The stochastic digital human is now enrolling for in silico imaging trials -- Methods and tools for generating digital cohorts

Randomized clinical trials, while often viewed as the highest evidentiary bar by which to judge the quality of a medical intervention, are far from perfect. In silico imaging trials are computational studies that seek to ascertain the performance of a medical device by collecting this information entirely via computer simulations. The benefits of in silico trials for evaluating new technology include significant resource and time savings, minimization of subject risk, the ability to study devices that are not achievable in the physical world, allow for the rapid and effective investigation of new technologies and ensure representation from all relevant subgroups. To conduct in silico trials, digital representations of humans are needed. We review the latest developments in methods and tools for obtaining digital humans for in silico imaging studies. First, we introduce terminology and a classification of digital human models. Second, we survey available methodologies for generating digital humans with healthy and diseased status and examine briefly the role of augmentation methods. Finally, we discuss the trade-offs of four approaches for sampling digital cohorts and the associated potential for study bias with selecting specific patient distributions

Nodular Dermatitis: Emergence of Novel Poxviral Infection in Russia

Nodular dermatitis, (dermatitis nodularis), is an exotic for the Russian Federation poxviral disease. Some epizootical characteristics of it, problems of laboratory diagnostics, and possible reasons of extension of agent spread areal are discussed in this review. Phylogenetic analysis of P32 gene nucleotide sequences of dermatitis nodularis virus has also been conducted. It is noted that taking into account the economic loss caused by the disease and possibility of its import into non-enzootic regions, it is necessary to use existing effective means of specific prophylacsis extensively. The swift outspread of the disease in the Russian Federation should be considered as the risk factor for biological safety of our country

Current State of the Development of Next-Generation Vaccines against Ebola Virus Disease

Representative of Ebolavirus gender, Filoviridae family, Ebola virus is an etiological agent of particularly dangerous viral fever, the lethality of which comes up to 88 %. According to the leading specialists and experts in the sphere, vaccination is the most effective and cost-efficient method for the protection from epidemic spread. Objective of the review is to analyze current state of the development of next generation vaccines against Ebola fever. It is established that focus areas of the activities are the construction of vaccines on the basis of alpha-virus replicons, virus-like particles, and the development of DNA-vaccines and vector recombinant vaccines. The paper discusses the most significant achievements in the sphere of obtainment of potent therapies for prophylaxis as regards Ebola fever. To date manufactured, using various approaches, have been the next-generation vaccine preparations, for a number of which high protective capacity is demonstrated in the course of experiments on the nonhuman primates. The most advanced and prospective prototype is the vector recombinant vesicular stomatitis virus-based vaccine

MOLECULAR-BIOLOGICAL PECULIARITIES OF ARENAVIRUS REPRODUCTION IN SENSITIVE CELLS

The Arenaviridae family consists of a large group of single strand ambisense RNA viruses that are separated phylogenetically, serologically and geographically into Old World and New World viruses. Recent studies indicate that cellular entry of arenaviruses requires a series of cellular protein interaction and molecular mechanisms. The arenaviruses entry into cells is initiated by the interaction of viral glycoprotein with one or more receptors on the surface of host cells. The main host cell factors that are involved in filovirus entry are attachment factors (α-dystroglycan for Old World and human transferrin receptor 1 for New World viruses), endolisosomal host cell factors (cathepsins B and L and Niemann-Pick C1 protein). The review presents the modern knowledge about the role of structural proteins of arenaviruses and some cell factors in pathogenesis of the diseases, caused by arenaviruses

Attempt to assess direct interactions between tumor burden, myeloid-derived suppressor cells and PD-1- and TIM-3-expressing T cells in multiple myeloma patients

