Total Stromal Fraction (TSF)-Fortified Adipose Tissue-Derived Stem Cells Source: An Emerging Regenerative Realm Against COVID-19 In-duced Pulmonary Compromise

The inception of the COVID-19 pandemic has jeopardized humanity with markedly dam-pening of worldwide resources. The viral infection may present with varying signs and symptoms, imitating pneumonia and seasonal flu. With a gradual course, this may progress and result in the deadliest state of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). More-over, following recovery from the severe brunt of COVID-19 infection, interstitial portions of alve-oli have been found to undergo residual scarring and further to have compromised air exchange. Such alterations in the lung microenvironment and associated systemic manifestations have been recognized to occur due to the extensive release of cytokines. The mortality rate increases with advancing age and in individuals with underlying co-morbidity. Presently, there is no availability of specific antiviral therapy or any other definitive modality to counter this progressive worsening. However, we believe principles and advancing cell-based therapy may prove fruitful in subjugating such reported worsening in these patients. This article reviews eminent knowledge and relevant ad-vancements about the amelioration of lung damage due to COVID-19 infection using adipose tis-sue-derived-total stromal fraction (TSF).Copyright © 2022 Bentham Science Publishers.

Plain language summary of Pfizer-BioNTech BNT162b2 COVID-19 vaccine safety in participants 16 years or older and protection against COVID-19 in participants 12 years or older

What is this summary about?This is a summary of an article about part of a clinical study for the BNT162b2 COVID-19 vaccine, also called the Pfizer-BioNTech vaccine. The article was published in the New England Journal of Medicine in September 2021. The part of the study described in the article began in July 2020 and is ongoing. This means that the final results may be different from the results included in this summary.What happened in this study?The participants in this study received 2 injections of either the BNT162b2 vaccine or a placebo, 21 days apart. The placebo looked like the BNT162b2 vaccine but had no active vaccine in it. None of the trial participants or study teams knew who received vaccine or placebo.What were the results?Most of the reactions to the injections were mild or moderate and lasted for a short period of time. The most common reactions were pain at the injection site, extreme tiredness (fatigue), and headache. These reactions usually happened in the first 7 days after receiving a vaccine dose. A small number of participants had severe reactions to the vaccine.Compared to participants who received the placebo, participants who received the BNT162b2 vaccine were much less likely to become ill if they were infected with the virus that causes COVID-19. The vaccine also had very good efficacy at preventing severe COVID-19.Participants in South Africa who received the BNT162b2 vaccine were less likely to become ill after infection with the beta variant of the virus compared to participants who received the placebo. The beta variant was very common in South Africa when the study was taking place.

COVID-19, oxidative stress, and male reproductive dysfunctions: Vitamin C as a potential remedy?

Few peculiarities have been observed in the aetiology of coronavirus disease 2019 (COVID-19), one such being its greater prevalence in men than women partly due to the higher expressions of angiotensin-converting enzyme-2 (ACE2) in the male reproductive tissues. Recent scientific reports are in line with some of the evidence-based hypotheses in the initial phase of the COVID-19 pandemic, regarding the involvement of oxidative stress (OS) and oxidant-sensitive pathways in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-mediated male reproductive disruptions. The seminal dissemination of SARS-CoV-2 or its components, testicular disruptions due to viral infection and oxidative damage in the testis have all been evidenced recently. High-dose of antioxidants, such as vitamin C, have been shown to be a useful treatment for COVID-19 patients, to alleviate systemic inflammation and OS. In addition, vitamin C is a major testicular antioxidant that neutralizes excess reactive oxygen species (ROS), prevents sperm agglutination, prevents lipid peroxidation, recycles vitamin E, and protects against DNA damage. Thus, the present review aims to discuss the mechanism of COVID-19-mediated male reproductive dysfunctions, based on the evidence available so far, and explore the possibility of using vitamin C in alleviating testicular OS and associated damage caused by COVID-19.

Challenges with COVID-19 vaccine developmentand assessing impact of the pandemic on oncology trial outcomes

