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Background. Annual studies of West Nile virus (WNV) circulating in endemic areas are necessary to characterize its properties and track them over time. Given the lack of specific antiviral therapy for West Nile fever (WNF), it is of interest to study sensitivity to drugs widely used in modern practice. The aim of the study is to study the sensitivity of West Nile virus strains circulating in the Russian Federation in 2018–2021 to drugs used to treat viral infections.Material and methods. The sensitivity of WNV strains to ribavirin, riamilovir, and umifenovir was determined using Vero cell culture.Results and discussion. A study of the sensitivity of WNV strains circulating in the Russian Federation in 2018–2021 to therapeutic drugs used to treat viral infections showed their heterogeneity in this regard. Thus, 5 strains (WNV_Volgograd_601/18, Volgograd_723/18, Volgograd_830/18, Voronezh_794/21, Astrachan_962/21) out of 10 studied were characterized by some differences in resistance to ribavirin and riamilovir. No statistically significant differences were revealed when comparing drug resistance indicators of the group of WNV strains of the «old» genovariant with those of the «new» group.Conclusion. Further analysis of the genome of the studied WNV strains will allow us to establish genetic characteristics, which may contribute to the establishment of molecular mechanisms of resistance to ribavirin, riamilovir, and umifenovir.

Objective: to assess budget impact of using empegfilgrastim for the prevention of febrile neutropenia in patients with early and locally advanced human epidermal growth factor receptor 2 positive (HER2+) breast cancer who receive neoadjuvant “docetaxel / carboplatin / trastuzumab + pertuzumab” regimen, considering possible subsequent adjuvant therapy with trastuzumab emtansine or trastuzumab within the Russian healthcare system.Material and methods. We searched and analyzed published clinical, epidemiological and pharmacoeconomic studies as well as regulatory and legal documents. A decision tree model was constructed to reflect the probabilities of switching to different adjuvant therapy regimens depending on the achievement of pathomorphological complete response in patients with early and locally advanced HER2+ breast cancer. The budget impact analysis was carried out comparing two primary prophylactic options, empegfilgrastim and filgrastim.Results. Despite the higher costs of prevention with empegfilgrastim compared to filgrastim (249 vs. 134 thousand rubles), due to the higher rate of achieving a pathomorphological complete response and, accordingly, fewer cases requiring adjuvant therapy with the more expensive trastuzumab emtanzine, savings of 916 thousand rubles per 1 patient per 1 year of therapy are possible. In general, prophylaxis in the target population diagnosed with early and locally advanced HER2+ breast cancer using empegfilgrastim will result in a cost reduction of 9.4 billion rubles per 1 year compared to filgrastim.Conclusion. Empegfilgrastim prophylaxis, despite its higher annual cost, is an efficient option within the Russian healthcare system. In addition to reducing the incidence of febrile neutropenia, the frequency and dose of chemotherapy are preserved, resulting in increased efficacy of the primary therapy.

The aim of the study was to carry out whole-genome sequencing and comparative analysis of the original and benzalkonium chloride-resistant strains of Burkholderia pseudomallei.Materials and methods. We used the strain B. pseudomallei 134 and resistant to benzalkonium chloride B. pseudomallei 134K. Whole-genome sequencing was conducted on the MiSeq Reagent Kit v3 platform (600-cucle).Genome assembly for both strains was performed with the help of SPAdes v3.11.1. In order to compare genome sequences of the studied strains, Snippy v4.6.0 software was applied. MEGA X program was used to align the nucleotide and amino acid sequences.Results and discussion. The search and analysis of determinants responsible for the emergence of resistance to biocides in B. pseudomallei 134K have revealed two genes: the TetR transcriptional repressor gene and the AmrAB-OprA efflux pump gene. A single nucleotide polymorphism has been found in the TetR regulator, which led to the replacement of serine by proline in the mutant protein, and, as a result, a change in its secondary structure. It is believed that this mutation causes the loss of regulatory protein functionality, resulting in an increased expression of the efflux pump genes (AcrB/AcrD/AcrF) regulated by it. This follows by both, decrease in the level of sensitivity to benzalkonium chloride and the emergence of resistance to ceftazidime. In the AmrAB-OprA efflux pump gene, an insertion of 16 nucleotides has been detected at the position 544 of the amrA operon, which led to an increase in the length of the cistron, a shift in the reading frame, a change in the amino acid composition, and, as a result, a change in the secondary structure of the encoded protein. It is most likely that this mutation contributes to the loss of AmrAB-OprA operon function and the failure of normal outflow of xenobiotics from the cytoplasm of the microorganism. This assumption is evidenced by the loss of resistance to gentamicin in the mutant strain.

