AIMS:To evaluate the immunogenicity, efficacy, and safety of a biosimilar insulin glulisine candidate (T-Glu) compared to the reference product (R-Glu) in patients with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS:In this phase III, randomised, open-label trial, adult patients with T1DM received either T-Glu or R-Glu by prefilled pens as their bolus insulin for 26 weeks. The primary outcome was the proportion of patients with an immune response at Week 26. Secondary endpoints included changes in glycaemia control parameters, insulin dose stability, treatment satisfaction, and other immunogenicity and safety outcomes. RESULTS:By Week 26, the immune response persisted in 16% of patients in the T-Glu group and 24% in the R-Glu group (p > 0.05), confirming similar immunogenicity. HbA1c reduction at Week 26 compared to baseline was similar between groups, with a mean change of 0.53% ± 1.19% in the T-Glu group and 0.38% ± 1.46% in the R-Glu group (mean difference: -0.15%, 95% CI: -0.50 to 0.20), demonstrating non-inferiority (according to a predefined margin of 0.4%). Fasting plasma glucose levels and the seven-point glucose profile showed no significant differences between groups (p > 0.05). Insulin dose remained stable throughout the study, and treatment satisfaction scores improved comparably in both groups (p > 0.05). The total number of AEs was similar, and hypoglycaemia was more frequent in the R-Glu group (p < 0.001), with no new safety concerns identified. CONCLUSIONS:T-Glu demonstrated similar immunogenicity, efficacy, and safety to R-Glu in adults with T1DM, supporting its use as a biosimilar insulin glulisine. CLINICALTRIALS:gov: NCT07070752.

INTRODUCTION: Topical diagnosis of pathologically altered parathyroid glands in patients with primary hyperparathyroidism is a challenge both for specialists of radial diagnostics and for planning the scope of surgical intervention. The choice of diagnostic modality for localization of parathyroid glands depends on the availability of the method for a particular medical center. PET/CT is a promising method to determine the localization of parathyroid adenomaOBJECTIVE: To analyze the experience of using PET/CT with 11C-methionine and PET/CT with 11C-choline for preoperative diagnosis of parathyroid pathology in patients with primary hyperparathyroidism.MATERIALS AND METHODS: 72 patients diagnosed with PHPT and underwent surgical treatment were included in the study. Before surgical intervention all patients underwent laboratory and instrumental investigations in the scope of: blood tests for PTH, TTH, ionized calcium, calcitonin, 25(OH)D, creatinine, phosphorus, ultrasound of the neck, computer tomography of the neck with intravenous bolus contrasting.RESULTS: PET/CT showed the highest rates of DA in the patient group before primary surgery — 90.9%, compared with ultrasound (89.6%) and CT with IV contrast (84.9%). In the group of solitary adenomas of ectopic MTCS, PET/CT also had a higher DA — 92.8% than the other modalities. In patients with relapsed or persistent disease, the informativity rates of CT with intravenous contrast and PET/CT were similar (Se — 100%, Sp — 94.1%, DT — 96.2%).DISCUSSION: The algorithm for preoperative evaluation of patients to identify the location of pathologic parathyroid glands now includes imaging with two modalities: Neck ultrasound and radionuclide imaging: planar scintigraphy (washout/subtraction), SPECT, SPECT-CT. If the results are questionable, a CT scan of the neck with contrast or PET/CT is performed as a second step. None of the modalities has 100% diagnostic accuracy. Our study demonstrated the superiority of PET/CT over ultrasound and CT w/in contrast in a group of patients scheduled for primary surgical treatment. In a small group of patients, high informative rates of PET/CT and CT with contrast were demonstrated before reoperation, confirming the great potential of these techniques in these patients.CONCLUSION: PET/CT with 11C-methionine and PET/CT with 11C-choline have high diagnostic accuracy in patients with primary hyperparathyroidism before reoperation. PET/CT and CT with contrast showed similarly high diagnostic accuracy for the diagnosis of parathyroid adenoma with persistence or recurrence of the disease in patients with primary hyperparathyroidism.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is a common endocrine disorder. Minimal invasive parathyroidectomy (PTX) is favorable surgical approach in PHPT treatment. Its success is highly dependent on accurate preoperative localization of all causative parathyroid adenomas. Despite the fact that wide range of visualization methods are applied in PHPT diagnostics, PHPT persistence occurs. Therefore, the search for additional visualizing tools of parathyroid adenomas remains relevant. Recently, positron emission tomography/computed tomography (PET/CT) has been used in order to improve PHPT diagnostics. OBJECTIVE: To evaluate the diagnostic effectiveness of PET/CT with 11 C-methionine and 11 C-choline in patients with PHPT based on the intensity of both tracers uptake in parathyroid adenomas. MATERIALS AND METHODS: The data of 26 patients diagnosed with PHPT was analyzed. PET/CT with 11 C-choline was performed in 14 patients, with 11 C-methionine — in 10 patients, with two radiopharmaceuticals — in two patients. All patients underwent PTX. Histological examination’s results were compared with the results of PET/CT. Using the software, the standardized uptake value of radiopharmaceuticals in histologically verified parathyroid adenomas/hyperplasias and in the trapezius muscle was obtained, then tumor-to-background ratios (TBR) of 11 C-methionine and 11 C-choline were calculated.Statistics: Software STATISTICA 10 was used in statistical analysis.RESULTS: 11 C-choline TBR median was of 2.3 (1.6; 3.2), median of 11 C-methionine TBR showed slightly higher values — 2.5 (1.9; 3,6). However, no significant difference was found between the two radiopharmaceuticals’ uptake in parathyroid adenomas.DISCUSSION: The scientific impact of current study is determined by the diagnostic effectiveness comparison between PET/CT with 11 C-methionine and 11 C-choline, which is based on the accumulation intensity of both radiopharmaceuticals in parathyroid adenomas.CONCLUSION: The intensity of accumulation of 11 C-methionine and 11 C-choline by hyperfunctioning parathyroid tissue does not differ significantly. Thus both tracers might be successfully applied for topic diagnosis of parathyroid adenomas in patients with PHPT.

