A comprehensive review on technological advances in alternate drug discovery process:Drug repurposing

The traditional de novo drug discovery is time consuming, costly and in some instances the drugs will fail to treat the disease which result in a huge loss to the organization. Drug repurposing is an alternative drug discovery process to overcome the limitations of the De novo drug discovery process. Ithelps for the identification of drugs to the rare diseases as well as in the pandemic situationwithin short span of time in a cost-effective way. The underlying principle of drug repurposing is that most of the drugs identified on a primary purpose have shown to treat other diseases also. One such example is Tocilizumab is primarily used for rheumatoid arthritis and it is repurposed to treat cancer and COVID-19. At present, nearly30% of the FDA approved drugs to treat various diseases are repurposed drugs. The drug repurposing is either drug-centric or disease centric and can be studied by using both experimental and in silico studies. The in silico repurpose drug discovery process is more efficient as it screens thousands of compounds from the diverse libraries within few days by various computational methods like Virtual screening, Docking, MD simulations,Machine Learning, Artificial Intelligence, Genome Wide Association Studies (GWAS), etc. with certain limitations.These limitationscan be addressed by effective integration of advanced technologies to identify a novel multi-purpose drug.Copyright © 2023, Association of Biotechnology and Pharmacy. All rights reserved.

Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases: Third of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development

This article expands on a session, titled "Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases," that was presented as part of a two-day meeting on Pediatric Drug Development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs, including implications for rare/orphan diseases. The speakers have written summaries of their talks. The session's lead Chair was Dr. Joan Busner, who wrote introductory and closing comments. Dr. Simon Day, regulatory consultant, outlined some of the past mistakes that have plagued trials that did not consult with patient groups in the early design phase. Dr. Atul Mahableshwarkar provided an industry perspective of a recent trial that benefited from the inclusion of patient input. Drs. Lucas Kempf and Maria Sheean provided regulatory input from the perspectives of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Dr. Judith Dunn outlined a novel approach for assessing and rank ordering patient and clinician clinical meaningfulness and the disconnect that may occur. Dr. Busner provided closing comments, tied together the presented issues, and provided a synopsis of the lively discussion that followed the session. In addition to the speakers above, the discussion included two representatives from patient advocacy groups, as well as an additional speaker who described the challenges of conducting a pediatric trial in the US and European Union (EU), given the often competing regulatory requirements. This article should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and rare diseases and seek to ensure a patient-centric approach.Copyright © 2023, Matrix Medical Communications. All rights reserved.

Multi-faceted CRISPR/Cas technological innovation aspects in the framework of 3P medicine.

Since 2009, the European Association for Predictive, Preventive and Personalised Medicine (EPMA, Brussels) promotes the paradigm change from reactive approach to predictive, preventive, and personalized medicine (PPPM/3PM) to protect individuals in sub-optimal health conditions from the health-to-disease transition, to increase life-quality of the affected patient cohorts improving, therefore, ethical standards and cost-efficacy of healthcare to great benefits of the society at large. The gene-editing technology utilizing CRISPR/Cas gene-editing approach has demonstrated its enormous value as a powerful tool in a broad spectrum of bio/medical research areas. Further, CRISPR/Cas gene-editing system is considered applicable to primary and secondary healthcare, in order to prevent disease spread and to treat clinically manifested disorders, involving diagnostics of SARS-Cov-2 infection and experimental treatment of COVID-19. Although the principle of the proposed gene editing is simple and elegant, there are a lot of technological challenges and ethical considerations to be solved prior to its broadly scaled clinical implementation. This article highlights technological innovation beyond the state of the art, exemplifies current achievements, discusses unsolved technological and ethical problems, and provides clinically relevant outlook in the framework of 3PM.