The avoidance of immune surveillance by malignant plasma cells (PCs) in multiple myeloma (MM) is mediated by different mechanisms, among which an induction of T cell exhaustion and expansion of myeloid-derived suppressor cells (MDSCs) appear to play substantial roles, but it is still a lack of data on possible MDSC-mediated induction of T cell exhaustion. The aim of the present work was to evaluate possible relationship between frequencies of MM PCs, MDSCs and phenotypically exhausted PD-1+ and TIM-3+ T cells in bone marrow (BM) samples and peripheral blood (PB) of MM patients at various disease stages. Peripheral blood (n = 88) and BM samples (n = 56) were obtained from MM patients (newly diagnosed (n = 6), patients in remission (n = 71) and with progressive disease (n = 11)). Frequencies of T cells expressing checkpoint receptors PD-1 and TIM-3, polymorphonuclear MDSCs (PMN-MDSCs, Lin-CD14-HLA-DR- CD33+CD15+/CD66b+), monocyte MDSCs (M-MDSCs, CD14+HLA-DRlow/-), early MDSCs (E-MDSCs, Lin-HLA-DR-CD33+CD15-/CD66b-), and MM PCs (CD45dimCD38+CD138+CD56+CD19-CD117+CD27- CD81-) were assessed with flow cytometry. Circulating and BM-resident PD-1+/TIM-3+T cell subsets, BM E-MDSCs, as soon as MM PCs and serum beta2-microglobulin (B2-M) levels were gradually increased in patients at different stages. Despite that, there were no associations between the markers of tumor load and the studied cell subsets. In patients in remission, BM PMN-MDSCs negatively correlated with CD4+T cells, CD4+PD-1+ and CD8+TIM-3+T cell subsets; there were positive correlations between BM E-MDSCs and CD4+PD-1+TIM-3+ cells and PB M-MDSCs and CD8+PD-1+ and (as a trend) CD8+TIM-3+T cells. We found no associations for the samples of patients at diagnosis and with progression. We can conclude that a possible mutual influence of malignant PCs, MDSCs and PD-1+/TIM-3+T cells is nonlinear, especially during a manifest tumor growth at diagnosis and progression. The detected negative correlations between resident PMN- MDSCs and T cell subsets might be associated with MDSC suppressive function, affecting both predominantly activated PD-1+ cells and exhausted TIM-3+ subsets. The positive correlations between BM E-MDSCs and CD4+PD-1+TIM-3+ cell subset and circulating M-MDSCs and PD-1+ and TIM-3+ CD8+T cells might confirm an ability of MDSCs to induce T cell exhaustion

Association of myeloid-derived suppressor cells with hematopoietic recovery after high-dose chemotherapy in multiple myeloma

Myeloid-derived suppressor cells (MDSCs) play an important role in the immune response regulation in many pathologies, primarily in malignant tumors, but their role in the hematopoietic stem cell engraftment and the hematopoietic recovery after high-dose chemotherapy and autologous stem cell transplantation remains practically unexplored. This study is aimed at studying the correlation between the number of MDSC subpopulations and blood parameters at the stage of hematopoietic recovery after high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with multiple myeloma (MM). Circulating MDSCs were assessed at the stage of leukopenia recovery (absolute leukocyte count in peripheral blood (PB) > 1 x 109/L) by flow cytometry. The number of transplanted CD34+CD45+ hematopoietic stem cells was 4.38 x 106/kg (IQR (3.1—5.6) x 106/kg). The duration of recovery from leukopenia varied from 8 to 18 days (Me 12 days). The number of MDSCs at the engraftment was not associated with the number of CD34+ cells/kg in the graft. The relative number of monocytic MDSCs (M-MDSCs, CD14+HLA-DRlow/-) directly correlated with the number of monocytes at the stage of recovery from leukopenia (R = 0.417, p = 0.002). Granulocytic MDSCs (PMN-MDSCs, Lin-HLA-DR-CD33+CD66b+) were characterized by an inverse correlation with the number of monocytes (R = -0.493, p = 0.0003) while the association with the absolute number of neutrophils was weak (R = 0.273, p = 0.048). The number of lymphocytes at the stage of recovery from leukopenia had an inverse correlation with PMN-MDSCs (R = -0.347, p = 0.014) and did not correlate with M-MDSCs. When analyzing the duration of leukopenia, an inverse correlation with this indicator was revealed for the percentage and absolute number of M-MDSCs (R = -0.347, p = 0.018 and R = -0.469, p = 0.0008, respectively). Multiple regression analysis showed dependence of the lymphopenia duration on the proportion of circulating M-MDSCs (p = 0.014) and the number of transplanted CD34+ cells/kg (p = 0.032). According to the data of multivariate analysis of variance, the number of transplanted CD34+ cells/kg and the number of M-MDSCs were significant factors for the duration of leukopenia. At the same time, such clinical parameters as the depth of response and minimal residual disease status before high-dose chemotherapy and hematopoietic stem cell transplantation, as well as the MM stage, did not affect the duration of hematopoietic recovery. Thus, the obtained results indicate the association of a higher number of M-MDSCs with a shorter duration of leukopenia after high-dose chemotherapy with autologous stem cell transplantation and indicate a positive role of M-MDSCs in hematopoietic recovery in the early post-transplant period in patients with MM

A Novel Hybrid Scheme Using Genetic Algorithms and Deep Learning for the Reconstruction of Portuguese Tile Panels

