Search For New Indicators Research Articles

Chiral distinction between hydroxychloroquine enantiomers in binding to angiotensin-converting enzyme 2, the forward receptor of SARS-CoV-2

Soon after the outset of the Coronavirus Disease 2019 (COVID-19) pandemic (March-April 2020), formulations of the old antimalarial racemic drug hydroxychloroquine (HCQ) sulfate were authorized by the U.S. Food and Drug Administration (FDA) for emergency treatment of hospitalized patients with COVID-19. A call for the chiral switch of HCQ to the single enantiomer (S)-(+)-HCQ for treating the disease followed. The above authorizations were later withdrawn. Angiotensin-converting enzyme 2 (ACE2) has been recognized to be the forward receptor of SARS-CoV-2, the virus responsible for COVID-19. The objective of the present study was to evaluate the chiral distinction in the potential preferential binding of the HCQ enantiomers to ACE2, as a basis for its future drug repurposing, using high-field solution Nuclear Magnetic Resonance (NMR) spectroscopy. Proton selective spin-lattice relaxation rates were measured for selected diagnostic nuclei; in particular, protons belonging to the quinoline ring proved to be the most affected by the presence of the protein, for both (S)-(+)-HCQ and (R)-(−)-HCQ enantiomers. An increase in mono-selective relaxation rates was observed for both enantiomers. A significant difference in the magnitude of the increase was detected for all protons investigated, up to a 5-fold and an 8-fold increase in the case of (R)-(−)-HCQ and (S)-(+)-HCQ, respectively. Furthermore, comparison between the normalized mono-selective relaxation rates of the two HCQ enantiomers in their binary mixtures with ACE2 pointed out a certain preference for the (S)-(+)-HCQ enantiomer over (R)-(−)-HCQ in the interaction with ACE2. The findings form the basis for a future application of the drug repurposing/chiral-switch combination strategy to racemic HCQ in previously reported indications for hydroxychloroquine treatment and in the search for new indications in which ACE2 receptors are involved.

Y-REALITY AS A SHIFT FROM "GREAT MODERATION" TO "GLOBAL CHAOS": ASSESSMENT OF GLOBAL MACROECONOMIC AND CRISIS PROCESSES THROUGH THE PRISM OF GENERATIONAL DIALOGUE AND DEVELOPMENT ISSUES

The purpose of the article is to determine the features of the development of the world economy during the formation of the predominant role of Gen Y in the structure of the population, Y-reality is defined as a common historical context for generations that affects their economic behavior and predetermines challenges that limit the choice of consumption patterns, savings and other economic activity for Gen Y(millennial), the maturation process occurred during the Great moderation period, which lasted from mid-1980 until at least 2007. Great moderation was characterized by a low level of inflation, stable economic growth, the end of the "era" of uncertainty, an increase in the willingness to take risks, an increase in the prices of financial assets, and a decrease in the volatility of business cycle fluctuations in developed countries compared to previous decades. The period of Great Moderation ended with the onset of the global financial crisis of 2008–2009. The "New Norm" of the world economy or "Global Chaos" since 2008 has been characterized by eight trends: deterioration of US-China relations; aggravation of political fragmentation within the EU; further accumulation of debts and injection of artificial liquidity not into the financial, but into the real sector; inflation; increasing tax pressure on the rich as one of the tools to combat economic inequality; actualization of environmental topics, in particular, the climate issue with the prospect of introducing a carbon tax; technological revolution and technological confrontation, which will be determined by the coexistence of different technological standards; intensifying intergenerational competition with Gen Y predominating by 2030, which will set the global agenda and ultimately the demand for policy and how it is implemented. It is noted that in the conditions of the formation of the information and digital economy, Gen Y revised their approaches to employment, which is accompanied by the transformation of Gen Y human capital into network human capital. Y-reality is characterized by: the transition from efficiency to sustainability in strategic planning, which will affect the slowdown in productivity growth; increased demand from market agents for government participation; development of public-private partnership; increased deglobalization, which will accelerate the decline in productivity; rising unemployment; decrease in consumption; decrease in savings; an increase in debt; declining coordination of international economic policy. The impact of the coronavirus crisis on the economy (coronanomics) not only provokes a temporary drop in production, but also changes the basis for the functioning of the world economy, laying the foundations for sustainable economic imbalances. A specific feature of Y-reality is recognized as a change in approaches to monetary policy (quantitative easing and hedge money), as well as a human-centric quantitative easing known as "basic guaranteed income". Y-reality will be characterized by the search for new indicators of well-being and economic growth, in particular, which will lead to the realization of a new purpose of economic systems and the formation of a "new norm" of rational economic behavior, taking into account the impact of human activities on the environment. The slowdown in economic growth under Y-reality conditions becomes sustainable, it is objectively determined by the presence of numerous imbalances, and therefore it should be treated as a given. "Global disorder" came to mean not only the existing state of affairs and contradictory trends, but also the desired state, transforming the meaningful content of the concept of "crisis", giving it the connotation of a stage of the cycle, which can give impetus to development. The acronyms SPOD, VUCA and BANI were considered, which characterized the transformational processes in the modern economic system and the formation of Y-reality.