Aim. To examine the role of very good partial response or better (VGPR+) as a surrogate predictor of progression-free survival (PFS) in multiple myeloma (MM) patients.Materials and methods. A systematic literature review of MEDLINE database (2010–2023) and materials presented at hematology and cancer congresses (2020–2022) was performed to identify studies reporting median progressionfree survival (PFS) and the rate of very good partial response (VGPR+). The study used Spearman’s weighted correlation and linear regression methods to analyze the association between median PFS and VGPR+. A total of 34,443 patients were involved in 182 original studies that included real-world clinical practice data.Results. Based on the number of patients or year of publication, the correlation between VGPR+ and median PFS was statistically significant (Spearman coefficient r = 0.61), but low. For refractory/recurrent MM (r = 0.69) and for monoclonal antibody therapy (r = 0.81), the correlation between VGPR+ and PFS was stronger. In addition to achieving VGPR+, the line of therapy and autologous stem cell transplantation also played an important role in determining PFS. Based on these factors, an increase of one percentage point in VGPR+ predicted a 0.21‑month increase in median PFS in the final adjusted linear regression model.Conclusion. In this study, VGPR+ was found to predict PFS, making it a universal early point of reference for MM prognosis regardless of the treatment type.

Relevance. Despite significant improvements in therapeutic options, patients with multiple myeloma (MM) experience a series of remissions and relapses requiring further lines of therapy, which requires the prescription of new lines of therapy. Methods. We analyzed the types and outcomes of treatment, attrition rates (AR) — the proportion of patients who dropped out of program therapy, and refractoriness to different lines of therapy (LOT) in 447 patients with MM between 2010 and 2022. Resalts. The AR was 17% between LOT-1 and LOT-2, 15% between LOT-2 and LOT-3, and 25% between LOT-3 and LOT- 4. In multivariate regression analysis, only high MM risk significantly increased AR risk. Each new progression of MM increased the number of patients with refractory to bortezomib, lenalidomide, or daratumumab. After LOT-1, LOT-2, and LOT-6%, 26%, and 53% of patients were double-refractory, respectively, and 54% were triple-refractory. Bortezomib- or lenalidomide-refractory patients had a 2.6-fold lower chance of achieving a very good partial response or better (VGPR+). From LOT-1 to LOT-4, the overall response rate and VGPR+ decreased from 74% and 53% to 25% and 15%, respectively. Overall survival (OS) in the entire population was 7.6 years, with an actuarial 5-year OS of 67% and a 10-year OS of 44%. The median of progression-free survival (PFS) was 20 months on LOT-1, 19 months on LOT-2, and 7 months on LOT-3, and the actuarial 5-year PFS was 25%, 18%, and 10%, respectively. Conclusions: In this regard, we observe a continuing trend in the use of cisplatin-containing "rescue" chemotherapy regimens, especially in patients with an aggressive course, including extramedullary forms of MM. These patients could be candidates for bispecific antibody therapy and CAR T-cell therapy, but these options are not yet available in Russia.

Relevance. Cardio-vascular diseases (CVD) are the one of the main reasons of mortality and disability. Hypercholesterinemia is a factor of CVD progression, and thus it should be corrected. Combination of statin + ezetemib is an effective option of a medical technology for this purpose. Pharmacoeconomic analysis of rosuvastatin and ezetemib fixed combination (FC) has been performed in this work in comparison with free combination (FrC) of these drugs.Materials and methods. Modelling of FC vs FrC in groups of CVD risk has been performed on 1–5 years horizon based on the local epidemiologic published data with aim of economic analysis. Efficacy of FC and FrC, direct medical costs, including cost of drugs, hospitalizations etc. were taken into account also. ICER has been calculated and compared with willingness to pay.Results. FC usage instead FrC can prevent 2960–3055 deaths and 8880–9164 admissions to hospital caused CVD. FC decrease of ambulance cost as well as others direct medical expenditures in compare with FrC treatment on 9,3 bln RUR per 5 years. ICER has been calculated and has negative (dominant) result.Conclusion. FC usage is an economic dominant technology in compare with FrC for hypercholesterolemia control.

