The Importance of the Study of the Hemodynamics of the Uterine Tumors by the Method of Dopplerometry in the Two- and Three-dimensional Echography Modes for Differential Diagnostics of Simple, Proliferating Leiomyomas and Uterine Sarcomas (Review of Litera

The article analyzes modern literature data on the importance of studying the hemodynamics of uterine tumors with dopplerometry in two - and three - dimensional regimens of echography for differential diagnosis of simple proliferating leiomyomas and sarcomas of the uterus. It is shown that the differential diagnosis of benign and Malignant tumors using the dopplerometry is based on various features of the blood supply of these tumors. On the basis of the analysis of literature data, it was concluded that in the dopplerometry evaluation of benign, borderline and Malignant tumors of myometrium in the two-dimensional regime, there were differences in the localization of the detected vessels in the CDM regimen, in the rates of vascular blood flow and vascular resistance in pulse dopplerometry. For a simple leiomyoma, the absence of a central intra-node localization of blood vessels in the CDM regimen, a low rate of arterial and venous blood flow, as well as an average resistance of arterial blood flow in the regime of impulsive dopplerometry are most typical; in a leiomyoma with eating disorders, the absence of a central intra-node localization of blood vessels, a low rate of arterial and venous blood flow in combination with high arterial resistance were more often observed. For the proliferating leiomyoma, the central intra-node localization of the vessels and the average blood flow velocities with low and medium resistance are characteristic. For sarcoma of the uterus, there is abundant vascularization both around the periphery and in the center, high blood flow rates and low resistance. The authors emphasize that there is information about the low specificity of this gradation, since the detection of a central type of vascularization and low resistance values can be in simple myomatous nodes with edema, eating disorders and destruction, and leads to diagnostic errors and suspicion of Malignancy. In the three-dimensional dopplerometry mode for simple leiomyomas, low indices of volume perfusion indices were characteristic, and for proliferating leiomyomas and sarcomas of the uterus – high indices of volume perfusion indices exceeding those in the uterus as a whole.Based on the review of the literature, the authors concluded that the presently available echographic and dopplerometric two- and three-dimensional markers are characterized by high sensitivity, but very low specificity. The low specificity of the known ultrasonic and dopplerometric criteria combined with the rarity of cases of sarcoma in the uterus against the background of a large number of similar echographically and dopplerometrically leiomyomas lead to low diagnostic accuracy of ultrasound diagnostics. This situation requires a further continuation of the scientific search for differential diagnostic ultrasound criteria by leiomyomas and sarcomas of the uterus using modern technologies, including three-dimensional echography

Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency

BACKGROUND: Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVE: We explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS: Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type vs. mutant LIG4 were performed in LIG4 knock-out Jurkat T cells and DNA damage tolerance was subsequently assessed. RESULTS: A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naïve CD4$^{+}$ T cells and low TCR-Vα7.2$^{+}$ T cells, while T/B-cell receptor repertoires showed only mild alterations. Cohort screening identified two other non-related patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSION: We provide evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Study of Hemodynamics of the Uterine Body by the Method of Three-dimensional Energy Dopplerography of Patients with Leiomyoma in Different Age Periods

To date, there is not enough papers to establish the reproducibility of the calculation of three-dimensional indices of blood flow and their threshold values for the diagnosis of a particular pathology. In this regard, the technique of three-dimensional Doppler sonography requires further study.The aim of research is studying the hemodynamics of the uterine body of patients with leiomyoma by three-dimensional energy Doppler ultrasonography to determine the possible patterns of changes in the indicators of three-dimensional vascularization indices depending on the phases of the menstrual cycle of women of reproductive age, in perimenopause and at different periods of menopause.Materials and methods. 326 women between the ages of 18 and 75 were surveyed (Me = 46.5). The comparison group consisted of 157 (48.15 %) healthy women, the main group was 169 women (51.84 %) with uterine leiomyoma. All patients in both groups were divided into women of reproductive age, women in peri - and menopause.In 3D reconstruction of the uterus using the energy mapping function and the VOCAL (Virtual Organ Computer - aided Analysis) option, an objective assessment of the hemodynamics of the uterine body was performed by calculating the vascularization index (VI), which characterizes the percentage of colour voxels in uterus body volume, flow intensity index (FI), showing the median luminance of colour voxels, which depends on the blood flow velocity in a given three-dimensional volume and vascularization-flow index (VFI), which is a product of multiplying the vascularization index and the flow index, divided by 100.Result. As a result, the main group identified the patterns of dynamics of three-dimensional indices of blood flow, depending on the survey at different ages, similar to the comparison group. In the reproductive period in patients with uterine leiomyoma, regardless of the size and degree of vascularization, the minimum values of the indexes VI, FI and VFI of the body of the uterus were registered in the early proliferative phase, significantly increasing to the middle secretion phase, coinciding with the fertility period of corpus luteum, secretion (p <0.05, CCU). In peri - and menopause, patients with leiomyomas have a statistically significant dynamics, similar to the nomograms of the comparison group, in reducing the values of the three-dimensional index of perfusion of the VI of the uterus as the period of absence of menstruation increases (CCU, p = 0.0472), with the highest values being characteristic of the perimenopause period. In the analysis of the dynamics of the FI and VFI indices of the body of the uterus of women with perio- and menopausal leiomyomas, the distribution of the studied indices was not confirmed by statistical significance. However, their pattern quite accurately reproduces the dynamics of a gradual decrease in these three-dimensional indices of blood flow in women with uterine body leiomyoma as the duration of absence of menstruation increases: the highest values were characteristic of the perimenopause period and the lowest - for the menopause period of more than 10 years.Conclusions. Taking into account the revealed patterns of dynamics of indicators of three-dimensional indices of blood flow depending on the age periods of women with leiomyoma will in the future increase the sensitivity and specificity of the method of three-dimensional energy Doppler sonography in the differential diagnosis of proliferative activity of uterine leiomyom