Von Willebrand Factor and Intima-Media Thickness in Patients With Rheumatoid Arthritis: A Cross-Sectional Study

Background. Cardiovascular risk assessment in patients with rheumatoid arthritis (RA) is often a real challenge and requires the search for new indicators to reveal the potential threat of developing atherosclerotic vascular lesions in the early stages.
 The study aimed to analyse the association between von Willebrand factor (vWF), disease activity, and intima-media thickness (IMT) score in RA patients.
 Materials and Methods. The study involved 60 RA patients divided into three groups based on the Disease Activity Score 28 (DAS-28) activity index and 20 individuals as healthy controls. Clinical and laboratory assessments included determining the number of swollen (SJ) and painful joints (PJ), the visual analogue scale (VAS) score, the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fibrinogen. The concentration of vWF in blood plasma was determined by an enzyme-linked immunosorbent assay (ELISA). The IMT was measured at the bifurcation of the external and internal carotid arteries. Asymptomatic vascular damage was identified as the IMT > 0.9 mm; an atherosclerotic plaque was verified when a focal structure encroached ≥ 0.5 mm or 50% of the adjacent IMT value into the carotid lumen or the IMT > 1.5 mm.
 Results. Most RA patients (39/60; 65.0%) showed an increase in the IMT (> 0.9 mm); atherosclerotic plaques (IMT > 1.5 mm) were confirmed in 16 (26.7%) individuals, which was significantly more as compared to the control group. VWF was positively associated with the IMT [OR 1.1 (1.06-1.2), p < 0.001]. In addition, elevated levels of vWF were associated with disease activity. The highest values of vWF were found in patients with moderate RA activity (43.3 [21.2-56.9]). There was a positive correlation between vWF and ESR, CRP, DAS-28 (0.564, 0.455, and 0.573, respectively).
 Conclusions. There was a positive correlation between vWF, inflammatory markers, and disease activity. VWF appeared to be a reliable predictor of the IMT score in RA patients.

Blood Leukocyte ROS Production Reflects Seminal Fluid Oxidative Stress and Spermatozoa Dysfunction in Idiopathic Infertile Men.

A large proportion of infertile men do not receive a clear diagnosis, being considered as idiopathic or unexplained cases due to infertility diagnosis based on standard semen parameters. Particularly in unexplained cases, the search for new indicators seems mandatory to provide specific information. In the etiopathogenesis of male infertility oxidative stress displays important roles by negatively affecting sperm quality and function. In this study, performed in a population of 34 idiopathic infertile men and in 52 age-matched controls, redox parameters were assessed in blood, leukocytes, spermatozoa, and seminal fluid and related to semen parameters. The main findings indicate that blood oxidative stress markers reflect seminal oxidative stress. Interestingly, blood leukocyte ROS production was significantly correlated to sperm ROS production and to semen parameters. Overall, these results suggest the potential employ of blood redox markers as a relevant and adjunctive tool for sperm quality evaluation aimed to preconception care.

The role of glucose transporter type 1 (GLUT1) and carbonic anhydrase IX (CAIX) expression by prostate adenocarcinoma tissue in determining disease prognosis and effectiveness of radical treatment

