A model of task-level human stepping regulation yields semistable walking.

A simple lateral dynamic walker, with swing leg dynamics and three adjustable input parameters, is used to study how motor regulation affects frontal-plane stepping. Motivated by experimental observations and phenomenological models, we imposed task-level multi-objective regulation targeting the walker's optimal lateral foot placement at each step. The regulator prioritizes achieving step width and lateral body position goals to varying degrees by choosing a mixture parameter. Our model thus integrates a lateral mechanical template, which captures the fundamental mechanics of frontal-plane walking, with a lateral motor regulation template, an empirically verified model of how humans manipulate lateral foot placements in a goal-directed manner. The model captures experimentally observed stepping fluctuation statistics and demonstrates how linear empirical models of stepping dynamics can emerge from first-principles nonlinear mechanics. We find that task-level regulation gives rise to a goal-equivalent manifold in the system's extended state space of mechanical states and inputs, a subset of which contains a continuum of period-1 gaits forming a semistable set: perturbations off of any of its gaits result in transients that return to the set, though typically to different gaits.

Psychometric Properties of Different Short Forms of Social Interaction Anxiety Scale in Chinese College Students.

Background: There exist four short forms of the Social Interaction Anxiety Scale (SIAS): 10-item version (SIAS-10), 6-item version by Peters et al (SIAS-6P), 6-item version by Fergus et al (SIAS-6F), and 5-item version (SIAS-5). This study aims to comprehensively examine the psychometric properties of the SIAS-10, SIAS-6P, SIAS-6F, and SIAS-5 and to determine which one performs relatively better in Chinese population. Methods: This study enrolled 733 Chinese college students. The unidimensionality of the SIAS-10, SIAS-6P, SIAS-6F, SIAS-5 was examined using Confirmatory Factor Analysis (CFA). Multi-Group CFA was further adopted to assess measurement equivalence across gender. Internal consistency reliability and criteria-related validity were also evaluated. Additionally, the measurement performance of the SIAS-10, SIAS-6P, SIAS-6F, and SIAS-5 was assessed with Item Response Theory (IRT), which estimated the discrimination parameter and the Item Characteristic Curve (ICC) for each item. Results: Except for the SIAS-5, the SIAS-10, SIAS-6P, and SIAS-6F displayed a good-fit to the one-factor model. Furthermore, the SIAS-10 achieved strict equivalence across gender while other versions did not. The SIAS-10, SIAS-6P, SIAS-6F and SIAS-5 all had acceptable internal consistency and significant correlations with criteria scales. The IRT results showed that the SIAS-10 included more items with higher discrimination and peaked ICCs (indicating more informative), whereas the SIAS-6P included more items with lower discrimination and flat ICCs (indicating less informative). Conclusion: For assessing social anxiety in Chinese under constrained conditions, the SIAS-10 is recommended to clinicians for it measuring equivalently across gender, reflecting the relevant criteria variables well, and discriminating various levels of social anxiety sensitively.

Inducing select/reject control in a matching-to-sample procedure with observing response: Effects on stimulus equivalence.

This study investigated a three-choice matching-to-sample procedure with an observing-response requirement to induce select and reject control during baseline training and examined their effects on the formation of equivalence classes. The study involved four girls, aged 8 to 10 years, who participated in a computer-based task that alternated between conditions designed to induce select and reject control by requiring observing responses to display the stimuli. In the select-control condition, the correct stimulus was revealed first on at least 75% of the trials, increasing the likelihood of selecting the correct stimulus without seeing the incorrect ones. In contrast, in the reject-control condition, the correct stimulus was revealed third on at least 75% of the trials, forcing the display of both incorrect stimuli. This procedure successfully generated both select and reject control, which increased progressively with the accuracy during baseline training trials. Select control was more prominent than reject control, but both led to the formation of equivalence classes. This finding suggests that reject control does not hinder control by the correct stimulus.

Medical device similarity analysis: a promising approach to medical device equivalence regulation.

