Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications.

As a result of cross-species transmission in December 2019, the coronavirus disease 2019 (COVID-19) became a serious endangerment to human health and the causal agent of a global pandemic. Although the number of infected people has decreased due to effective management, novel methods to treat critical COVID-19 patients are still urgently required. This review describes the origins, pathogenesis, and clinical features of COVID-19 and the potential uses of mesenchymal stem cells (MSCs) in therapeutic treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. MSCs have previously been shown to have positive effects in the treatment of lung diseases, such as acute lung injury, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, lung cancer, asthma, and chronic obstructive pulmonary disease. MSC mechanisms of action involve differentiation potentials, immune regulation, secretion of anti-inflammatory factors, migration and homing, anti-apoptotic properties, antiviral effects, and extracellular vesicles. Currently, 74 clinical trials are investigating the use of MSCs (predominately from the umbilical cord, bone marrow, and adipose tissue) to treat COVID-19. Although most of these trials are still in their early stages, the preliminary data are promising. However, long-term safety evaluations are still lacking, and large-scale and controlled trials are required for more conclusive judgments regarding MSC-based therapies. The main challenges and prospective directions for the use of MSCs in clinical applications are discussed herein. In summary, while the clinical use of MSCs to treat COVID-19 is still in the preliminary stages of investigation, promising results indicate that they could potentially be utilized in future treatments.

Incidence of childhood cancer in Canada during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has had a major impact on access to health care resources. Our objective was to estimate the impact of the COVID-19 pandemic on the incidence of childhood cancer in Canada. We also aimed to compare the proportion of patients who enrolled in clinical trials at diagnosis, presented with metastatic disease or had an early death during the first 9 months of the COVID-19 pandemic compared with previous years. METHODS: We conducted an observational study that included children younger than 15 years with a new diagnosis of cancer between March 2016 and November 2020 at 1 of 17 Canadian pediatric oncology centres. Our primary outcome was the monthly age-standardized incidence rates (ASIRs) of cancers. We evaluated level and trend changes using interventional autoregressive integrated moving average models. Secondary outcomes were the proportion of patients who were enrolled in a clinical trial, who had metastatic or advanced disease and who died within 30 days. We compared the baseline and pandemic periods using rate ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Age-standardized incidence rates during COVID-19 quarters were 157.7, 164.6, and 148.0 per million, respectively, whereas quarterly baseline ASIRs ranged between 150.3 and 175.1 per million (incidence RR 0.93 [95% CI 0.78 to 1.12] to incidence RR 1.04 [95% CI 0.87 to 1.24]). We found no statistically significant level or slope changes between the projected and observed ASIRs for all new cancers (parameter estimate [ß], level 4.98, 95% CI -15.1 to 25.04, p = 0.25), or when stratified by cancer type or by geographic area. Clinical trial enrolment rate was stable or increased during the pandemic compared with baseline (RR 1.22 [95% CI 0.70 to 2.13] to RR 1.71 [95% CI 1.01 to 2.89]). There was no difference in the proportion of patients with metastatic disease (RR 0.84 [95% CI 0.55 to 1.29] to RR 1.22 [0.84 to 1.79]), or who died within 30 days (RR 0.16 [95% CI 0.01 to 3.04] to RR 1.73 [95% CI 0.38 to 15.2]). INTERPRETATION: We did not observe a statistically significant change in the incidence of childhood cancer, or in the proportion of children enrolling in a clinical trial, presenting with metastatic disease or who died early during the first 9 months of the COVID-19 pandemic, which suggests that access to health care in pediatric oncology was not reduced substantially in Canada.

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2021 Update.