Introduction. Today, due to the insufficient diagnostic accuracy of existing tools for determining clinically significant forms of prostate cancer, the search for new indicators that predict the course of the disease and the effectiveness of radical treatment is relevant. Various malignant tumors could increase glucose consumption and grow under hypoxic conditions. It seems promising to assess the expression level of glucose transporter type 1 (GLUT1) and carbonic anhydrase IX (CAIX) in prostate adenocarcinoma cells of different malignancy score.Objective. To determine CAIX and GLUT1 expression in ISUP grades 1-5 prostate adenocarcinoma cells for evaluation of the disease prognosis and radical prostatectomy effectiveness.Materials and methods. Immunohistochemical study of postoperative material after radical prostatectomy with determination of GLUT1 and CAIX expression by tumor cells was carried out. The presence or absence of biochemical recurrence within one year after surgery was determined. The correlation between the level of expression, the presence of biochemical relapse and a few other clinical parameters was determined.Results. GLUT1 expression level statistically significant correlated with ISUP 4 and 5 (r = 0.457, p < 0.0001), prostate-specific antigen (PSA) level (r = 0.378, p < 0.0001), pT3b disease stage (r = 0.380, p < 0.0001), extracapsular extension (r = 0.355, p = 0.001), and inversely correlated with ISUP 1 (r = -0.274, p = 0.009). CAIX immunoexpression was observed in 10.0% of samples and the intensity was low (< 20% of cells).Conclusion. Elevated expression of glucose transporter type 1 (GLUT1) by prostate adenocarcinoma cells among patients after radical prostatectomy is associated with high grade of malignancy (ISUP 4 and 5), pT3b disease stage, extracapsular extension of the tumor, as well as high PSA, which allows using it for the prognosis evaluation.

Translated article] Biological Biomarkers in Respiratory Diseases

In recent years, personalized or precision medicine has made effective inroads into the management of diseases, including respiratory diseases. The route to implementing this approach must invariably start with the identification and validation of biological biomarkers that are closely related to the diagnosis, treatment, and prognosis of respiratory patients. In this respect, biological biomarkers of greater or lesser reliability have been identified for most respiratory diseases and disease classes, and a large number of studies are being conducted in the search for new indicators. The aim of this review is to update the reader and to analyze the existing scientific literature on the existence and diagnostic, therapeutic, and prognostic validity of the most important biological biomarkers in the main respiratory diseases, and to identify future challenges in this area.

Biomarcadores biológicos en las enfermedades respiratorias

In recent years, personalized or precision medicine has made effective inroads into the management of diseases, including respiratory diseases. The route to implementing this approach must invariably start with the identification and validation of biological biomarkers that are closely related to the diagnosis, treatment, and prognosis of respiratory patients. In this respect, biological biomarkers of greater or lesser reliability have been identified for most respiratory diseases and disease classes, and a large number of studies are being conducted in the search for new indicators. The aim of this review is to update the reader and to analyze the existing scientific literature on the existence and diagnostic, therapeutic, and prognostic validity of the most important biological biomarkers in the main respiratory diseases, and to identify future challenges in this area.

Prediction of early death after myocardial infarction in patients with reduced left ventricular ejection fraction. The search for new indications for cardioverter-defibrillator implantation (ICD)

The highest rate of death is in the first few weeks after myocardial infarction (MI). However, the assessment of indications for primary prevention implantable cardioverter-defibrillator (ICD) implantation should be postponed until at least 40 days after MI. Our aim was to identify the subgroup of high-risk patients with reduced left ventricular ejection fraction (LVEF) who would benefit from primary prevention ICD implantation within 40 days of MI. Out of 205 606 patients with MI, in this study, we included 18 736 patients treated invasively, with LVEF <40%, who survived until hospital discharge. Patients were divided into two groups according to the survival status at 40 days - patients who died within this period (n = 1331) and patients who survived (n = 17405). Among all patients who died within 12-months after MI, 37.7% did die during the first 40 days. Patients with cardiac arrest before hospital admission or within the first 48 hours of hospitalization (hazard ratio [HR], 3.35; 95% confidence interval [CI], 2.82-3.98; P <0.0001], cardiogenic shock before admission or during hospitalization (HR, 3.06; 95% CI, 2.62-3.59; P <0.0001), unsuccessful percutaneous coronary interventions (PCI; HR, 2.42; 95% CI, 2.11-2.84; P <0.0001), LVEF <20% (ref. LVEF ≥30%; HR, 2.75; 95% CI, 2.25-3.36; P <0.0001) had approximately threefold and patients with chronic kidney disease almost 1.5-times (HR, 1.25; 95% CI, 1.47-3.59; P = 0.0053) higher 40-day mortality compared to patients without these risk factors. The most striking differences in mortality between these subgroups were observed shortly after discharge. The highest risk of death in patients with reduced LVEF who survived until hospital discharge occurred within the first 40 days after MI. There is a possibility to select patients with the worst prognosis and treat them more aggressively.