BACKGROUND: This study aims to facilitate the identification of similar devices for both, the European Medical Device Regulation (MDR) and the US 510(k) equivalence pathway by leveraging existing data. Both are related to the regulatory pathway of read across for chemicals, where toxicological data from a known substance is transferred to one under investigation, as they aim to streamline the accreditation process for new devices and chemicals. RESEARCH DESIGN AND METHODS: This study employs latent semantic analysis to generate similarity values, harnessing the US Food and Drug Administration 510k-database, utilizing their 'Device Descriptions' and 'Intended Use' statements. RESULTS: For the representative inhaler cluster, similarity values up to 0.999 were generated for devices within a 510(k)-predicate tree, whereas values up to 0.124 were gathered for devices outside this group. CONCLUSION: Traditionally, MDR equivalence involves manual review of many devices, which is laborious. However, our results suggest that the automated calculation of similarity coefficients streamlines this process, thus reducing regulatory effort, which can be beneficial for patients needing medical devices. Although this study is focused on the European perspective, it can find application within 510(k) equivalence regulation. The conceptual approach is reminiscent of chemical fingerprint similarity analysis employed in read-across.

This study addresses improvement of the registration process for medical devices by using automated methods to determine how similar they are to existing devices. Such a process is already used in chemistry for analysis of related substances. In the context of Medical Device Regulation (MDR), which sets standards for these devices, this process might be applicable in device equivalence evaluation.Traditionally, proving equivalence involves manually finding devices that are similar, but this is time-consuming, repetitive and labor-intensive. This study proposes a new approach, using advanced computer methods and a database from the US Food and Drug Administration (FDA) to automatically identify similar devices. This could make the process much quicker and more accurate and furthermore reduce bias.The study suggests that by applying these automated methods, the impact of recent regulatory changes could be reduced. This means that proving equivalence, a critical step to facilitate device accreditation, could be done more efficiently. The study shows potential for a significant transformation in compliance processes within the medical device industry, making them more streamlined and automated.

Apples inside orange peels: Exploring the use of functional equivalents for comparing curriculum processes across contexts.

Comparative education research is complicated by the difficulty of identifying comparable units across contexts. This paper considers the advantages and limitations of a functional equivalence approach to comparative education. The functional equivalence approach allows us to meaningfully compare the operations that serve each function in the full curriculum value chain of design, application, and updating. We use a theory-based list of common processes in each phase to develop a survey for experts from nine countries, then code their responses to derive ten key common functions. The functional equivalence approach allows us to aggregate some operations that serve the same functions, so our set of functional equivalents is slightly shorter than the theory-based list of processes. In comparing across contexts, we find easily identifiable functional equivalents, functional equivalents that manifest through very different operations, functional equivalents carried out by a wide variety of actors and institutions, similar operations that are not functionally equivalent, and functional equivalents that are not consistently present in all contexts. The functional equivalence approach helps identify comparable operations despite contextual diversity.

Relating in the Wild: Toward an Analysis of Equivalence Relations Under More Naturalistic Conditions.

Since the first proposal 50 years ago, numerous experiments have documented how arbitrarily related stimuli can become functionally interchangeable. These studies have sought to understand how different variables can moderate the probability of equivalence class formation. However, the well-established evidence regarding this phenomenon in experimental settings does not necessarily guarantee an understanding about how equivalence relations are produced in natural settings. In typical experiments, experimenters control critical variables to produce equivalence relations, such as, the requirement of proficiency with baseline relations, the number of opportunities to relate two or more stimuli, the efforts to promote stimulus control topography coherent with the experimenter-defined relations, etc. All these variables, however, are not controlled in our daily lives. The present article elucidates how some differences between experimental and natural settings can likely affect how the phenomenon of equivalence relations can occur in noncontrolled, naturalistic environments. Furthermore, we suggest new areas of research to promote the generalization of basic experimental data to contingencies in our daily lives.