This paper presents a novel scheme, based on a unique combination of genetic algorithms (GAs) and deep learning (DL), for the automatic reconstruction of Portuguese tile panels, a challenging real-world variant of the jigsaw puzzle problem (JPP) with important national heritage implications. Specifically, we introduce an enhanced GA-based puzzle solver, whose integration with a novel DL-based compatibility measure (DLCM) yields state-of-the-art performance, regarding the above application. Current compatibility measures consider typically (the chromatic information of) edge pixels (between adjacent tiles), and help achieve high accuracy for the synthetic JPP variant. However, such measures exhibit rather poor performance when applied to the Portuguese tile panels, which are susceptible to various real-world effects, e.g., monochromatic panels, non-squared tiles, edge degradation, etc. To overcome such difficulties, we have developed a novel DLCM to extract high-level texture/color statistics from the entire tile information. Integrating this measure with our enhanced GA-based puzzle solver, we have demonstrated, for the first time, how to deal most effectively with large-scale real-world problems, such as the Portuguese tile problem. Specifically, we have achieved 82% accuracy for the reconstruction of Portuguese tile panels with unknown piece rotation and puzzle dimension (compared to merely 3.5% average accuracy achieved by the best method known for solving this problem variant). The proposed method outperforms even human experts in several cases, correcting their mistakes in the manual tile assembly

Participation of biological and psychosocial factors in the pathogenesis of schizophrenoform postnatal psychosis: a literary review

In connection with the current socio-demographic situation in the country and in the world, the study of the pathogenic characteristics of postpartum psychosis is highly relevant. The aim of this work was to analyze the literature data on the factors of the pathogenesis of schizophreniform postpartum psychoses. The application of the general scientific method and the analysis of publications in the PubMed, Cyberleninka, e-Library databases helped to confirm the multifactorial nature of postpartum psychoses, proceeding with schizophreniform symptoms, indicating that genetic changes in the coding of neurophysiological mechanisms that manifest themselves after delivery can play a significant role in their genesis. Women in relation to nonspecific influences, and the action of acute or chronic stress factors play the role of triggers for the implementation of the pathogenic cascade, which phenomenologically can be realized into a psychotic disorder. Thus, the formation of postpartum schizophreniform psychoses follows the concept of stress vulnerabilityВ связи со сложившейся социально-демографической ситуацией в стране и в мире изучение патогенетических особенностей послеродовых психозов является весьма актуальным. Целью данной работы являлся анализ ли тературных данных о факторах патогенеза шизофреноформных послеродовых психозов. Применение обще- научного метода и анализ публикаций баз данных PubMed, Cyberleninka, e-Library позволили подтвердить полифакторность послеродовых психозов, протекающих с шизофреноформной симптоматикой, указав, что в их генезе существенную роль могут играть генетические изменения в кодировании нейрофизиологических механизмов, проявляющиеся после родоразрешения, что повышает уязвимость женщины по отношению к неспец ифическим воздействиям, а действие острого или хронического стрессовых факторов играют роль пусковых механизмов для реализации патогенетического каскада, который феноменологически может реализоваться в психотическое расстройство. Таким образом, формирование послеродовых шизофреноформных психозов следует концепции стресс-уязвимост

CLINICAL EFFECTS OF MESENCHYMAL STROMAL CELLS IN LYMPHOMA PATIENTS WITH AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION

The clinical and laboratory effects of bone-marrow derived mesenchymal stromal cells (MSC) in patients with malignant lymphomas following autologous hematopoietic stem cell transplantation (auto-HSCT) have been investigated. Co-transplantation of MSC in average dose of 0,178 106/kg was conducted in 74 patients with auto-HSCT. The control group included 83 patients eligible for standard HSCT. We revealed the decreasing of the period of neutropenia and thrombocytopenia when hematopoietic stem cells were co-transplanted with low doses ex vivo expanded autologous MSC. Patients with MSC co-transplantation were differed by more effective early lymphocyte recovery. At the same time MSC co-transplantation did not increase the incidence of infectious complications and cases of renal and. hepatic toxicity. Patients with MSC co-transplantation did not differ from opposite group by 5-year overall survival, but were characterized by significantly better progression-free survival

The Molecular Genetic Peculiarities of Genomic Structure of Members of the <i>Ebolavirus</i> Genus

The molecular genetic peculiarities of genomic structure of the Ebolavirus genus members are viewed in the review. The Ebola virus disease outbreaks in West African countries constitute a threat not only for Africa, but for the whole world in view of possible introduction of the agent in non-endemic regions. The members of the Ebolavirus genus have different pathogenicity for humans, thus differ severity and mortality of the disease they cause. There is a significant genetic divergence among members of the Ebolavirus genus. The differences of pathogenic potential of members of the Ebolavirus genus may be explained as the result of mutations in the genes of virus structural proteins. It is possible, that some of these mutations may affect virulence of strains within one virus species. So far as most effective modern medicines for specific prophylaxis and treatment of Ebola fever are target-oriented, genotyping of the agent will promote elaboration of strategy of such preparations development