Oral semaglutide: the innovation in type 2 diabetes management

Oral semaglutide is the first-in-class glucagon-like peptide-1 receptor agonist available in the form of pills administered per os. PIONEER — the clinical trial program assessing the efficacy and safety of oral semaglutide — demonstrated the dose-­dependent efficacy of the drug: the reduction of up to -1,4% in terms of glucose-lowering effects and the decrease of up to 5 kg in terms of weight loss. Moreover, oral semaglutide is superior in this regard compared to empagliflozin 25 mg, liraglutide 1,8 mg and sitagliptin 100 mg according to the dedicated trials of clinical program. From the cardiovascular perspective oral semaglutide has been proven to be safe. Therapeutic concentration of semaglutide in oral form is reached under ­several conditions: taking tablets on a daily basis in a fasting state with up to half a glass of water and waiting 30 minutes before drinking, eating, or taking other drugs. Most frequent adverse events were GLP-1 associated gastrointestinal reactions (­nausea, vomiting and diarrhea), most of the events were transient and occurred generally during dose escalation

Remarks on the "non-canonicity puzzle": Lagrangian symmetries of the Einstein-Hilbert action

Given the non-canonical relationship between variables used in the Hamiltonian formulations of the Einstein-Hilbert action (due to Pirani, Schild, Skinner (PSS) and Dirac) and the Arnowitt-Deser-Misner (ADM) action, and the consequent difference in the gauge transformations generated by the first-class constraints of these two formulations, the assumption that the Lagrangians from which they were derived are equivalent leads to an apparent contradiction that has been called "the non-canonicity puzzle". In this work we shall investigate the group properties of two symmetries derived for the Einstein-Hilbert action: diffeomorphism, which follows from the PSS and Dirac formulations, and the one that arises from the ADM formulation. We demonstrate that unlike the diffeomorphism transformations, the ADM transformations (as well as others, which can be constructed for the Einstein-Hilbert Lagrangian using Noether's identities) do not form a group. This makes diffeomorphism transformations unique (the term "canonical" symmetry might be suggested). If the two Lagrangians are to be called equivalent, canonical symmetry must be preserved. The interplay between general covariance and the canonicity of the variables used is discussed.Comment: 23 page

Covariance and Time Regained in Canonical General Relativity

Canonical vacuum gravity is expressed in generally-covariant form in order that spacetime diffeomorphisms be represented within its equal-time phase space. In accordance with the principle of general covariance, the time mapping {\T}: {\yman} \to {\rman} and the space mapping {\X}: {\yman} \to {\xman} that define the Dirac-ADM foliation are incorporated into the framework of the Hilbert variational principle. The resulting canonical action encompasses all individual Dirac-ADM actions, corresponding to different choices of foliating vacuum spacetimes by spacelike hypersurfaces. In this framework, spacetime observables, namely, dynamical variables that are invariant under spacetime diffeomorphisms, are not necessarily invariant under the deformations of the mappings \T and \X, nor are they constants of the motion. Dirac observables form only a subset of spacetime observables that are invariant under the transformations of \T and \X and do not evolve in time. The conventional interpretation of the canonical theory, due to Bergmann and Dirac, can be recovered only by postulating that the transformations of the reference system ({\T},{\X}) have no measurable consequences. If this postulate is not deemed necessary, covariant canonical gravity admits no classical problem of time.Comment: 41 pages, no figure

Quantum Cosmology Aspects Of D3 Branes and Tachyon Dynamics

We investigate aspects of quantum cosmology in relation to string cosmology systems that are described in terms of the Dirac-Born-Infeld action. Using the Silverstein-Tong model, we analyze the Wheeler-DeWitt equation for the rolling scalar and gravity as well for $R\times{S^3}$ universe, by obtaining the wave functions for all dynamical degrees of freedom of the system. We show, that in some cases one can construct a time dependent version of the Wheeler-DeWitt (WDW) equation for the moduli field $\phi$. We also explore in detail the minisuperspace description of the rolling tachyon when non-minimal gravity tachyon couplings are inserted into the tachyon action.Comment: 29 pages, 3 figures, REVTeX 4; v2 clarifications, comments and references added; v3 more typos corrected, additional comments on the minisuperspace description of unstable universes, version published in JHE