In this article emotional disturbances developing in the postcovid period, their features and risk factors are reviewed, as well as sleep disorders after coronavirus infection (COVID-19). The nervous system (NS) is one of the SARS-CoV-2 main targets, which is confirmed by hypo-/anosmia, which develops in most patients during the acute period of COVID-19, and in some patients it is the first symptom. Currently, the main direct routes of coronavirus impact on the NS are considered to be hematogenous and neuronal. In addition, there is an immune-mediated effect on the NS due to the cytokine storm. After an acute period of coronavirus infection postcovoid syndrome often develops. Neurological manifestations, in particular emotional disorders, occupy a significant place in its structure. Depression, anxiety, fatigue, as well as sleep disorders bother patients most often. In dynamics, the severity of most symptoms in a certain part of patients decreases, however, according to some studies, postcovid manifestations persist or worsen for a long time. Currently, female gender and psychiatric comorbidity are most often considered risk factors for the development of postcovid emotional disorders. Despite the fact that the pandemic is officially considered over, and the acute period of COVID-19 is currently much easier than in 2020–2021, internists and neurologists are still treated by patients with newly emerged emotional disorders in the postcovid period, which underlines the continuing relevance of this problem. It is worth noting that emotional disorders in the postcovid period can develop in patients of all age groups, reducing their quality of life and workability. Public awareness, early diagnosis and initiation of treatment of these disorders will help to avoid global consequences.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Aim. To assess endothelial function and arterial stiffness over time in patients after hospitalization with coronavirus disease 2019 (COVID-19) and compare them with a control group. Material and methods. A total of 53 patients over 18 years of age were hospitalized for COVID-19 in June — August 2021 was examined at two visits: the first — 10-16 months, the second — 14-23 months after discharge from the hospital. Control group included 53 patients from the ESSE-RF epidemiological study of a St. Petersburg population who did not have COVID-19, selected by sex, status of smoking, hypertension and type 2 diabetes. Endothelial function was assessed by the levels of vascular cell adhesion molecule 1 (VCAM-1) and von Willebrand factor (vWF) in plasma and the reactive hyperemia index (lnRHI) on the EndoPAT 2000 system. Carotid-femoral pulse wave velocity (cfPWV) was determined using the SphygmoCor device, while cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) — using the VaSera device. Results. The prevalence of endothelial vasomotor function disorders at the first and second visits in the active group did not differ significantly as follows: lnRHI £0,51 — 21% and 21%, cfPWV >10 m/s — 17% and 14%, and SLSI >9 — 28% and 34%, respectively. Plasma VCAM-1 levels were significantly higher during hospitalization than at the first and second visits — no differences were found between visits. The levels of lnRHI, vWF, cfPWV, CAVI, ABI at the first and second visits did not differ significantly. Post-COVID-19 patients differed from the control group only by a significantly higher ABI level at the second visit. According to the analysis of covariance, COVID-19 is associated with a CAVI increase at the first visit, as well as with an increase in ABI at both visits. Conclusion. The 1,5-2-year follow-up of patients after COVID-19, which required hospitalization, showed a decrease in the plasma endothelial dysfunction parameter VCAM-1. There is no changes in endothelial function and arterial stiffness over a period of time from 10-16 months to 14-23 months after hospitalization with COVID-19.