Multiple myeloma (MM) accounts for 1 % of all cancers and about 10 % of all hemoblastoses. The use of innovative technologies with the inclusion of targeted drugs leads to a significant improvement in the quality of pharmacotherapy and the achievement of overall survival (OS).The aim of the work is to conduct a pharmacoeconomic analysis of the most used MM therapy regimens with the use of targeted drugs and to determine the dominant treatment regimens using a costeffectiveness analysis.Materials and methods. To determine the cost of a course of treatment, we summed up the costs of drugs included in the pharmacotherapy regimen, taking into account taxes, marginal trade markup and duration of the course. Dosing of the targeted drug included in the regimen was determined according to the official instructions for the drug. Progression-free survival (PFS) was adopted as the main criterion for the effectiveness of treatment. Information on PFS of targeted drugs was obtained from data from international phase III RCTs — ASPIRE, TOURMALINEMM1, POLLUX and ELOQUENT2.Results. Based on the results of the pharmacoeconomic analysis, the dominant treatment regimen for MM was determined — daratumumab / lenalidomide / dexamethasone, which has the best cost-effectiveness ratio. The combination of elotuzumab / lenalidomide / dexamethasone was recognized as the least effective technology.

Introduction. The Culex pipiens mosquito is one of the proven vectors of the West Nile virus (WNV). Culex pipiens f. molestus (Cx. p. f. molestus) is a synanthropic, autogenous, widespread form of the species that can feed on a broad range of hosts, including humans. The temperature of the habitat of insects affects the potential for virus transmission, which determines the likelihood of them carrying the pathogen of West Nile fever. The goal is an experimental study of the temperature of the habitat of larvae on the competence of mosquitoes Cx. p. f. molestus as carriers of WNV. Materials and methods. We used a strain of the WNV (WNV_Volg601/18 genotype 2) and a laboratory culture of mosquitoes Cx. p. f. molestus. The concentration of the virus was detected by plaque formation using Vero cells. Insects were infected orally at the larval stage, with subsequent incubation at 20, 22 or 28C. 72 hours after the emergence of all adults from the pupae, the mosquitoes were immobilized by cold, the sex of imago was determined, the salivary glands were isolated from the females, and the presence of WNV in glandes and its titer were detected. Results. The titer of WNV sufficient to transmit the pathogen through the insect biting was observed in the salivary glands of insects kept at a temperature of 22 and 28C, with the virus titer rising with the temperature increasing. No virus was detected in the salivary glands of female insects kept at a temperature of 20C. Conclusion. Thus, it appears that the habitat temperature is an important factor limiting the replication and content of WNV in the salivary glands of Cx. p. f. molestus.

The aim of the study was to investigate the features of resistance formation in Burkholderia pseudomallei to quaternary ammonium compounds, as well as to analyze its influence on the development of antibiotic resistance.Materials and methods. 10 strains of melioidosis causative agent with typical cultural and morphological properties have been studied. The selection of variants resistant to benzalkonium chloride was carried out by successive passages on a dense nutrient medium with the addition of a disinfectant in increasing concentrations. The determination of sensitivity to benzalkonium chloride was performed through serial dilutions in agar, to antibacterial drugs from the groups of sulfonamides, β-lactams and tetracyclines – using disk diffusion method. Statistical processing of the obtained results was conducted with the help of the Microsoft Excel 2019 software. Arithmetic mean values and errors of mean values were calculated. The significance of differences between the parameters was determined applying Student’s t-test.Results and discussion. All parental strains showed a similar degree of resistance to the disinfectant compound and most of the strains – susceptibility to the antibiotics tested. Cultivation of B. pseudomallei strains on a nutrient medium with the addition of benzalkonium chloride led to an increase in resistance to this disinfectant. In addition, an increase in the level of resistance to all studied antibiotics was found. Statistical processing of the data collected revealed a significant correlation between the change in sensitivity to benzalkonium chloride and the emergence of resistance to amoxicillin/ clavulanic acid and ceftazidime. It was found that the causative agent of melioidosis, with a natural high susceptibility to benzalkonium chloride, has a high potential for developing resistance to this disinfectant compound, which is of practical importance in the development of disinfection regimens using quarternary ammonium compounds. For the first time, a direct correlation between a decrease in the sensitivity to benzalkonium chloride in B. pseudomallei and emergence of resistance to amoxicillin/clavulonic acid and ceftazidime has been demonstrated.