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease (COVID)-19 in infected individuals. Since its first outbreak at the end of 2019, COVID-19 has rapidly evolved into a global pandemic and has infected more than 85 million (M) people worldwide and has resulted in over 1.85 M deaths. The pandemic has led to the race for finding therapeutics and vaccines, and to date, there have been two vaccines approved within the United States and the potential for more to follow in the coming months. In addition, this has also forced clinical researchers to look into the impact this may have on ongoing trials, given the risk of COVIDrelated complications confounding with the efficacy and safety outcomes and necessitating the collection of additional data and evaluating alternate ways of analyzing trial results. This is of particular concern in patients with cancer who are often immunosuppressed as a result of both their disease and the treatment they receive, which puts them at increased risk of severe complications from COVID-19. In this session, we will focus on two important but very distinct topics that have emerged due to the onset of the pandemic: (1) the issues and challenges related to vaccine development including trial design, rapid execution, real-time regulatory feedback, and overall interpretation of trial results and (2) understanding potential impact of COVID-related deaths in Oncology trials, on time to event endpoints of overall survival and progression-free survival. Topic 1: Challenges with COVID-19 Vaccine development The SARS-CoV-2, first identified in December 2019, has caused a worldwide pandemic leading to widespread morbidity and mortality. There was no Food and Drug Administration-approved vaccine for the prevention of the coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2. The urgent need for safe and effective interventions to mitigate the global spread of SARS-CoV-2 has prompted international efforts to develop antivirals and vaccines. Numerous vaccine candidates based on traditional and new platforms are currently being evaluated including nucleic acid (DNA and RNA), viral vector (replicating and non-replicating), virus-like particles, peptide-based, recombinant protein, and live attenuated and inactivated virus modalities. COVID-19 vaccines are in various stages of clinical development, with several candidates in pivotal phase 3 clinical trials, including mRNA-based vaccines, of which two vaccines, one developed by Pfizer and the other by Moderna recently received the emergency use authorization from the Food and Drug Administration in December 2020. In this session, we will share experiences and challenges in the development of these two vaccines. We will share the practical and statistical challenges and considerations when designing COVID-19 vaccine studies, such as target population(s), endpoint selection and assessment, statistical analysis method, timing of interim analyses, and questions continuously to be answered after receiving the emergency use authorization and/or during the Biologics License Application review. We show that, when planning a vaccine pivotal study against a novel virus causing ongoing worldwide pandemic, special consideration needs to be given for the designing of interim analyses related to efficacy, so that a vaccine with favorable benefit-risk profile can be made available as early as possible;special attention also needs to be given for an independent data safety monitoring board for vaccine-associated enhanced respiratory disease and other safety signal monitoring to mitigate the risk for trial participants during an ongoing pandemic. Topic 2: Impact of COVID-19 on Oncology trial outcomes using overall survival or progression-free survival Simulations were conducted to assess (1) the impact of the COVID-19-related death and (2) missed RECIST visits on the statistical analysis of time-to-event outcomes in randomized phase 3 oncology trials and explore mitigation options for this r sk when COVID- 19 cohort is well-defined. Two simulated case studies of Phase 3 randomized controlled trials ongoing during the pandemic outbreak were used to evaluate five approaches (1, ITT approach;2, modified ITT excluding COVID-19-related deaths;3, censoring COVID-19- related deaths with target number of non-COVID-19- related deaths;4, censoring COVID-19-related deaths with original date-cut-off;5, Fine & Gray modeling of competing risk approach to treat COVID-19-related death and non-COVID-19-related death separately), at presence of COVID-19-related deaths with different pandemic onsets relative to timing of analysis and varying pandemic durations, the impact of COVID-19- related death due to pandemic, on the primary endpoints of overall survival and/or progression-free survival in terms of type 1 error, power, and hazard ratio estimates. It was found that COVID-19-related deaths would impact time-to-event analysis in terms of type 1 error and power for log rank test, and provide biased treatment effect estimation from Cox model if ITT approach is used;impact would be more severe if there was an imbalance in COVID-19-related deaths mainly in experimental arm. With same number of COVID-19- related deaths, the earlier the timing of the pandemic window, will lead to greater loss in power. Approaches censoring COVID-19-related deaths would minimize impact on power loss and bias in hazard ratio estimation, particularly if data cut-off was extended to mitigate for events loss due to censoring. The simulations conducted in this analysis provide a framework to help understand how to mitigate the risk to the randomized oncology trials in which COVID-19- related deaths are observed in the blinded assessment during the COVID-19 pandemic.