Recent studies have demonstrated the relationship between vitamin D deficiency, infection severity and mortality from COVID-19. This study aimed to analyze the vitamin D metabolites and cytokine expression levels of COVID-19 patients who were hospitalized with bolus cholecalciferol supplementation. Materials and methods: This study represents the next stage of the open-label randomized pilot conducted by the Almazov National Medical Research Centre. A total of 44 hospitalized patients, comparable in demographic, clinical, laboratory and instrumental baseline characteristics, with moderate/severe COVID-19 were included. All patients had similar doses of concomitant corticosteroid therapy. Twenty-two patients received 50,000 IU cholecalciferol on the first and eighth days of hospitalization. The serum 25(OH)D, 1,25(OH)2D and 28 plasma cytokines were estimated for each group initially and on the ninth day of hospitalization. Results: Initially, there were no differences in the 1,25(OH)2D and cytokine levels in patients with vitamin D deficiency and normal 25(OH)D. Bolus cholecalciferol therapy at a total dose of 100,000 IU led to an increase in 25(OH)D levels in hospitalized patients with COVID-19, while the levels of the active metabolite (1,25(OH)2D) did not show significant differences between the groups or in its increased level over time, regardless of cholecalciferol supplementation. Furthermore, cholecalciferol supplementation at a total dose of 100,000 IU did not affect the majority of the cytokines estimated on the ninth day of hospitalization, except for the pro-inflammatory marker IL-1b, the concentration of which was lower in the group of patients without vitamin D supplementation. Conclusions: The 25(OH)D level was positively associated with an anti-inflammatory immune response, but cholecalciferol supplementation at a total dose of 100,000 IU did not affect the active-form vitamin D or cytokine expression levels. This fact may be explained by the impact of corticosteroid therapy, and it requires further investigation in a post-COVID-19 context.

Background: Acute and chronic brain damage in type 2 diabetes mellitus (DM) determines the need to investigate the neuroprotective potential of glucose-lowering drugs. The purpose was to directly compare the neuroprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with different duration of action and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in type 2 diabetic rats with and without stroke. Methods: DM was modelled using high-fat diet and nicotinamide+streptozotocin protocol. The following groups (n = 15 each) were formed: DM without treatment, treatment with liraglutide, dulaglutide, canagliflozin as well as control group without DM and treatment. After 8 weeks, 10 rats from each group underwent middle cerebral artery occlusion. In the reperfusion period neurological deficit, neuroglial damage markers and brain necrosis were evaluated. Brain slices from the remaining 5 animals in each group were histologically examined for microglial activation and neuronal damage. Results: Brain damage was similar in “DM” and “Control” (17.53 [14.23; 26.58] and 15.87 [13.40; 22.68] % of total brain volume, respectively). All study drugs diminished damage volume comparing with “DM” and “Control” whereas the necrosis volume in “DM+Liraglutide” was smaller than in “DM+Canagliflozin” and did not significantly differ from “DM+Dulaglutide” (2.9 [1.83; 4.71], 6.17 [3.88; 8.88] and 4.57 [3.27; 7.90] %). The neurological deficit was more prominent in “DM” than in “Control”, while all the drugs demonstrated similar positive effect. Neurofilament light chains (NLC) did not differ between “DM” and “Control”. Dulaglutide and canagliflozin caused a marked decrease in NLC. Protein S100BB level was similar in “DM” and “Control”. Liraglutide caused the largest S100BB decrease, while canagliflozin did not influence it. In chronic brain ischaemia, all drugs increased the number of normal neurons, but GLP-1RAs had a more pronounced effect. DM was accompanied by increased number of activated microglial cells in Cornu Ammonis (CA)1 hippocampal region. Both GLP-1RAs reduced the number of Iba-1-positive cells, with dulaglutide being more effective than liraglutide, whereas canagliflozin did not affect this parameter. Conclusions: GLP-1RAs and SGLT-2i have neuroprotective properties against acute and chronic brain damage in diabetic rats, although the infarct-limiting effect of GLP-1RAs may be more pronounced. GLP-1RAs and SGLT-2i exert their protective effects by directly influencing neuronal survival, whereas GLP-1RAs also affect microglia.