Evaluation of the Fill-it-up-design to use historical control data in randomized clinical trials with two arm parallel group design.

PURPOSE: In the context of clinical research, there is an increasing need for new study designs that help to incorporate already available data. With the help of historical controls, the existing information can be utilized to support the new study design, but of course, inclusion also carries the risk of bias in the study results. METHODS: To combine historical and randomized controls we investigate the Fill-it-up-design, which in the first step checks the comparability of the historical and randomized controls performing an equivalence pre-test. If equivalence is confirmed, the historical control data will be included in the new RCT. If equivalence cannot be confirmed, the historical controls will not be considered at all and the randomization of the original study will be extended. We are investigating the performance of this study design in terms of type I error rate and power. RESULTS: We demonstrate how many patients need to be recruited in each of the two steps in the Fill-it-up-design and show that the family wise error rate of the design is kept at 5 % . The maximum sample size of the Fill-it-up-design is larger than that of the single-stage design without historical controls and increases as the heterogeneity between the historical controls and the concurrent controls increases. CONCLUSION: The two-stage Fill-it-up-design represents a frequentist method for including historical control data for various study designs. As the maximum sample size of the design is larger, a robust prior belief is essential for its use. The design should therefore be seen as a way out in exceptional situations where a hybrid design is considered necessary.

Effect of pulmonary rehabilitation duration on exercise capacity and health-related quality of life in people with chronic obstructive pulmonary disease (PuRe Duration Trial): A randomized controlled equivalence trial.

BACKGROUND AND OBJECTIVE: There is no strong evidence on the optimal duration of pulmonary rehabilitation (PR) programmes. The aim of the study was to determine whether an 8-week PR programme was equivalent to a 12-week PR programme in improving endurance exercise capacity in people with chronic obstructive pulmonary disease (COPD). METHODS: Participants with COPD were randomized to either an 8-week (8-wk Group) or 12-week (12-wk Group), twice weekly, supervised PR programme consisting of endurance and strength training and individualized self-management education. Between group comparisons were made at completion of each programme (i.e., week 8 or week 12), for both programmes at week 12, and at 6-12-month follow-up. The primary outcome was endurance exercise capacity measured by the endurance shuttle walk test (ESWT) with the minimally important difference of 186 s set as the equivalence limit. RESULTS: Sixty-six participants [mean (SD); age 69 (7) years, FEV1 48 (17) %predicted] were randomized (33 per group). Between-group comparisons demonstrated that the ESWT time was equivalent for the 12-wk Group compared to the 8-wk Group at programme completion [mean (95% CI)] [71 s (-61 to 203)], week 12 [70 s (-68 to 208)], and 6-12-month follow-up [93 s (-52 to 239)], though superiority of the 12-wk Group could not be ruled out at each time point. CONCLUSION: Equivalence was shown between 8-and 12-week PR programmes for endurance exercise capacity, but superiority could not be ruled out for the 12-wk Group. Decisions about programme duration may depend on local waitlist times, healthcare budgets and patient preference.

Self-concealment scale (SCS) in middle-aged people: psychometric features and cross-age equivalence test.