Personalized approach to the management of a patient with COVID-19 with a complicated comorbid background

The aim of the work is to form the principles of a personalized approach to the management of patients with COVID-19 with a complicated comorbid background. Material and methods. The article describes a clinical case of successful recovery of an 87-year-old patient from a new coronavirus infection COVID-19, complicated by pneumonia involving 36% of the lung parenchyma area. Along with age, the situation was aggravated by the comorbid status of the patient: the presence of chronic lymphocytic leukemia, hypertension, mechanical prostheses of the mitral and aortic valves, postinfarction cardiosclerosis, paroxysmal atrial fibrillation, type 2 diabetes mellitus, stage 4 CKD, anemic syndrome, and subclinical hypothyroidism. Results. The C-reactive protein level at admission was 114.46 mg/L. The patient refused hospitalization. Baricitinib 4 mg, favipiravir according to the scheme, vitamin D 2000 units were prescribed for the previously taken therapy. Already after 3 days, C-reactive protein decreased by 4.6 times, and by the 8th day by 15.5 times and amounted to 7.38 mg/ml. The temperature returned to normal on day 2 from the start of baricitinib. In dynamics, a decrease in creatinine level to 177.0 mumol/l was noted, the glomerular filtration rate increased to 30 ml/min/1.73 m2, which corresponded to stage 3b of CKD (a pronounced decrease in glomerular filtration rate). Conclusion. Despite the age of the patient, many comorbidities, each of which could be fatal, the timely use of baricitinib on an outpatient basis made it possible to stop the progressive course of the disease.Copyright © Eco-Vector, 2023. All rights reserved.

Overview on Mrna Vaccines Beyond Covid-19

COVID-19 mRNA vaccines: COVID-19 pandemic has made an extraordinary impact on global vaccine technology platform developments. Never in human history have there at least 6 vaccine platforms including: inactivated, protein subunit, VLP and other 3 new platforms i.e., mRNA, viral vector, and DNA, with more than 160 vaccine candidates being developed and tested in clinical trials. Nonetheless, among these several vaccine platforms, mRNA vaccine has been proven to be one of the most effective vaccines against COVID-19. There are two mRNA vaccines authorized for emergency use within a year and currently more than 20 mRNA vaccines are in clinical trials. The main advantages of mRNA vaccines are that they are speedily to design and develop, induce strong antibody and T-cell responses, manufacturing faster and at a lower cost. However, one of the major limitations is that it must be stored in cold temperatures. Currently more than billion doses of COVID-19 mRNA vaccines have been given globally. mRNA vaccines will be a key platform for next pandemics preparedness, it is therefore establishing this platform in various regions and LMICs is critical. Beyond COVID-19: A number of viral and cancer mRNA vaccines have been developing even before COVID-19. At least 12 mRNA vaccines against various infectious diseases are now in clinical evaluation, including Chikungunya virus, Cytomegalovirus, Epstein-Barr virus, Human metapneumovirus and parainfluenza virus type3, HIV, Influenza, Nipah, Rabies, Lasa, RSV, Zika, Varicella-zoster virus. Only few are entering phase 3 such as a CMV vaccine, RSV, seasonal influenza. Current mRNA cancer vaccines development, including brain, breast, melanoma, esophagus, lung, ovarian, prostate and solid tumors. Most are aimed for personalized therapy. By 2023, at least 1 viral mRNA vaccine may get approval, whereas a cancer vaccine might take much longer time. Nevertheless, the remaining challenge at the global level is how to truly overcome the vaccine inequity issues in a sustainable way.Copyright © 2023

Features and characteristics of publicly available mHealth apps for self-management in chronic obstructive pulmonary disease.

Mobile health applications (mHealth apps) may be able to support people living with chronic obstructive pulmonary disease (COPD) to develop the appropriate skills and routines for adequate self-management. Given the wide variety of publicly available mHealth apps, it is important to be aware of their characteristics to optimize their use and mitigate potential harms. Objective: To report the characteristics and features of publicly available apps for COPD self-management. Methods: MHealth apps designed for patients' COPD self-management were searched in the Google Play and Apple app stores. Two reviewers trialed and assessed the eligible apps using the MHealth Index and Navigation Database framework to describe the characteristics, qualities, and features of mHealth apps across five domains. Results: From the Google Play and Apple stores, thirteen apps were identified and eligible for further evaluation. All thirteen apps were available for Android devices, but only seven were available for Apple devices. Most apps were developed by for-profit organizations (8/13), non-profit organizations (2/13), and unknown developers (3/13). Many apps had privacy policies (9/13), but only three apps described their security systems and two mentioned compliance with local health information and data usage laws. Education was the common app feature; additional features were medication reminders, symptom tracking, journaling, and action planning. None provided clinical evidence to support their use. Conclusions: Publicly available COPD apps vary in their designs, features, and overall quality. These apps lack evidence to support their clinical use and cannot be recommended at this time.