Features of Pathogenesis and Treatment of Breast Cancer in the Works of Modern Oncologists

To increase the effectiveness of treatment for breast cancer, representatives of various oncological schools use various approaches and scientific results obtained using high technologies, as evidenced by the analysis of scientific publications of specialists.The aim of this literature review was to analyze the influence of some scientific achievements using high technologies on modern ideas of oncologists about the pathogenesis of breast cancer and new approaches to increasing the efficiency of its treatment.Material and research methods. Scientific articles in journals specializing in Oncology, materials of scientific conferences, Internet resourcesResearch results and their discussion. Unsatisfactory results of the treatment of breast cancer, frequent relapses of this pathology, high mortality, on the one hand, and the results of scientific studies using high technologies, on the other hand, led oncologists to search for new approaches to solving the problem by improving surgical, medicinal and radiation treatments.Conclusions. The search for new approaches to solving the issue of increasing the effectiveness of breast cancer treatment is carried out in different directions: in the field of improving surgical treatment methods, drug methods, taking into account inhibitors of immune control points, new drugs for targeted therapy and the theory of cancer stem cells. The development of new approaches to the treatment of breast cancer has great prospects in addressing the issue of increasing the effectiveness of its treatmen

Morphometric Parameters of Hepatocytes in Experimental Complete Extrahepatic Bile Duct Obstruction

Liver changes observed in complete extrahepatic bile duct obstruction (CEBDO) with consideration to its morphometric parameters, may reflect the upcoming decompensation of liver function and may serve as objective criteria for the disease prognosis.The aim. To study the morphological changes of hepatocytes in experimental CEBDO using macro- and micromorphometry.Materials and methods. In 41 rats, the CEBDO was done by ligation and transection of the common bile duct. The time points were on postoperative Day 1, 3, 7, 14, 21, 28 and 35. Control group included 10 non-operated rats. The total blood bilirubin (TB), liver volume (LV), the area of hepatocytes (AH), the hepatocyte nuclear-cytoplasmic ratio (HNCR), the hepatocyte bulk density (HBD) were investigated. The LV and HBD parameters were used to calculate the total volume of hepatocytes (TVH).Results. The highest mortality was recorded on Day 22-35 of the experiment (7 out of 11 animals). Bilirubin level was significantly higher than in the control group with its maximum on Day 1 (295±100 vs. 8±6, μmol/l, p<0.001). The highest LV value was observed on Day 14 (14.1±1.1 vs. 8.4±1.4cm³, p<0.01). The processes prevailing in the livers were cell proliferation, fibrosis with gradual displacement of hepatocytes by proliferating bile ducts, and complete loss of normal liver histostructure. The proportion of hepatocytes in the liver (HBD) was progressively decreasing from 0.94 (Control) to 0.44 (Day 35). In spite of that, the TVH level was initially increased (max 9.7±0.36cm³ on Day 3 vs. 8.3±0.26cm³ on Day 1, p<0.05), but after Day 14 it decreased, with no significant differences from the Control group on Day 21(8.2±1.2 vs. 7.9±1.6cm³, p>0.05), with its lowest level (5.0±0.9cm³) on Day 35 (p<0.05 compared with max value on Day 3). The HNCR index, which reflects proliferative activity of hepatocytes, had its maximum on Day 14 (0.53±0.01 vs. 0.21±0.05 in Control group, p<0.001).Conclusions. In experimental CEBDO, reduction of the HBD index less than 60 % and reduction of TVH less than the value of a normal liver are accompanied by highest mortality, i.e., are a sign of hepatic decompensation. That was preceded by the maximum proliferative activity of hepatocytes, the criterion of which is the HNCR inde

Organ-saving and Reconstructive Plastic Surgery of Breast Cancer

Surgical treatment of breast cancer is an integral part of complex treatment. In recent years, the goal of treatment is not only to ensure long-term relapse-free and metastatic survival, but also a proper quality of life, which requires new approaches to surgery.The aim of the literature review was to analyze current trends in the development of methods of surgical treatment of the breast cancer and ways to improve immediate and late results.The results of the analysis and discussion. Until recently, radical mastectomy was performed to treat breast cancer, which causes long-term lymphovenous complications and significantly impairs the quality of life of patients. In recent decades, there has been a development of breast cancer surgery in the direction of the introduction of organ-saving and reconstructive plastic surgery with the improvement of technology for their implementation. There is no generally accepted concept of the optimal method of surgical treatment, both in terms of the volume of the operation and the choice of the method of reconstruction.Conclusions. The problem of choosing the optimal method of surgical treatment of breast cancer, which should provide oncological radicalism and at the same time a good cosmetic result remains unresolved and requires further researc