BACKGROUND: Despite the COVID-19 pandemic, there has been considerable activity in the clinical development of novel and improved drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) during 2020. The agents that were investigated can be divided into "symptomatic" (alleviating the features of the condition) and "disease modifying" (attempting to address the underlying biology of PD) treatments, ST and DMT respectively, with further categorisation possible based on mechanism of action and class of therapy. OBJECTIVE: Our goal in this report was to provide an overview of the pharmacological therapies -both ST and DMT - in clinical trials for PD during 2020-2021, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst commercial and academic researchers as well as between the research and patient communities. METHODS: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of February 18th 2021. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. RESULTS: We identified 142 trials on ClinicalTrials.gov and 14 studies on the WHO registries that met our analysis criteria. Of these 156 trials, 91 were ST and 65 were DMT, Of the 145 trials registered on ClinicalTrials.gov in our 2020 analysis, 45 fell off the list and 42 were added. Despite this change, the balance of ST to DMT; the distribution across phases; the profile of therapeutic categories; and the proportion of repurposed therapies (33.5%); all remained very similar. There are only two DMTs in phase 3, and we identified 33 in-between-phase projects. CONCLUSIONS: Despite the effects of the coronavirus pandemic, investment and effort in clinical trials for PD appears to remain strong. There has been little change in the profile of the clinical trial landscape even though, over the past year, there has been considerable change to the content of the list.

Cancer Clinical Trial Participation at the 1-Year Anniversary of the Outbreak of the COVID-19 Pandemic.

Importance: During the initial outbreak of the COVID-19 pandemic, cancer clinical trial participation decreased precipitously. Given the continued pandemic-especially the severe wave of new cases and deaths in winter 2020 to 2021-a vital question is whether trial enrollments have remained low or even worsened. Objective: To examine the experience of cancer clinical trial enrollment 1 year after the COVID-19 outbreak. Design, Setting, and Participants: This cohort study examines initial enrollments to treatment trials and cancer control and prevention (CCP) trials conducted by the SWOG Cancer Research Network between January 1, 2016, and February 28, 2021. Participants include patients enrolled in the trials. Exposures: Landmark time points reflecting the onset and the apex, respectively, of the initial COVID-19 wave (March 1 to April 25, 2020) and the winter 2020 to 2021 wave (October 4, 2020, to January 23, 2021). Main Outcomes and Measures: This study used interrupted time-series analysis to examine enrollments over time related to the COVID-19-derived exposure variables using negative-binomial regression. Relative risk (RR) estimates representing weekly enrollment changes compared with expected rates (had the pandemic not occurred) were derived. The numbers of enrollments lost during the pandemic were estimated. Results: Overall, 29 398 patients (mean [SD] age, 60.3 [13.2] years) were enrolled (24 034 before the pandemic and 5364 during the pandemic), with 9198 patients (31.3%) aged 65 years or older, 17 199 female patients (58.6%), 3039 Black patients (10.8%), and 2260 Hispanic patients (7.9%). Most enrollments (19 451 [66.2%]) were to treatment trials. During the initial COVID-19 wave, there was a 9.0% model-estimated weekly reduction in enrollments (RR, 0.91; 95% CI, 0.89-0.93; P < .001), with effects compounding each week. Enrollment recovered thereafter, but decreased again during the winter 2020 to 2021 wave, although by only 2.0% each week (RR, 0.98; 95% CI, 0.97-0.99; P < .001). Overall, during the pandemic, actual enrollments were 77.3% of expected enrollments (5364 of 6913 enrollments; 95% CI, 70.5%-85.0%; P < .001). Actual enrollments were 54.0% of expected enrollments for CCP trials (1421 of 2641 enrollments; 95% CI, 43.0%-67.0%; P < .001) and 91.0% of expected enrollments for treatment trials (3922 of 4304 enrollments; 95% CI, 81.0%-102.0%; P = .12). Conclusions and Relevance: In this cohort study, clinical trial enrollments decreased during the full year of the COVID-19 pandemic. Enrollment reductions were primarily to CCP trials, whereas, remarkably, there was not strong evidence of enrollment reductions to treatment trials. This finding suggests that clinical research rapidly adapted to the circumstances of enrolling and treating patients on protocols during the COVID-19 pandemic.

Clinical Trials of COVID-19 Therapies Should Account for Diabetes and Hyperglycemia.