Guidelines for the diagnosis and treatment of testosterone deficiency (hypogonadism) in male patients with diabetes mellitus (Draft)

Hypogonadism in male patients is defined as a decrease in the serum testosterone level; it is associated with specific symptoms and/or signs (see the detailed description below). It is a common complication in diabetes mellitus. The guidelines do not review all disorders leading to the development of hypogonadism but focus on options for the treatment of hypogonadism, which is generally observed in male patients with diabetes. In the literature, data on the prevalence of hypogonadism in patients with diabetes are available. In the section on diagnostics, the medical history of patients with hypogonadism and diabetes, including the necessary methods for physical and laboratory inspection. Risk factors for and the clinical consequences of hypogonadism are separately considered. In the section on treatment options, variations in treatment using various androgenic therapeutic agents based on patients’ requirements, conservation of their reproductive function, and their risk factors are provided. Special attention is given to indications of, contraindications of and risk factors for androgenic therapy in male patients with diabetes, particularly those in their advanced age. The principles of the clinical monitoring are developed. The favourable effects of androgenic therapy for hypogonadism in male patients with diabetes are shown

Diagnosis and rational treatment of painful diabetic peripheral neuropathy: an interdisciplinary expert consensus

Diabetic peripheral neuropathy is a common chronic complication of diabetes mellitus, significantly impairing well-being, quality of life and functioning of patients. The prevalence of diabetic peripheral neuropathy in the Russian Federation ranges from 0.1% to 67.2% in type 1 and from 0.1 to 42.4% in type 2 diabetes mellitus. However, based on the large-scale epidemiological studies, the true prevalence of diabetic peripheral neuropathy is much higher (50 to 70%), with its painful variant occurring in 16% to 30% of patients. Despite the fact that diabetic peripheral neuropathy remains the most common chronic complication of diabetes mellitus, its diagnosis and therapy leave much to be desired. To optimize diagnostic and treatment approaches to painful diabetic peripheral neuropathy, a group of experts representing the leading Russian professional medical associations has developed clinical guidelines for the diagnosis and rational therapy of patients with painful diabetic peripheral neuropathy. This document presents practical aspects of the clinical diagnosis of painful diabetic peripheral neuropathy and an algorithm for differential diagnosis of pain in the lower extremities in patients with diabetes mellitus. The use of symptomatic analgesics with central action, such as anticonvulsants, antidepressants and opioids, is based on the main aspects of neuropathic pain pathophysiology. The characteristics of each drug class are given, with consideration of evidence on their efficacy, tolerability, and the possibility of combination therapy. The data on the first, second, and third lines of agents is presented in accordance with several international clinical guidelines. The need for a tailored drug choice, taking into account the evidence-based data on their efficacy and safety, concomitant drug therapy, tolerability, cost and preferences of the patient, age of the patient and concomitant disorders, is emphasized