BACKGROUND: Individuals' concealment of negative information and privacy may lead to impaired social interactions and threatened health conditions. This study aimed to investigate the effectiveness of the Self-Concealment Scale (SCS) in the middle-aged Chinese population and to examine the equivalence of the SCS among different age groups. METHODS: The current research adopted the SCS, Distress Disclosure Index (DDI), Revised Cheek and Buss Shyness Scale (RCBS), Social Interaction Anxiety Scale (SIAS), Social Phobia Scale (SPS), UCLA Loneliness Scale (ULS-8), and Kessler Psychological Distress Scale (K10) to survey 1124 middle-aged people. To explore the factor structure of the SCS, the study employed exploratory factor analysis and confirmatory factor analysis. The reliability of the SCS was measured based on Cronbach's α coefficients, McDonald's Omega coefficients, and split-half reliability. Correlation analysis was applied to examine the relationship between SCS and RCBS, SIAS, SPS, ULS-8, and K10. Moreover, this study recruited 1458 emerging adults and 1104 older adults to identify the cross-age invariance of the SCS. RESULTS: Exploratory factor analysis of the middle aged adults' data supported a single factor model. The factor loadings of SCS items ranged from 0.62 to 0.73, the commonality ranged from 0.39 to 0.53, and the single-factor model fitted well. The scale showed a Cronbach's α coefficient value of 0.895, McDonald's Omega coefficient of 0.893, and a split-half reliability coefficient value of 0.861. In addition, the SCS demonstrated invariance in emerging adults, middle-aged adults, and older adults. Further analysis showed that the scores of the SCS (F = 3.55, p = 0.029) among emerging adults (M = 26.43, SD = 7.96) were significantly higher than among middle-aged (M = 25.77, SD = 7.79), and older cohort (M = 25.69, SD = 7.91). CONCLUSION: The SCS revealed favorable psychometric characteristics among the middle-aged Chinese population. The degree of self-concealment among emerging adults was higher than that of middle-aged and older people.

Planning Split-Apheresis Designs for Demonstrating Comparability of Cellular and Gene Therapy Products.

A recent FDA draft guidance discusses statistical considerations for demonstrating comparability of cell and gene therapy products and processes. One experimental study described in the guidance is the split-apheresis design. The FDA draft guidance recommends a paired data analysis for such a design. This paper demonstrates that the paired analysis is under powered for some quality attributes for practical sample sizes of three to five donors unless a significant portion of variability is attributed to donor. Addition of historic lots from the pre-change process can increase the power for these attributes. This paper provides appropriate statistical methods for including this information.

(Don't fear) the factors: An item-level meta-analysis of the fear of COVID-19 Scale's factor structure and measurement invariance.

The global COVID-19 pandemic saw marked research and clinical interest in evaluating pandemic-related distress, namely fear and anxiety regarding infection and death. The most widely used and earliest developed measure of COVID-19 distress is Ahorsu et al. (2022) seven-item Fear of COVID-19 Scale (FCV-19S). To investigate the factor structure and measurement equivalence of the FCV-19S, we conducted an item-level meta-analysis synthesizing 1155 effect sizes across k = 55 independent samples comprising N = 71,161 individuals. We found that a two-factor measurement model comprising a four-item Emotional factor and a three-item Psychosomatic factor exhibits better fit than the originally proposed single-factor measurement model. Moreover, the bidimensional FCV-19S exhibits partial scalar/strong invariance across the general population, healthcare workers, schoolteachers, and university students as well as partial metric/weak invariance across samples from Bangladesh, China, Japan, Pakistan, Poland, and Portugal. Despite the theoretical and practical implications of these findings, more primary research across a wider range of sample types and countries is undoubtedly needed for further evaluation of the FCV-19S's psychometric properties and generalizability.

Forced Friends: Why the Free Energy Principle Is Not the New Hamilton's Principle.

The claim that the free energy principle is somehow related to Hamilton's principle in statistical mechanics is ubiquitous throughout the subject literature. However, the exact nature of this relationship remains unclear. According to some sources, the free energy principle is merely similar to Hamilton's principle of stationary action; others claim that it is either analogous or equivalent to it, while yet another part of the literature espouses the claim that it is a version of Hamilton's principle. In this article, we aim to clarify the nature of the relationship between the two principles by investigating the two most likely interpretations of the claims that can be found in the subject literature. According to the strong interpretation, the two principles are equivalent and apply to the same subset of physical phenomena; according to the weak interpretation, the two principles are merely analogous to each other by virtue of their similar formal structures. As we show, adopting the stronger reading would lead to a dilemma that is untenable for the proponents of the free energy principle, thus supporting the adoption of the weaker reading for the relationship between the two constructs.

Optimization and Evaluation of Accelerated Corrosion Tests Based on Mechanism Equivalence Principles.