Background: Parathyroid tumors are classified as parathyroid neuroendocrine neoplasia (NEN) by the IARC-WHO classification. These tumors can occur with NENs from other sites, which often require total-body [68Ga]-DOTA-peptides PET/CT. This study aimed to assess the utility of [68Ga]-DOTA-peptide PET/CT in imaging parathyroid NENs and to evaluate the underlying mechanisms. Methods: Fifty patients with primary hyperparathyroidism (PHPT) and parathyroid NENs histologically confirmed as parathyroid adenomas (PAs) were included. PET/CT with [68Ga]-DOTA-peptide was performed in 16 patients with localized PAs, including 10 with MEN1 syndrome. Somatostatin receptor types 2 and 5 (SST2 and SST5) staining was performed on PAs from 48 patients. Somatostatin analogs (SSA) were prescribed in four patients with MEN 1 syndrome and 1 with persistent acromegaly, all with PAs and PHPT. The therapy effects on calcium and parathyroid hormone (iPTH) were evaluated. Results: [68Ga]-DOTA-peptide PET/CT detected 20 PAs with high radiopharmaceutical uptake. SST2 expression was negative on PA cell membranes in all cases and positive on endothelium in 39 (81%) PAs. Membrane SST5 expression was positive in 25 (52%) PAs and endothelial was positive in 40 (83%). Serum calcium levels decreased in patients on SSA therapy, while iPTH did not. Conclusions: PET/CT with [68Ga]-DOTA-peptides can detect parathyroid NENs. The incidental detection of high [68Ga]-DOTA-peptide uptake in the parathyroid region during whole-body PET/CT may prompt biochemical evaluation for PHPT. We suggest that endothelial SST expression mediates high radiopharmaceutical uptake by PAs and that SSA treatment can reduce hypercalcemia in PHPT patients.

BACKGROUND: Diabetic peripheral polyneuropathy (DPPN) is a common and early chronic complication of diabetes mellitus (DM). This complication can be associated with bone tissue damage and low-trauma fractures, particularly in type 1 DM. Therefore, evaluating the relationship between DPPN and bone metabolism parameters is crucial for clinical practice.AIM: To assess bone remodeling parameters in patients with type 1 DM with varying degrees of DPPN.MATERIALS AND METHODS: The study included 90 patients with type 1 DM and DPPN aged 18 to 55 years on stable insulin therapy for the past 3 months. Assessment was conducted for levels of HbA1c, 25(OH)D, total calcium (Ca), phosphorus (P), parathyroid hormone (PTH), osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX), fibroblast growth factor 23 (FGF-23) in serum. The degree of neurological deficit was determined using the Neuropathy Disability Score (NDS), Neuropathy Symptoms Score (NSS), and Michigan Neuropathy Screening Instrument (MNSI). Dual-energy X-ray absorptiometry (DXA) was performed to determine bone mineral density (BMD) and trabecular bone score (TBS).RESULTS: Regardless of the degree of DPPN severity, patients with type 1 DM were comparable in HbA1c and 25(OH)D levels. A direct correlation was found between the severity of neurological disorders and BMI (r=0.214; p=0.044) and duration of DM (r=0.246, p=0.019). Vitamin D insufficiency and deficiency were diagnosed in 79% of examined patients with type 1 DM, but the level of 25(OH)D in serum did not depend on the degree of DPPN severity, HbA1c level, duration of DM, and daily insulin dose (p>0.05). A positive correlation was established between PTH level and severity of neurological symptoms, and a ­negative one with HbA1c level. Patients with type 1 DM and varying degrees of DPPN did not differ in BMD and TBS. A Z-score of less than -2.0 SD was only recorded in six patients, and partially degraded microarchitecture of bone tissue was observed in 8 patients.CONCLUSION: Therefore, BMD, TBS, and bone remodeling markers in patients with type 1 DM and DPPN were independent of the degree of neurological deficit, degree of compensation, and duration of DM. Vitamin D deficiency is common in most patients with type 1 DM, but the 25(OH)D level is not influenced by HbA1c level, duration of the disease, and daily insulin dose.