Методы оценки размеров раневого дефекта при синдроме диабетической стопы

Object. The study of the informativeness by various methods of visualizing the dimensions of wound defects and the dynamics of their healing in patients with diabetic foot syndrome (DFS).Materials and Methods. The descriptive research analyzed various methods for determining the size of wounds in 77 patients with DFS. 63 (81.8 %) patients (1st group) were performed classical planimetry by film using. The wound size at 6 (7.8 %) patients (2nd group) was estimated by using a computer program, 8 (10.4 %) patients (3d group) underwent magnetic resonance imaging (MRI) their feet.Results. In the course of the study, the median area of wounds in Group 1 patients were 25.0 [16.2; 44.5] cm2, median depth — 3.3 [1.5; 6.5] cm. It was required about 15–20 minutes of the expert work. The median area of wounds by patients Group 2, measured with the mobile application V2F, was 8.95 [6.8; 10.6] cm2. The depth determined by the same method was 0.25 [0.2; 0.5] cm. The study duration amount to 5 minutes approximately. The 3d patients Group that was measured with MRI had wound defects depth equal to 3.2 [2.6; 4.5] cm, wound area - 23.5 [12.3; 55.3] cm2. This study duration was similar to the standard MRI protocol.Conclusion. The planimetric method of wound size analysis is a routine way for assessing the dynamics of the wound defects state, its size and depth. Determining the size of wounds with special software is rather quick and simple method, but it allows to evaluate only the planar characteristics of the wound and has a high error. The MRI procedure of a wound with an alginate dressing allows to reliably estimate the volume of wound defect and exclude the presence of a hidden infection focus.Цель. Изучение информативности различных методов визуализации размеров раневых дефектов и динамики их заживления у пациентов с синдромом диабетической стопы (СДС).Материалы и методы. В описательном исследовании были проанализированы различные методы определения размеров ран у 77 пациентов с СДС. 63 (81,8 %) пациентам (группа 1) провели классическую планиметрию с использованием пленки. У 6 (7,8 %) человек (группа 2) размеры раны оценивали с помощью компьютерной программы. 8 (10,4 %) больным (группа 3) проводили МРТ стопы. Результаты. В ходе проведенного исследования медиана площади ран у пациентов группы 1 составляла 25,0 [16,2; 44,5] см2, медиана глубины — 3,3 [1,5; 6,5] см. На проведение данного исследования в среднем требовалось около 15–20 минут специалиста. У пациентов группы 2 медиана площади ран, измеренная с помощью мобильного приложения V2F, составляла 8,95 [6,8; 10,6] см2. Глубина, определенная аналогичным методом, – 0,25 [0,2; 0,5] см. Длительность исследования составляла около 5 минут. У больных группы 3 медиана глубины раневых дефектов, измеренная при помощи МРТ, составляла 3,2 [2,6; 4,5] см, площадь раны — 23,5 [12,3; 55,3] см2. Продолжительность данного исследования аналогична стандартному протоколу МРТ.Заключение. Исследование размеров ран планиметрическим методом является рутинным способом оценки динамики состояния раневого дефекта, его размеров и глубины. Определение размеров ран при помощи специального программного обеспечения – достаточно быстрый и простой метод, однако он позволяет оценить лишь плоскостные характеристики раны и отличается высокой погрешностью. Методика проведения МРТ раны с альгинатной повязкой позволяет достоверно оценить объем раневого дефекта и исключить наличие скрытого очага инфекции.

Resolution on the results of the First All-Russian Forum "Therapeutic Education in Endocrinology"

According to the decision of the WHO, therapeutic education (TE) of patients is an independent branch of medicine and an essential component of the treatment of chronic diseases, primarily diabetes mellitus and obesity. TE is implemented through the creation of “Schools for patients with diabetes mellitus” and “Schools for patients with overweight” (“Schools”) as a structural unit of a medical institution. On April 25–26, 2022, the First All-Russian Forum «Therapeutic Education in Endocrinology» was held online, organized by the Public Organization «Russian Association of Endocrinologists», which was attended by leading experts in this field. As a result of its work, this Resolution was adopted by the experts. It discusses the methodological and pedagogical foundations of TE, it is proposed to make changes related to the organization of the work of «Schools», tariffing in the obligatory health insurance system, and training of personnel, including nurses

The first and only combination of basal and prandial insulin analogs degludec and aspart: the position of Russian endocrinologists