Drug repurposing strategy for treating Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease with a long preclinical period of ∼20 years is a chronic, insidious, and progressive neurodegenerative disease of old age. Neuropathologically AD is characterized by the presence of accumulated Amyloid‐beta in plaques (in extracellular spaces, and walls of blood vessels) and aggregated tau protein in neurofibrillary tangles. Drug repurposing is the search for new indications or molecular targets distinct from a drug’s acknowledged activity, pharmacological effect or binding specificities. With the ever‐increasing rates of termination of drugs in clinical trials, drug repositioning has risen as one of the effective solutions against the risk of drug failures.MethodA comprehensive literature search was performed in the Pub Med/Science direct/Google scholar/Plos one databases and connected papers to review relevant articles in English, using keywords ‘‘Drug repurposing and neurological disorder, drug repurposing and dementia, drug repurposing and Alzheimer 'disease. The research papers were scrutinized and studied thoroughly.ResultAccording to literature it has been found that some repurposed drugs i.e, Allopurinol, Bromocriptine, Bupropion, Raloxifene, Thalidomide, Zidovudine may have a potential to treat Alzheimer’s disease.ConclusionThe repurposing drug approach may be used to treat Alzheimer’s and these drugs are needed to studied further.

An Overview of the Application of Systems Biology in an Understanding of Chronic Rhinosinusitis (CRS) Development.

Chronic rhinosinusitis (CRS) is an inflammatory disease of the paranasal sinuses. It is defined as the presence of a minimum of two out of four main symptoms such as hyposmia, facial pain, nasal blockage, and discharge, which last for 8–12 weeks. CRS significantly impairs a patient’s quality of life. It needs special treatment mainly focusing on preventing local infection/inflammation with corticosteroid sprays or improving sinus drainage using nasal saline irrigation. When other treatments fail, endoscopic sinus surgery is considered an effective option. According to the state-of-the-art knowledge of CRS, there is more evidence suggesting that it is more of an inflammatory disease than an infectious one. This condition is also treated as a multifactorial inflammatory disorder as it may be triggered by various factors, such as bacterial or fungal infections, airborne irritants, defects in innate immunity, or the presence of concomitant diseases. Due to the incomplete understanding of the pathological processes of CRS, there is a continuous search for new indicators that are directly related to the pathogenesis of this disease—e.g., in the field of systems biology. The studies adopting systems biology search for possible factors responsible for the disease at genetic, transcriptomic, proteomic, and metabolomic levels. The analyses of the changes in the genome, transcriptome, proteome, and metabolome may reveal the dysfunctional pathways of inflammatory regulation and provide a clear insight into the pathogenesis of this disease. Therefore, in the present paper, we have summarized the state-of-the-art knowledge of the application of systems biology in the pathology and development of CRS.

GROSS VALUE ADDED AS THE MAIN INDICATOR PRODUCTIVITY OF ENTERPRISES

Topicality. Traditionally, output and profit are used as the main indicators of enterprise productivity, but they have significant shortcomings. All this determines the relevance of the search for new indicators that will provide an adequate idea of the productivity of enterprises and a single conceptual basis for assessing the results of economic activity at the micro, mega and macro levels. Aim and tasks. To analyze the existing indicators for assessing the productivity of enterprises, to identify their main short comings. Consider the experience of the Republic of Belarus in the use of gross value added as an indicator of productivity of enterprises. Justify the use of gross value added as a conceptual basis for assessing the results of economic activity at the micro, mega and macro levels. Identify the main indicators for assessing the productivity of enterprises on the basis of gross value added. Research results. As the main indicators of the enterprise, use "output" and "profit". The first indicator consists of gross value added and intermediate consumption and therefore it depends on the performance of other enterprises. In this case, the external contribution can be decisive and therefore the indicator "output" does not give an adequate idea of the productivity of enterprises. Another key indicator of enterprise activity is profit. With a focus on it, wages, social security financing and employee training are the costs of the enterprise and the smaller they are, the greater the company's profits. But in modern conditions to ensure sustainable economic development of the individual enterprise and the country as a whole, it is important to consider that employees are carriers of intellectual capital. The loss or reduction of this capital can lead to more significant losses than the loss of physical and financial capital. Under such conditions, it is advisable to change the benchmark, namely the use of gross value added as the main indicator of productivity of the enterprise. It is on the basis of this indicator that the main result of economic activity of the country (gross domestic product) and regions (gross regional product) is determined. Gross value added is a very important indicator in terms of meeting the needs of all stakeholders in the performance of the enterprise: employees, business owners, the state. The indicator "gross value added" is the main indicator of the enterprise in terms of the interests of society as a whole, and the indicator "profit" - the main in terms of the interests of business owners. The presence of these two indicators reflects the contradiction between the interests of society and business owners. Conclusion. Gross value added has a greater analytical value than the indicators "output" and "profit", because, firstly, it gives a more adequate picture of the results of enterprises, secondly, it determines the potential for capital accumulation and thirdly provides a single conceptual basis for evaluation of economic performance at the micro, mega and macro levels.