Bayesian modeling in COVID-19-disease modeling, therapeutics, and vaccines

COVID-19 efforts have dominated the headlines in 2020. These efforts have involved efforts across the medical and statistical spectrum, from modeling of the pandemic to the development of therapeutics to the testing of possible vaccines. Novel methodologies have been utilized, such as platform trials, Bayesian modeling of pandemic uncertainty, and Bayesian adaptive trials to facilitate timely vaccine delivery. In this session, we will present four real examples of Bayesian methods across this range of activities. These include the official modeling of the epidemic within Los Angeles County by the leader of the team, both design and execution of platforms trials within the COVID-19 pandemic, and the Bayesian Pfizer vaccine trial. All speakers confirmed. Roger Lewis is the leader of the COVID-19 epidemic modeling team for Los Angeles County, California, advising government officials on the progress of the epidemic and projecting future developments. He will discuss the Bayesian SEIR modeling performed for Los Angeles, including capturing uncertainty in the predictions and real-world issues in data collection and adjusting modeling in the presence of evolving medical care and government policies. Ben Saville will discuss therapeutic adaptive platform trials like PRINCIPLE and REMAP-CAP (focus on PRINCIPLE). Both trials are ongoing adaptive platform trials investigating multiple therapies for COVID- 19. PRINCIPLE is a UK national priority trial and is focused on ambulatory participants with suspected COVID-19 and a higher risk of morbidity (e.g. .50 years age with comorbidities). The trial is open-label and has co-primary endpoints of subject-reported time to recovery and hospitalization. REMAP-CAP includes both open-label and blinded interventions focused on hospitalized patients in the intensive care unit across eight countries. The primary endpoint is the number of organ support-free days, and includes multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Both trials use innovative Bayesian modeling that account for potential drift over time, with frequent interim analyses allowing early decisions of futility or superiority. Response-adaptive randomization is used to increase allocation to interventions with better observed outcomes, which can increase statistical power for finding effective therapies and result in better participant outcomes. Mark Fitzgerald will present some of the challenges of execution for the statistical analysis committee for a trial that is rapidly adapting to an ongoing pandemic, with a focus on REMAP-CAP. REMAP-CAP is an adaptive platform trial that explores the efficacy of interventions across a range of treatment domains, including the combinations across domains, that utilizes a novel endpoint: organ-support free days. The international effort combines data from five continents, evaluates thousands of treatment combinations, and rapidly evolves to accommodate information from external sources. The statistical analysis committee faces unique challenges in adjusting to rapid changes when combining data from disparate sources, updating models and reports to incorporate new design features, and producing results for public disclosure for closed domains or interventions, all while ensuring proper communication and maintaining trial integrity. Satrajit Roychoudhury will discuss the design of the Pfizer Bayesian adaptive vaccine trial. This trial incorporates multiple interim analyses, each based on achieving a sufficiently high Bayesian posterior probability of vaccine efficacy. The trial also incorporates early stopping for futility based on Bayesian predictive probabilities. In November 2020, the trial is currently ongoing. Additional information may be publicly available at the time of SCT 2021 that may be discussed, but this will depend on future events at time of submission.

Is there impact of the SARS-CoV-2 pandemic on steroidogenesis and fertility?

In December of 2019, several cases of unknown atypical respiratory diseases emerged in Wuhan, Hubei Province in China. After preliminary research, it was stated that the disease is transmittable between humans and was named COVID-19. Over the course of next months, it spread all over the world by air and sea transport and caused a global pandemic which affects life of everyone now-a-days. A large number of countries, have since been forced to take precautions such as curfews, lockdowns, wearing facemasks etc. Even with vaccines being produced in mass numbers, lack of targeted therapy continues to be a major problem. According to studies so far it seems that elderly people are more vulnerable to severe symptoms while children tend to by asymptomatic or have milder form the disease. In our review, we focused on gathering data about the virus itself, its characteristics, paths of transmission, and its effect on hormone production and secretion. In such, there is insufficient information in the literature worldwide, especially the ones that focus on the effect of COVID-19 on individual organs systems within the human body. Hence, the present evidence-based study focused on the possible effects of COVID-19 on adrenal gland and gonads i.e. on the process of steroidogenesis and fertility.

VIRAL PANDEMICS OF TWENTY-FIRST CENTURY

Pandemics are regarded as large-scale outbreaks of infectious disease that has the potential to significantly increase morbidity and mortality over a wide geographical area, which is accompanied by economic, social and political disruption. The likelihood of pandemic, especially caused by viral infectious diseases has increased over the past few years. The 21st century is just two decades old but it has already witnessed some of the deadliest viral pandemics having far-reaching consequences. These include Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) (2002), Influenza A virus subtype H1N1 (H1N1) (2009), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (2012) and Ebola virus (2013) and the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (2019-present). The viruses may adopt various mechanisms to invade and hijack the cellular machinery of the host cell, followed by infection-mediated immunomodulation and progressive inflammation, which in turn, may affect the functioning of different organ systems of the body. Although effective commercial vaccines are unavailable for most of these viruses, those against SARS-CoV-2 are being developed at an unprecedented speed with few of the vaccines already being approved for commercial distribution. Significant policy attention is required to limit the outbreak of such pandemics and to expand and sustain investment to build preparedness and health capacity. © 2021. All Rights Reserved.