The ICU department’s mortality rate is one of the most important indicators of quality of care. Based on real clinical data, we attempted to build a prognostic model for patients with blood diseases in the ICU with using of the logistic regression method. The study included 202 patients in total. The median age was 57 (19–82) years. There were 112 (55 %) males and 90 (45 %) females. The statistical analysis was performed by using R software, version 3.4.2. The absolute risk of death (mortality rate) was 67 from 202 (33 %), odds — 0.496. The odds of death in ICU grow up to ~20 times if the patient has a Glasgow score of less than 15. Also, the odds of death increase by 1.3 and 11 times of PLT, or serum total protein level decreases by 2 times accordingly. Our model for “high-risk of death” detection classified patients in the test dataset with 0.816 accuracy (95 % CI 0.679–0.912), with sensitivity 0.823, and specificity 0.80. Despite the simple method for data analysis, we got a pretty accurate model of mortality prognosis with efficacy more than qSOFA and MEWS scales. Research in this area should continue.

The development of high-capacity and high-voltage electrode materials can boost the performance of sodium-based batteries. Here, the authors report the synthesis of a polyanion positive electrode active material that enables high-capacity and high-voltage sodium battery performance.

Background. The treatment options for patients with multiple myeloma who refractory to previous bortezomib and lenalidomide therapy are limited. Pomalidomide is ап immunomodulatory agent that was registered for the treatment of patients with double refractory multiple myeloma.Aim. To evaluate efficacy, safety and optimal course of the therapy with pomalidomide in routine practice in patients with double refractory multiple myeloma.Materials and methods. Overall, 71 patients with double refractory multiple myeloma were included in the retrospective analysis. There were 36 males and 35 females. The median age was 61 years (range 35-79). According to Durie-Salmon staging system, there were 53 (79.1 %) patients in stage III, 13 (19.4 %) - stage II, and 1 (1.5 %) - stage I.The stage was unknown in 4 patients. Kidney impairment at the onset was in 10 (15 %) patients, the normal function was in 57 (85 %) patients and 4 patients had no data. Most patients (n = 68, 95.8 %) received pomalidomide in one therapy line, in 3 (4.2 %) patients - drug was given in two lines, totally 74 episodes of use. Median number of drugs prescribed prior to pomalidomide were 4 (2-9) drugs, including target ones - 2 (2-5). In the first remission 31 (43.6 %) patients received high-dose therapy with autologous stem cell transplantation. pomalidomide was administered in combination with low doses of dexamethasone (PomDex, n = 44; 59.4 %) and as a part of triple regimens (n = 30; 40.6 %). previously exposed (n = 22; 73.3 %) and new drugs (n = 8; 26.7 %) were used in the combination treatment. In 44 (61.9 %) patients pomalidomide was administered more than 3 years after the onset of the disease, median 63.5 (37-184) months. In 27 (38.1 %) patients it was given within less than 3 years after the onset, median 21 (6-36) months. The primary endpoint was progression-free survival. Secondary endpoints - pomalidomide tolerability, response rate and optimal third drug in the triple regimen. The dependence of progression-free survival, frequency of response and adverse events from the pretreatment, the choice of the third drug, gender, age, immunochemical variant, stage according to the International Staging System and to Durie-Salmon classification was studied.Results. The median time from the diagnosis to the start of pomalidomide therapy was 44.5 (6-184) months. The median of cycles with pomalidomide was 3 (1-30). The response was achieved in 52 (70 %) patients. The median progression-free survival was 4 (1-30) months, overall survival - 6 (0.5-42) months. Adverse effects were noted in 34 (46.5 %) patients. The most frequent adverse events were neutropenia grade III-IV (n = 14; 41.3 %), infection (n = 7; 20.7 %) and fatigue with limitation of daily activity (n = 6; 20.6 %). The rate of adverse events was higher in patients with triplets than doublets regimens of therapy: 43.3 % (n = 13) and 27.2 % (n = 12) respectively (p = 0.008). There were no statistically significant differences in progression-free survival between pomalidomide treatment options (two- or three-component regimen).Conclusion. Compared to the three-component therapy consisting of drugs to which refractoriness was previously diagnosed the PomDex scheme is less toxic and equally effective. Therapy with pomalidomide is effective in the majority of patients with double refractory multiple myeloma even in heavily pretreated. The toxicity is acceptable.

