining the class of admissible adversaries via a statistical notion of unpredictability. Following our attack, BHK (ePrint 2013/424, September 2013), independently adopted this approach in their work. In the updated version of their paper, BHK (ePrint 2013/424, September 2013) also introduce two other novel source classes, called bounded parallel sources and split sources, which aim at recovering the computational applications of UCEs that fall outside the statistical fix. These notions keep to a computational notion of unpredictability, but impose structural restrictions on the adversary so that our original iO attack no longer applies. We extend our attack to show that indistinguishability obfuscation is sufficient to also break the UCE security of any hash function against bounded parallel sources. Towards this goal, we use the randomized encodings paradigm of Applebaum, Ishai, and Kushilevitz (STOC 2004) to parallelize the obfuscated circuit used in our attack, so that it can be computed by a bounded parallel source whose second stage consists of constant-depth circuits. BHK, in the latest version of their paper (ePrint 2013/424, May 2014), have subsequently replace bounded parallel sources with new source classes. We conclude by discussing the composability and feasibility of hash functions secure against split sources

Limitations of the Meta-reduction Technique: The Case of Schnorr Signatures

We revisit the security of Fiat-Shamir signatures in the non-programmable random oracle model. The well-known proof by Pointcheval and Stern for such signature schemes (Journal of Cryptology, 2000) relies on the ability to re-program the random oracle, and it has been unknown if this property is inherent. Pailler and Vergnaud (Asiacrypt 2005) gave some first evidence of the hardness by showing via meta-reduction techniques that algebraic reductions cannot succeed in reducing key-only attacks against unforgeability to the discrete-log assumptions. We also use meta-reductions to show that the security of Schnorr signatures cannot be proven equivalent to the discrete logarithm problem without programming the random oracle. Our result also holds under the one-more discrete logarithm assumption but applies to a large class of reductions, we call *single-instance* reductions, subsuming those used in previous proofs of security in the (programmable) random oracle model. In contrast to algebraic reductions, our class allows arbitrary operations, but can only invoke a single resettable adversary instance, making our class incomparable to algebraic reductions. Our main result, however, is about meta-reductions and the question if this technique can be used to further strengthen the separations above. Our answer is negative. We present, to the best of our knowledge for the first time, limitations of the meta-reduction technique in the sense that finding a meta-reduction for general reductions is most likely infeasible. In fact, we prove that finding a meta-reduction against a potential reduction is equivalent to finding a ``meta-meta-reduction\u27\u27 against the strong existential unforgeability of the signature scheme. This means that the existence of a meta-reduction implies that the scheme must be insecure (against a slightly stronger attack) in the first place