Web-based drug repurposing tools: a survey.

Drug repurposing (a.k.a. drug repositioning) is the search for new indications or molecular targets distinct from a drug's putative activity, pharmacological effect or binding specificities. With the ever-increasing rates of termination of drugs in clinical trials, drug repositioning has risen as one of the effective solutions against the risk of drug failures. Repositioning finds a way to reverse the grim but real trend that Eroom's law portends for the pharmaceutical and biotech industry, and drug discovery in general. Further, the advent of high-throughput technologies to explore biological systems has enabled the generation of zeta bytes of data and a massive collection of databases that store them. Computational analytics and mining are frequently used as effective tools to explore this byzantine series of biological and biomedical data. However, advanced computational tools are often difficult to understand or use, thereby limiting their accessibility to scientists without a strong computational background. Hence it is of great importance to build user-friendly interfaces to extend the user-base beyond computational scientists, to include life scientists who may have deeper chemical and biological insights. This survey is focused on systematically presenting the available Web-based tools that aid in repositioning drugs.

INDICATORS AFFECTING VIDZEME REGION SMART DEVELOPMENT

The study aims to determine the main indicators of rural smart development concept for territorial development analysis and decision-making in Vidzeme region (Latvia). In the framework of the study the theoretical literature and planning documents were analysed, focusing on the indicators of rural areas and sustainable development. For a long time the development was associated primarily with the economic growth - GDP, employment and income growth. In recent years, the economic dimension is supplemented with social, environmental, cultural and political aspects. A holistic approach interprets close relations and balanced integration between the economic, social, political, ecological and cultural dimensions of local and regional development. Such approach requires the search for new indicators that describe the development of rural areas and are directly relevant to each individual area. The results present that in the development of Vidzeme smart specialization, the local governments and the state has the greatest impact. It is most affected by the local government's capacity to develop cooperation with residents and entrepreneurs, and a stable and sustainable economic situation in the country.

Emerging sublingual immunotherapy drugs

Importance of the field: There is epidemiological evidence that respiratory allergy has reached epidemic proportions; owing to the related socio-economic impact, this topic deserves particular attention. An integrated approach involving pharmacotherapy and the immunomodulatory effect of immunotherapy is expected to optimize the management of respiratory allergy, reducing its clinical and economic burdens. Sublingual immunotherapy (SLIT) has gained increasing interest for its efficacy comparable to traditional subcutaneous immunotherapy and its good safety profile.Areas covered in this review: A review of the up-to-date state of the art concerning the key aspects of SLIT is provided; the critical issues are discussed in the light of the comprehensive revision of the recent World Allergy Organization position paper and the subsequent literature, paying particular attention to efficacy, safety, additional effects, adherence and clinical developments.What the reader will gain: The overview of current certainties and concerns, related to the use of SLIT, allows the reader's insight into the future directions of research and clinical applications of SLIT, aimed at covering current unmet needs.Take home message: A large amount of experimental evidence sustains the use of SLIT, though some aspects still need to be clarified to provide clear, evidence-based recommendations. Unmet needs represent the basis for future research, while clinical hypotheses would open the search for new indications and modalities.

Novelties of financial crises in the 1990s and the search for new indicators

This paper argues that, first, despite some similarities, financial crises in the 1990s have featured substantial differences between them: the ERM crisis of 1992–1993 was mainly due to stringent monetary policies; the Mexican crisis of 1994–1995 was associated to private overconsumption; and the East Asian crisis of 1997–1999 were basically the result of private overinvestment. Therefore, as crises do not seem to present strong regularities over time, the task of trying to predict them on the basis of past developments is surely doomed to fail. As crises might be simply unpredictable, specialists should refrain from creating and developing predictors and focus instead on simpler early-warning indicators. Second, the paper reviews the main body of literature on leading indicators of crises and it suggests that the bulk of these conventional indicators do not seem to be appropriate to the East Asian episodes. In order to create a new set of early-warning indicators, economists should focus on non-conventional deficiencies, such as those related to financial fragility associated with financial deregulation and with capital inflows, to a declining efficiency of investment, and to a high short-term external debt (especially as a proportion of foreign exchange reserves).