Identification of a sub-group of critically ill patients with high risk of intensive care unit-acquired infections and poor clinical course using a transcriptomic score.

BACKGROUND: The development of stratification tools based on the assessment of circulating mRNA of genes involved in the immune response is constrained by the heterogeneity of septic patients. The aim of this study is to develop a transcriptomic score based on a pragmatic combination of immune-related genes detected with a prototype multiplex PCR tool. METHODS: As training cohort, we used the gene expression dataset obtained from 176 critically ill patients enrolled in the REALISM study (NCT02638779) with various etiologies and still hospitalized in intensive care unit (ICU) at day 5-7. Based on the performances of each gene taken independently to identify patients developing ICU-acquired infections (ICU-AI) after day 5-7, we built an unweighted score assuming the independence of each gene. We then determined the performances of this score to identify a subgroup of patients at high risk to develop ICU-AI, and both longer ICU length of stay and mortality of this high-risk group were assessed. Finally, we validated the effectiveness of this score in a retrospective cohort of 257 septic patients. RESULTS: This transcriptomic score (TScore) enabled the identification of a high-risk group of patients (49%) with an increased rate of ICU-AI when compared to the low-risk group (49% vs. 4%, respectively), with longer ICU length of stay (13 days [95% CI 8-30] vs. 7 days [95% CI 6-9], p < 0.001) and higher ICU mortality (15% vs. 2%). High-risk patients exhibited biological features of immune suppression with low monocytic HLA-DR levels, higher immature neutrophils rates and higher IL10 concentrations. Using the TScore, we identified 160 high-risk patients (62%) in the validation cohort, with 30% of ICU-AI (vs. 18% in the low-risk group, p = 0.06), and significantly higher mortality and longer ICU length of stay. CONCLUSIONS: The transcriptomic score provides a useful and reliable companion diagnostic tool to further develop immune modulating drugs in sepsis in the context of personalized medicine.

Oral Microbiome and Innate Immunity in Health and Disease: Building a Predictive, Preventive and Personalized Therapeutic Approach

An average person carries 1 to 2 kg of microbes in the alimentary track, including the oral cavity. There are more bacteria in a person's mouth than the total human population in the entire world. Oral health is critical to the general systemic health of an individual. The harmonious co-existence between more than 1000 bacterial species and the host's immune system underpins sustained, long-term homeostasis, the sine qua non of oral health. In a similar manner, global oral health is essential for general population health of the world. Since our last review of this subject in 2019, while significant clinical advances continue, the disparity, lack of prevention, insufficient care, and political unrest have persisted or significantly deteriorated. This review focuses on the following important questions: 1.What is oral microbiome? How to detect, characterize, compare, report, and interpret the results?2.How does oral microbiome affect and respond to local and systemic innate immunity?3.What is the role of oral microbiome in the pathogenesis of diseases of the mouth?4.What are the impacts of oral health or the lack of it at the systemic level?5.Why is oral health important at the population level?6.How can the healthcare providers restore and sustain harmonious co-existence between host and oral microbiome?Copyright © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Coronavirus infection and organizational changes in the clinical process in patients with non-muscle-invasive bladder carcinoma.

