Streamlining statistical reproducibility: NHLBI ORCHID clinical trial results reproduction

Reproducibility in medical research has been a long-standing issue. More recently, the COVID-19 pandemic has publicly underlined this fact as the retraction of several studies reached out to general media audiences. A significant number of these retractions occurred after in-depth scrutiny of the methodology and results by the scientific community. Consequently, these retractions have undermined confidence in the peer-review process, which is not considered sufficiently reliable to generate trust in the published results. This partly stems from opacity in published results, the practical implementation of the statistical analysis often remaining undisclosed. We present a workflow that uses a combination of informatics tools to foster statistical reproducibility: an open-source programming language, Jupyter Notebook, cloud-based data repository, and an application programming interface can streamline an analysis and help to kick-start new analyses. We illustrate this principle by (1) reproducing the results of the ORCHID clinical trial, which evaluated the efficacy of hydroxychloroquine in COVID-19 patients, and (2) expanding on the analyses conducted in the original trial by investigating the association of premedication with biological laboratory results. Such workflows will be encouraged for future publications from National Heart, Lung, and Blood Institute-funded studies.

Phycocyanin: A Natural Antioxidant to Combat Free Radicals

: Various research showed that antioxidants can effectively overcome the damage caused by free radicals to the human health. Therefore, antioxidants are identified as one of the main directions in the development of health care and cosmetics products due to high demand in the market. This review mainly focuses on the phycocyanin, a type of natural antioxidant mainly found in cyanobacteria. This mini review summarizes the phycocyanin sources and numerous extraction methods of phycocyanin along with the analytical methods in determining its ability to suppress free radicals. Phycocyanin has been proven to play an important role in scavenging free radicals and enhancing the body’s antioxidant capacity. However, there are lack of long-term randomized clinical trial results that can be used as evidence in showing the benefits of phycocyanin. The existing phycocyanin extraction methods using solvents, ultrasonic-assisted, freeze-thaw and etc. can extract high-quality phycocyanin efficiently and quickly. Scientists are also trying to incorporate advanced technologies such as "Industry 4.0" to optimize and enhance the industrial production of phycocyanin. Lastly, this review also describes the difficulties faced during the phycocyanin production or extraction process and financial obstacles in order to achieve the popularization of phycocyanin.

Automated Generation of Core Outcome Measures for Clinical Trials

Common outcome sets are vital for ensuring usability of clinical trial results and enabling inter-study comparisons. The task of identifying clinical outcomes for a particular field is cumbersome and time-consuming. The aim of this work was to develop an automated pipeline for identifying common outcomes by analyzing outcomes from relevant trials reported at ClinicalTrials.gov and to assess the pipeline accuracy. We validated the output of our pipeline by comparing the outcomes it identified for acute coronary syndromes and coronary artery disease with the set of outcomes recommended for these conditions by a panel of experts in a widely cited report. We found that our pipeline identified the same or similar outcomes for 100% of the outcomes recommended in the experts’ report. The coverage of the pipeline’s results dropped only slightly (to 21 out of 23 outcome domains, 91%) when we restricted the pipeline to trials posted before the publication of the report, indicating a great potential for this pipeline to be used in aiding and informing the future development of core outcome measures in clinical trials.

Enhancing Endocannabinoid Control of Stress with Cannabidiol

The stress response is a well-defined physiological function activated frequently by life events. However, sometimes the stress response can be inappropriate, excessive, or prolonged; in which case, it can hinder rather than help in coping with the stressor, impair normal functioning, and increase the risk of somatic and mental health disorders. There is a need for a more effective and safe pharmacological treatment that can dampen maladaptive stress responses. The endocannabinoid system is one of the main regulators of the stress response. A basal endocannabinoid tone inhibits the stress response, modulation of this tone permits/curtails an active stress response, and chronic deficiency in the endocannabinoid tone is associated with the pathological complications of chronic stress. Cannabidiol is a safe exogenous cannabinoid enhancer of the endocannabinoid system that could be a useful treatment for stress. There have been seven double-blind placebo controlled clinical trials of CBD for stress on a combined total of 232 participants and one partially controlled study on 120 participants. All showed that CBD was effective in significantly reducing the stress response and was non-inferior to pharmaceutical comparators, when included. The clinical trial results are supported by the established mechanisms of action of CBD (including increased N-arachidonylethanolamine levels) and extensive real-world and preclinical evidence of the effectiveness of CBD for treating stress.

The randomized clinical trial results of the anxiety treatment in patients with somatoform dysfunction and neurotic disorders

The existing treatments for somatoform dysfunction (SfD), reaction to severe stress (RSS), and adjustment disorders (AjD) are insufficiently effective and safe. Anxiolytic drug Tenoten proved effective in clinical trials (CT). The aim of this multicenter double-blind placebo-controlled randomized CT was to investigate the safety and efficacy of Tenoten in the treatment of anxiety in adults with SfD, RSS, AjD and other neurotic disorders (oNDs). 390 adult patients with SfD, RSS and AjD or oNDs with the Hospital Anxiety and Depression scale-anxiety (HADS-A) score ≥ 11 were randomized into 4 groups (n = 127 in Tenoten group 1 (4 tablets/day); n = 131 in Tenoten group 3 (8 tablets/day), n = 132 in combined Placebo group 2 + 4). The changes from baseline in the mean Hamilton Anxiety Rating Scale (HAM-A) score in groups 1 and 3 after 12 weeks were the primary outcome. The decrease of the HAM-A score from 18.81 ± 5.81 to 7.26 ± 4.63 (in group 1) and from 18.38 ± 4.3 to 6.40 ± 4.02 (in group 3) was observed post-treatment (pgroup 1/placebo = 0.0055, pgroup 3/placebo < 0.0001). Overall, 46 adverse events (28 in the Tenoten groups and 18 in the Placebo) were reported without any difference between the study groups. Tenoten performed significantly more effective than placebo in the anxiety treatment of adults with SfD, RSS, AjD and oNDs (clinicaltrials.gov NCT03036293).

Fragility indices for only sufficiently likely modifications

The fragility index is a clinically meaningful metric based on modifying patient outcomes that is increasingly used to interpret the robustness of clinical trial results. The fragility index relies on a concept that explores alternative realizations of the same clinical trial by modifying patient measurements. In this article, we propose to generalize the fragility index to a family of fragility indices called the incidence fragility indices that permit only outcome modifications that are sufficiently likely and provide an exact algorithm to calculate the incidence fragility indices. Additionally, we introduce a far-reaching generalization of the fragility index to any data type and explain how to permit only sufficiently likely modifications for nondichotomous outcomes. All of the proposed methodologies follow the fragility index concept.