Insulin therapy for diabetes mellitus is the most effective way to control glycemia with the progression of the disease and the ineffectiveness of other sugar-lowering drugs. At the same time, the existing limitations of traditional insulin preparations, along with increasing attention to the individualized treatment of this disease, are pushing developers to create drugs that most closely reproduce the effect of natural human insulin. In this regard, the appearance of a combination of insulin analogs, the action profile of which practically imitates insulin secretion by a healthy pancreas, presents new possibilities in the treatment of diabetes mellitus. Insulin degludec / insulin aspart (IDegAsp, Ryzodeg®, Novo Nordisk, Denmark) is the first and only soluble combination preparation containing 70% of the ultra-long-acting insulin analogue degludec and 30% of the ultra-short-acting insulin analogue aspart in one injection, which meets the need for both basal and prandial insulin. The combined drug has nothing in common with traditional mixed insulin preparations (both human and analog) and provides doctors and patients with significant advantages over the latter. The article presents the position of Russian experts-diabetologists with extensive experience in the use of IDegAsp regarding the role and place of the drug in real clinical practice. Data from real clinical practice confirm that IDegAsp is a reasonable choice for starting and intensifying insulin therapy for type 2 diabetes mellitus when basal and prandial glycemic control is required. The use of the drug is most appropriate in patients who are on basal, biphasic, basal-plus/basal-bolus regimens and who do not achieve the goals of glycemic control during prior therapy. One of the leading reasons for choosing IDegAsp may also be a lower risk of developing hypoglycemia compared to insulin analogues of previous generations — biphasic insulin aspart and basal insulin glargine 100 U/ml. In addition, IDegAsp is a simple, flexible and safe insulin therapy for patients on premix therapy and basal-plus/basis-bolus regimens who require basal and prandial glycemic control. IDegAsp is a simple, flexible and safe insulin therapy. The greatest benefit of this drug use can be obtained by patients for whom adherence to a complex therapy regimen is difficult (the elderly, with cognitive impairment, after a stroke, with dementia), as well as patients who have an active lifestyle, accompanied by irregular food intake. It is important to note that since January 1, 2021, there is no need for a decision by a special medical commission to prescribe (IDegAsp) Ryzodeg®. This fact, as well as a significant price reduction at the end of 2020, opens up broader prospects for using the drug in the routine practice of a Russian endocrinologist

Spatio‐temporal patterns of tree growth as related to carbon isotope fractionation in European forests under changing climate

Aim To decipher Europe-wide spatiotemporal patterns of forest growth dynamics and their associations with carbon isotope fractionation processes inferred from tree rings as modulated by climate warming. Location Europe and North Africa (30‒70°N, 10°W‒35°E). Time period 1901‒2003. Major taxa studied Temperate and Euro-Siberian trees. Methods We characterize changes in the relationship between tree growth and carbon isotope fractionation over the 20th century using a European network consisting of 20 site chronologies. Using indexed tree-ring widths (TRWi), we assess shifts in the temporal coherence of radial growth across sites (synchrony) for five forest ecosystems (Atlantic, Boreal, cold continental, Mediterranean and temperate). We also examine whether TRWi shows variable coupling with leaf-level gas exchange, inferred from indexed carbon isotope discrimination of tree-ring cellulose (Δ13Ci). Results We find spatial autocorrelation for TRWi and Δ13Ci extending over up to 1,000 km among forest stands. However, growth synchrony is not uniform across Europe, but increases along a latitudinal gradient concurrent with decreasing temperature and evapotranspiration. Latitudinal relationships between TRWi and Δ13Ci (changing from negative to positive southwards) point to drought impairing carbon uptake via stomatal regulation for water saving occurring at forests below 60°N in continental Europe. A rise in forest growth synchrony over the 20th century together with increasingly positive relationships between TRWi and Δ13Ci indicate intensifying drought impacts on tree performance. These effects are noticeable in drought-prone biomes (Mediterranean, temperate and cold continental). Main conclusions At the turn of this century, convergence in growth synchrony across European forest ecosystems is coupled with coordinated warming-induced drought effects on leaf physiology and tree growth spreading northwards. Such a tendency towards exacerbated moisture-sensitive growth and physiology could override positive effects of enhanced leaf intercellular CO2 concentrations, possibly resulting in Europe-wide declines of forest carbon gain in the coming decades