The spread of the aggressive disease caused by the novel respiratory syndrome coronavirus-2 (SARS-CoV-2) has had an impact not only on the health and psyche of people, but also on the state of health systems in different countries, by complicating the treatment and diagnostic process. These changes have affected patients with cancers to a greater extent. The diagnosis, treatment, and follow-up of patients are of particular scientific and practical interest when working in conditions of special anti-epidemic control. Objective. To assess the possibility of reducing the frequency of hospitalization of patients with non-muscle-invasive bladder carcinoma (NMIBC) during the Covid-19 period. Subjects and methods. Sixty-four patients with urinary tract malignancy, including 19 (29.7%) patients with low-and high-risk re-current NMIBC, were followed up in two clinics (Saint Petersburg, Russia) in March to October 2020. All the patients were oper-ated on;the patients at high risk for recurrence received a cycle of adjuvant BCG therapy. Methods for cytological examination of urine sediment and the biomarkers UBC and Cyfra 21-1 were used for special laboratory diagnosis;the server stations of both clinics were applied for telehealth consultations (TCs). Results. TCs were used to reduce hospitalization rates: after TCs, all the patients reported a reduction in transport costs and recovery time after hospitalization. TCs could protect the followed-up patients against COVID-19 infection, by observing the rules of clinical examination, and achieve maximum individualization of treatment. The authors refused to perform diagnostic operations for low-risk NMIBC and to use laboratory tests using urinary biomarkers. At the place of their residence, outpatients underwent urinalysis for several indicators, transmitting the result to the clinic's servers or through a monitoring system. Inpatient treatment was used only in cases of gross hematuria or after recording abnormal laboratory test results. Control cystoscopy detected no re-current tumor. Conclusion. During the spread of COVID-19, the periods of endoscopic examinations and control diagnostic operations can be post-poned, by replacing face-to-face consultations with TC monitoring. Outpatient laboratory and radiation examinations are indicat-ed in patients with new-onset gross hematuria or after combination treatment. Repeated operations, including diagnostic ones, should be performed in the case of multiple NMIBCs or after incomplete excision of the primary tumor.Copyright © 2021.

Metabolomics: From Scientific Research to the Clinical Diagnosis

Metabolomics supports uncovering relevant pathophysiological mechanisms and identifying biomarkers of risk and progression in diseases. Furthermore, metabolomics has allowed the characterization of the proteins and metabolites of COVID-19, neurodegenerative processes, gestational diabetes mellitus, cancer breast, process of kidney transplantation, and Parkinson diagnosis, among other diseases (Table 7.1). Metabolomics employs noninvasive human biological samples such as serum, breath, and urine to screen and identify novel biomarkers. The combination of NMR, LC/MS, and CG/MS is desirable to detect, identify, and quantify hundreds of thousands of metabolites, useful in biomarker discovery toward clinical applications. The generation of biological information has led to the creation of databases such as BioBankWarden, which can be used to store and retrieve specific information from different clinical fields linked to biomaterials collected from patients. The use of metabolomics allows greater precision in the diagnosis and follow-up of the treatment of any disease. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Derivation and validation of clinical phenotypes and associated treatment responses in critically ill COVID-19 patients

Introduction: Due to variability in the host response, a uniform treatment strategy for severe COVID-19 may be inadequate. We applied unsupervised clustering methods to large cohorts of COVID-19 ICU patients to derive and validate clinical phenotypes, and to explore treatment responses in these phenotypes. Method(s): Phenotypes were derived in 13.279 critically ill COVID-19 patients admitted to 82 Dutch ICUs from September 2020 to February 2022. Twenty-one features were selected from clinical characteristics measured within 24 h after ICU admission. Phenotypes were assigned using consensus k means clustering. External validation was performed in 6225 critically ill COVID-19 patients admitted to 55 Spanish ICUs from February 2020 to December 2021. Individual patient data on corticosteroids therapy enabled us to investigate phenotype-specific responses in this cohort. Result(s): Three distinct clinical phenotypes were derived (Fig. 1A). Patients with phenotype 1 (43%) were younger, had lower APACHE IV scores, higher BMI as well as a lower P/F ratio and 90-day in-hospital mortality (18%, Fig. 1A). Phenotype 2 patients (37%) were older and had slightly higher APACHE IV scores compared with phenotype 1, a lower BMI, and higher mortality compared to phenotype 1 (24%, p = 2.95e-07). Phenotype 3 (20%) included the oldest patients with the most comorbidities and highest APACHE IV scores, severe renal and metabolic impairment, and the worst outcome (47% mortality, p = 6.6e-16 and p = 6.6e-16 versus phenotypes 1 and 2, respectively). Phenotype distribution and outcome were very similar in the validation cohort (Fig. 1B). This cohort also revealed that corticosteroid therapy only benefited phenotype 3 (65% vs. 54% mortality, p = 2.5e-03, Fig. 1C). Conclusion(s): COVID-19 ICU phenotypes based on clinical data are related to outcome and treatment responses. This can inform treatment decisions as well as randomized trials employing precision medicine approaches.