Relevance. Ademetionine is a hepatoprotective drug, is included in the draft Russian clinical guidelines for the diagnosis and treatment of non-alcoholic fatty liver disease (NAFLD) and in the clinical guidelines for treating intrahepatic cholestasis (ITH), the cost analysis of treating patients with ITH and NAFLD is topical. Aim. The cost analysis of treatment with ademetionine for ITH and NAFLD in the Russian Federation. Methods. This clinical and economic analysis was conducted in accordance with the requirements of GOST R 57525–2017 and the methodological recommendations of the Center for Expertise and Quality Control of Medical Care. At the first stage, to determine the structure and number of costs, a review of legal acts and publications on the pharmacoeconomic analysis of clinical situations and drugs of interest in the e-Library and ConsultantPlus databases was carried out. The source of prices for medical services was the tariffs of the compulsory medical insurance system and data from the tariff agreement in Moscow within the framework of the compulsory medical insurance system, and in the absence of tariffs, the prices for paid medical services. Prices for drugs were obtained from an open source — the Russian Pharmaceutical Portal (Pharmindex.rf). In the absence of data on the cost structure, a survey of physicians conducted through a questionnaire. Results. Because of the literature review, 34 publications were found in the e-Library database on the use of ademetionine in NAFLD and ITH. Additionally, outside the scope of the literature review, a study was found in 2011, which provides a comparative clinical and economic analysis of the use of ademetionine (Heptral®) and essential phospholipids (Essentiale) in alcoholic liver damage and in infectious hepatitis. A review of legal acts in the ConsultantPlus database initially identified 93 documents, of which 25 turned out to be irrelevant to the current purpose of the study, that is, they didn’t allow analyzing the costs of ademetionine therapy. Of the 20 identified standards of medical care, only 2 are devoted to diseases of the liver and biliary tract. Because of the analysis, it was revealed that the cost per case of NAFLD treatment in a round-the-clock hospital amounted to 24.6 thousand rubles; in a day hospital, the cost per case of both NAFLD and ITH in adults amounted to 19.8 thousand rubles each. The average total cost of treating one patient during the year on an outpatient basis for NAFLD amounted to 65.3 thousand rubles, of which only 14.3 thousand rubles. covered by the compulsory medical insurance system, 16.9 thousand rubles outside the compulsory medical insurance system and 34.1 thousand rubles — drug costs. The average total costs for treating one patient during the year on an outpatient basis from ITH amounted to 65.4 thousand rubles, of which 23.9 thousand rubles. covered by the compulsory medical insurance system, 17.6 thousand rubles outside the compulsory medical insurance system and 23.9 thousand rubles — drug costs. Conclusion. Because of the study, the average costs for treating patients with NAFLD and ITH were calculated, which can later be used to conduct other types of pharmacoeconomic analysis.

The current strategy of chronic lymphocytic leukemia (CLL) treatment is based on genetic risk factors such as del(17p), TP53 mutations and/or unmutated variant of IGHV genes. Guidelines recommend the usage of targeted drugs, e.g. ibrutinib, in the first line for patients with unfavorable risk factors due to dismal results of other treatment options. Unfortunately, in real-life treatment decisions are often made without full knowledge of genetic risk factors in the treated patient. Our aim was to find the optimal therapeutic strategy for such patients, that is, those providing the best 5-year progression-free survival (PFS). Using a relatively simple game theory-based approach we here show, that currently, the used strategy is more advantageous (success rate 71%) compared to administration of immunochemotherapy to all patients (success rate with fludarabine + cyclophosphamide + rituximab — 45%, bendamustine + rituximab — 32%). However, the optimal strategy for CLL treatment in the conditions of unknown genetic risks is the administration of ibrutinib to all patients (success rate 73%). Our simple method can be used for optimization of treatment strategy of any oncologic disease and can be integrated into relevant clinical decision support systems.