Conventional indoor corrosion test design methods primarily focus on the rapid evaluation of material corrosion resistance, often neglecting the impact of environmental stress levels on the equivalence of corrosion mechanisms. This study introduces a novel indoor corrosion test design method based on the principle of corrosion mechanism equivalence, aimed at improving the accuracy of indoor accelerated corrosion simulations. We define the characteristic of corrosion mechanism equivalence as the Corrosion Mechanism Equivalence Degree (CMed), which quantifies the similarity between corrosion mechanisms in indoor accelerated tests and field tests. Then, modified conventional link function models are defined, integrating the probability distribution of environmental factors to estimate corrosion model parameters more precisely. Finally, an optimization problem is constructed for accelerated corrosion tests based on CMed, incorporating constraints on environmental stress levels and acceleration factors. A case study demonstrates the proposed method's ability to accurately simulate the actual service environment of materials, determining the appropriate stress levels for indoor accelerated corrosion tests while ensuring the desired acceleration factor and corrosion mechanism equivalence.

From Behavioral Genetics to Idiographic Science: Methodological Developments and Applications Inspired by the Work of Peter C. M. Molenaar.

This special issue is a collection of papers inspired by Dr. Molenaar's work and innovations - a tribute to his passion for advancing science and his ability to ignite a spark of creativity and innovation in multiple generations of scientists. Following Dr. Molenaar's creative breadth, the papers address a wide variety of topics - sharing of new methodological developments, ideas, and findings in idiographic science, study of intraindividual variation, behavioral genetics, model inference/identification/selection, and more.

"Just clearly the right thing to do": perspectives of correctional services leaders on moving governance of health-care in custody.

PURPOSE: Governance models are a defining characteristic of health-care systems, yet little research is available about the governance of health-care delivered in correctional facilities. This study aims to explore the perspectives of correctional services leaders in British Columbia, Canada, on the motivations for transferring responsibility for health-care services in provincial correctional facilities to the Ministry of Health, as well as key lessons learned. DESIGN/METHODOLOGY/APPROACH: Eight correctional services leaders participated in one-on-one interviews between September 2019 and February 2020. The authors used inductive thematic analysis to explore key themes. To triangulate early effects of the transfer identified by participants the authors used complaints data from Prisoners' Legal Services to examine changes over time. FINDINGS: The authors identified four major themes related to the rationale for this transfer: 1) quality and equivalence of care, 2) integration and throughcare, 3) values and expertise and 4) funding and resources. Facilitators included changes in the external environment, having the right people in the right places, a strong sense of alignment and shared goals and a changing culture in corrections. Participants also highlighted challenges, including ongoing human resourcing issues, having to navigate and define shared responsibilities and adapting a large bureaucracy to the environment in corrections. Consistent with outcomes described by participants, data showed that a lower proportion of complaints received after the transfer were related to health-care. ORIGINALITY/VALUE: The perspectives of correctional leaders on the transfer of governance for health-care services in custody to the community health-care system provide novel insights into the processes and potential of this change.

Psychometric validity of the sum score of the Sniffin' Sticks-Extended Test.

A common tool to measure olfactory function is the Sniffin' Sticks Test extended version (SSET). The SSET evaluates olfactory ability by summing the scores of three subtests: Threshold, Discrimination, and Identification. Recent meta-scientific literature revealed that many psychometric instruments currently in use have not been adequately validated, leading to a measurement crisis that raises concerns about the validity of the conclusions drawn with these instruments. Two examples of the measurement crisis are (i) the use of sum scores without testing their assumptions (e.g. unidimensionality and tau-equivalence), which indicate that all subtests have the same, stable relationship with their underlying construct, and (ii) the lack of assessment of measurement invariance across groups. Here, we aim to investigate the unidimensionality and tau-equivalence assumptions, internal consistency, and measurement invariance of sex and age groups of the SSET. We tested 988 (555 females, mean ±â€…SD: 39.75 ±â€…18.60 years) participants with the Italian version of the SSET. The tau-equivalent model demonstrated excellent fit indices (CFI robust = 1, TLI robust = 1, RMSEA robust = 0, SRMR = 0.013), which best explain the data, indicating that all subtests are equally important in measuring olfactory function, but not necessarily equally precise. The results also revealed full measurement invariance across age groups and configural, partial metric, and scalar invariance across sexes, indicating that the use of latent means to compare sex groups should be chosen over raw scores. However, the SSET demonstrated moderate internal consistency. Future studies should clarify whether the reliability of the SSET can be increased.