Physical and cognitive correlates, inflammatory levels, and treatment response in post-COVID-19 first-onset vs. recurrent depressive episodes.

Psychiatric symptoms have been frequently reported in patients affected by COVID-19, both as new occurring and recurrences of pre-existing diseases. Depressive symptoms are estimated to affect at least 30% of patients following infection, with specific physical and cognitive features and relevant immune-inflammatory alterations. This study aimed to retrospectively characterize post-COVID-19 first-onset and recurrent major depressive episodes (MDE) and to evaluate the effects of antidepressants on physical and cognitive correlates of depression, in addition to mood, anxiety, and underlying inflammatory status. We evaluated 116 patients (44.8% males, 51.1 ± 17 years) with post-COVID-19 first-onset (38.8%) and recurrent (61.2%) MDE at baseline and after one- and three-month treatment with antidepressants (31% SSRIs, 25.9% SNRIs, 43.1% others). We assessed sociodemographic and clinical features and psychopathological dimensions through: Hamilton Depression and Anxiety Rating Scales; Short Form-36 Health Survey Questionnaire; Perceived Deficits Questionnaire-Depression 5-items. The systemic immune-inflammatory index was calculated to measure inflammation levels. Alongside the reduction of depression and anxiety (p < 0.001), physical and cognitive symptoms improved (p < 0.001) and inflammatory levels decreased (p < 0.001) throughout treatment in both groups. Post-COVID-19 recurrent MDE showed a significantly more severe course of physical and cognitive symptoms and persistently higher levels of inflammation than first-onset episodes. Antidepressants proved to be effective in both post-COVID-19 first-onset and recurrent MDE. However, a sustained inflammatory status might blunt treatment response in patients with recurrent depression in terms of physical correlates and cognition. Therefore, personalized approaches, possibly involving combinations with anti-inflammatory compounds, could promote better outcomes in this clinical population.

Immunologic Profile of Severe COVID-19 Patients in Alborz Province, Iran

Background: The coronavirus disease 2019 (COVID-19) pandemic has prompted researchers to look for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenicity in depth. Immune system dysregulation was one of the major mechanisms in its pathogenesis. The evidence regarding the levels of interferons (IFNs) and pro-and anti-inflammatory cytokines in COVID-19 patients is not well-established. Objective(s): Therefore, this study evaluated the expression level of type-I, II, III IFNs, along with interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), and FOXP3 genes in patients with severe COVID-19 to provide additional insights regarding the regulation of these cytokines during COVID-19 infection. Method(s): Peripheral blood mononuclear cells were isolated from two groups, including severe COVID-19 patients and healthy con-trols. Ribonucleic acid was extracted to evaluate the expression level of IFN-a, IFN-b, IFN-g, IFN-la, IL-1, IL-6, IL-10, and FOXP3 genes using real-time polymerase chain reaction. The correlations between the expression levels of these genes were also assessed. Result(s): A total of 40 samples were divided into two groups, with each group consisting of 20 samples. When comparing the severe COVID-19 group to the controls, the expression levels of IFN-g, tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-10 genes were sig-nificantly higher in the severe COVID-19 group. The two groups had no significant differences in IFN-a, IFN-b, IFN-la, IL-1, and FOXP3 expression. The correlation analysis revealed a negative correlation between type I and type III IFNs (i.e., IFN-a and IFN-la) and pro-inflammatory cytokines (i.e., IL-1 and IL-10). Conclusion(s): This study suggests the possible upregulation of IFN-g, IL-6, IL-10, and TNF-alpha during SARS-CoV-2 pathogenicity. The pre-liminary findings of this study and those reported previously show that the levels of IFNs and pro-and anti-inflammatory cytokines are not uniformly expressed among all COVID-19 patients and might differ as the disease progresses to the severe stage.Copyright © 2023, Author(s).