Complications of Coronavirus Disease 2019 (COVID-19) occur with increased frequency in people admitted to the hospital with diabetes or hyperglycemia. The increased risk for COVID-19 infections in the presence of these metabolic conditions is in part due to overlapping pathophysiologic features of COVID-19, diabetes, and glucose control. Various antiviral treatments are being tested in COVID-19 patients. We believe that in these trials, it will be useful to evaluate treatment effect differences in patients stratified according to whether they have diabetes or hyperglycemia. In this way, it will be possible to better facilitate development of antiviral treatments that are most specifically beneficial for the large subset of COVID-19 patients who have diabetes or hyperglycemia.

Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?

The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-evidence database shows 2814 COVID-19 randomized trials registered as of February 16, 2021. Most were small (only 18% have a planned sample size > 500) and the rare completed ones have not provided published results promptly (only 283 trial publications as of February 2021). Small randomized trials and observational, nonrandomized analyses have not had a successful track record and have generated misleading expectations. Different large trials on the same intervention have generally been far more efficient in producing timely and consistent evidence. The rapid generation of evidence and accelerated dissemination of results have led to new challenges for systematic reviews and meta-analyses (eg, rapid, living, and scoping reviews). Pressure to regulatory agencies has also mounted with massive emergency authorizations, but some of them have had to be revoked. Pandemic circumstances have disrupted the way trials are conducted; therefore, new methods have been developed and adopted more widely to facilitate recruitment, consent, and overall trial conduct. On the basis of the COVID-19 experience and its challenges, planning of several large, efficient trials, and wider use of adaptive designs might change the future of clinical research. Pragmatism, integration in clinical care, efficient administration, promotion of collaborative structures, and enhanced integration of existing data and facilities might be several of the legacies of COVID-19 on future randomized trials.

Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context.

The pleiotropic cytokine interleukin-6 (IL-6) has been implicated in the pathogenesis of COVID-19, but uncertainty remains about the potential benefits and harms of targeting IL-6 signalling in patients with the disease. The efficacy and safety of tocilizumab and sarilumab, which block the binding of IL-6 to its receptor, have been tested in adults with COVID-19-related acute respiratory illness in randomised trials, with important differences in trial design, characteristics of included patients, use of co-interventions, and outcome measurement scales. In this Series paper, we review the clinical and methodological heterogeneity of studies of IL-6 receptor antagonists, and consider how this heterogeneity might have influenced reported treatment effects. Timing from clinical presentation to treatment, severity of illness, and concomitant use of corticosteroids are among the factors that might have contributed to apparently inconsistent results. With an understanding of the sources of variability in these trials, available evidence could be applied to guide clinical decision making and to inform the enrichment of future studies.

Utilizing Artificial Intelligence to Manage COVID-19 Scientific Evidence Torrent with Risklick AI: A Critical Tool for Pharmacology and Therapy Development.

INTRODUCTION: The SARS-CoV-2 pandemic has led to one of the most critical and boundless waves of publications in the history of modern science. The necessity to find and pursue relevant information and quantify its quality is broadly acknowledged. Modern information retrieval techniques combined with artificial intelligence (AI) appear as one of the key strategies for COVID-19 living evidence management. Nevertheless, most AI projects that retrieve COVID-19 literature still require manual tasks. METHODS: In this context, we pre-sent a novel, automated search platform, called Risklick AI, which aims to automatically gather COVID-19 scientific evidence and enables scientists, policy makers, and healthcare professionals to find the most relevant information tailored to their question of interest in real time. RESULTS: Here, we compare the capacity of Risklick AI to find COVID-19-related clinical trials and scientific publications in comparison with clinicaltrials.gov and PubMed in the field of pharmacology and clinical intervention. DISCUSSION: The results demonstrate that Risklick AI is able to find COVID-19 references more effectively, both in terms of precision and recall, compared to the baseline platforms. Hence, Risklick AI could become a useful alternative assistant to scientists fighting the COVID-19 pandemic.