Aim. To evaluate the prognostic value of pAKT1 expression by tumor cells in patients with diffuse large B-cell lymphoma.Materials and methods. The study included 90 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), who were treated at the clinic of Kirov Research Institute of Hematology and Blood Transfusion from 2014 to 2017 and received standard first-line polychemotherapy according to the R-CHOP regimen. Using immunohistochemical and morphometric methods, the relative number of tumor cells expressing pAKT1 was determined. Using the two-sided Fisher’s exact test, the relationship of different levels of marker expression with clinical and laboratory parameters of patients and long-term treatment results was analyzed. The impact of pAKT1 on the risk of an adverse event was assessed using the Cox regression analysis.Results. Overexpression of pAKT1 is associated with unfavorable clinical characteristics of patients with DLBCL, excessive expression of the BCL2 and c-Myc oncoproteins, as well as with low rates of overall and progressive survival. Overexpression of pAKT1 is an independent prognostic factor and statistically significantly affects the risk of an adverse outcome in DLBCL.Conclusion. The degree of pAKT1 expression is an informative criterion that allows to predict the course of diffuse large B-cell lymphoma. It is advisable to use the indicated marker when stratifying patients into risk groups.

Relevance. Natural and climatic conditions, a variety of species composition of arthropods and vertebrates determine the possibility of circulation of arboviruses in the Volgograd region. The existence of natural foci of some arbovirus infections and the possibility of the formation of others suggests the need for annual monitoring of the causative agents of arbovirus diseases. Аim. Evaluation of the results of monitoring of arbovirus infections in the Volgograd region in 2019.Materials and methods: 806 blood serum samples from donors, 44 blood serum samples from febrile sick people, 300 blood serum samples from horses and 94 pools of blood-sucking mosquitoes were examined by immunofernal analysis. Result of the study of serum samples from donors in the Volgograd region, in 140 (17.4%) of 806 were found to have antibodies to the pathogen of West Nile fever (in 35 (4.3%) – IgM, in 105 (13.0%) – IgG), in 7 (2.2%) of 319 – to the Crimean hemorrhagic fever virus (in 4 (1.3%) – IgM, in 3 (0.9%) –IgG), and in 7 (2.9%) of 240 – IgG to the viruses of the California serogroup. Specific antibodies against viruses of Sindbis, Batai and Uukuniemi in the samples was not detected. The largest number of positive samples with the presence of IgG and IgM to the West Nile virus was found among residents of Volgograd (61 out of 240, 25.4%) and Volzhsky (25 out of 100, 25, 0%). Among 44 blood serums of febrile patients, 1 sample (2.3%) was found to contain an antigen of the Sindbis virus, and 2 samples (4.5%) – antigens California serogroup viruses. Specific immunoglobulins against West Nile virus were detected in 84 (28%) of 300 blood serums of farm animals (horses). In the study of 94 samples of field material (blood-sucking mosquitoes), West Nile virus antigen was detected in 14 (14.9%), Sindbis virus – in one sample (1.0%), Batai virus – in four samples (4.2%). Conclusions: the obtained results, along with the circulation of West Nile virus and Crimean hemorrhagic fever virus virus in the Volgograd region, indicate the presence of Sindbis, Batai and California serogroup viruses and necessitate further study of their role in the infectious pathology of the population.

In this paper, we report an approach to design nanolayered memristive compositions based on TiO2/Al2O3 bilayer structures with analog non-volatile and volatile tuning of the resistance. The structure of the TiO2 layer drives the physical mechanism underlying the non-volatile resistance switching, which can be changed from electronic to ionic, enabling the synaptic behavior emulation. The presence of the anatase phase in the amorphous TiO2 layer induces the resistive switching mechanism due to electronic processes. In this case, the switching of the resistance within the range of seven orders of magnitude is experimentally observed. In the bilayer with amorphous titanium dioxide, the participation of ionic processes in the switching mechanism results in narrowing the tuning range down to 2–3 orders of magnitude and increasing the operating voltages. In this way, a combination of TiO2/Al2O3 bilayers with inert electrodes enables synaptic behavior emulation, while active electrodes induce the neuronal behavior caused by cation density variation in the active Al2O3 layer of the structure. We consider that the proposed approach could help to explore the memristive capabilities of nanolayered compositions in a more functional way, enabling implementation of artificial neural network algorithms at the material level and simplifying neuromorphic layouts, while maintaining all benefits of neuromorphic architectures.