Introduction: Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NET development continues to expand. Application of targeted gene panels (TGPs) in next-generation sequencing is a central strategy for elucidating novel variants associated with NET development. Methods: In this study, we conducted comprehensive molecular genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n = 26), pheochromocytoma and paraganglioma (PPGL) (n = 38), parathyroid adenoma (n = 18, including three with insulinoma), and NETs of other locations (n = 14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines. Results: Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mecanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8. Conclusion: Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.

Introduction. Stroke remains one of the major causes of death in type diabetes mellitus (DM). Injectable form of glucagon-like peptide-1 receptor agonist semaglutide, Ozempic® decreases the stroke risk. In Russia there appeared a biosimilar Semavic® but its effects on the brain are not yet studied.Aim. To compare neuroprotective properties of Semavic® and Ozempic® while used before ischemic stroke in rats without DM.Materials and methods. The study was conducted in male Wistar rats that were divided into the following groups: “Control” (n = 10) – 0.9% NaCl, “MET” (n = 9) – metformin 200 mg/kg once daily per os, “Ozempic” (n = 10) – Ozempic® 0.012 mg/kg s.c. once daily, “Semavic” (n = 9) – Semavic® 0.012 mg/kg s.c. once daily. After 7 days ischemic stroke was modelled, after 48 hour of reperfusion neurological deficit and brain damage volume were evaluated. Glycemia was measured on the 3rd, 7th days as well as during and after ischemia.Results. None of the study drugs caused hypoglycemia including in poststroke period. Neurological deficit in “MET” group did not differ from that in the “Control” (11.00 [6.50; 12.50] and 10.0 [6.25; 12.00] scores). Both semaglutide drugs caused comparable improvement in neurological status (14.00 [12.00; 18.00] and 14.00 [11.00; 18.00] scores in “Ozempic” and “Semavic” groups). Brain necrosis volume in “Control” group was 16.60 [13.40; 28.58] %. All the study drugs had infarct-limiting effect but brain damage volume in “Ozempic” (6.00 [4.32; 8.44] %) and “Semavic” (7.69 [2.99; 11.33] %) was smaller than in “MET” group (13.07 [8.67; 29.94] %). There were no differences between semaglutide drugs.Conclusions. Biosimilar Semavic® and original Ozempic® demonstrate comparable neuroprotective effect while used in animals without DM prior to ischemic stroke modelling. This protective effect is not due to the drugs’ influence on glycemic profile.

COVID-19, caused by SARS-CoV-2, triggers a complex immune response, with T regulatory cells (Tregs) playing a crucial role in maintaining immune homeostasis and preventing excessive inflammation. The current study investigates the function of T regulatory cells during COVID-19 infection and the subsequent recovery period, emphasizing their impact on immune regulation and inflammation control. We conducted a comprehensive analysis of Treg subpopulations in peripheral blood samples from COVID-19 patients at different stages: acute infection, early convalescence, and long-term recovery. Flow cytometry was employed to quantify Tregs including “naïve”, central memory (CM), effector memory (EM), and terminally differentiated CD45RA+ effector cells (TEMRA). Additionally, the functional state of the Tregs was assessed by the expression of purinergic signaling molecules (CD39, CD73). Cytokine profiles were assessed through multiplex analysis. Our findings indicate a significant decrease in the number of Tregs during the acute phase of COVID-19, which correlates with heightened inflammatory markers and increased disease severity. Specifically, we found a decrease in the relative numbers of “naïve” and an increase in EM Tregs, as well as a decrease in the absolute numbers of “naïve” and CM Tregs. During the early convalescent period, the absolute counts of all Treg populations tended to increase, accompanied by a reduction in pro-inflammatory cytokines. Despite this, one year after recovery, the decreased subpopulations of regulatory T cells had not yet reached the levels observed in healthy donors. Finally, we observed the re-establishment of CD39 expression in all Treg subsets; however, there was no change in CD73 expression among Tregs. Understanding these immunological changes across different T regulatory subsets and adenosine signaling pathways offers important insights into the disease’s pathogenesis and provides a broader view of immune system dynamics during recovery.