Effect evaluation of outpatient long-term video EEGs for people with seizure disorders - study protocol of the ALVEEG project: a randomized controlled trial in Germany.

BACKGROUND: Epilepsy and other seizure disorders account for a high disease burden in Germany. As a timely diagnosis and accurate treatment are crucial, improving the management of these disorders is important. Outside of Germany, outpatient long-term video EEGs (ALVEEGs) have demonstrated the potential to support the diagnosis and management of epilepsy and other seizure disorders. This study aims to evaluate the implementation of ALVEEGs as a new diagnostic pathway in eastern parts of Germany to diagnose epilepsy and other seizure disorders and to assess if ALVEEGs are equally effective as the current inpatient-monitoring gold standard, which is currently only available at a limited number of specialized centers in Germany. METHODS: ALVEEG is a prospective, multicenter, randomized controlled equivalence trial, involving five epilepsy centers in the eastern states of Germany. Patients will be randomized into either intervention (IG) or control group (CG), using a permuted block randomization. The sample size targeted is 688 patients, continuously recruited over the trial. The IG will complete an ALVEEG in a home setting, including getting access to a smartphone app to document seizure activity. The CG will receive care as usual, i.e., inpatient long-term video-EEG monitoring. The primary outcome is the proportion of clinical questions being solved in the IG compared to the CG. Secondary outcomes include hospital stays, time until video EEG, time until diagnosis and result discussion, patients' health status, quality of life and health competence, and number and form of epilepsy-related events and epileptiform activity. Alongside the trial, a process implementation and health economic evaluation will be conducted. DISCUSSION: The extensive evaluation of this study, including an implementation and health economic evaluation, will provide valuable information for health policy decision-makers to optimize future delivery of neurological care to patients affected by epilepsy and other seizure disorders and on the uptake of ALVEEG into standard care in Germany. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00032220), date registered: December 11, 2023.

About statistical significance, and the lack thereof.

Absence of statistical significance (i.e., p > 0.05) in the results of a frequentist test comparing two samples is often used as evidence of absence of difference, or absence of effect of a treatment, on the measured variable. Such conclusions are often wrong because absence of significance may merely result from a sample size that is too small to reveal an effect. To conclude that there is no meaningful effect of a treatment/condition, it is necessary to use an appropriate statistical approach. For frequentist statistics, a simple tool for this goal is the 'two one-sided t-test,' a form of equivalence test that relies on the a priori definition of a minimal difference considered to be relevant. In other words, the smallest effect size of interest should be established in advance. We present the principles of this test and give examples where it allows correct interpretation of the results of a classical t-test assuming absence of difference. Equivalence tests are also very useful in probing whether certain significant results are also biologically meaningful, because when comparing large samples it is possible to find significant results in both an equivalence test and in a two-sample t-test, assuming no difference as the null hypothesis.

Testing for similarity of multivariate mixed outcomes using generalized joint regression models with application to efficacy-toxicity responses.

A common problem in clinical trials is to test whether the effect of an explanatory variable on a response of interest is similar between two groups, for example, patient or treatment groups. In this regard, similarity is defined as equivalence up to a pre-specified threshold that denotes an acceptable deviation between the two groups. This issue is typically tackled by assessing if the explanatory variable's effect on the response is similar. This assessment is based on, for example, confidence intervals of differences or a suitable distance between two parametric regression models. Typically, these approaches build on the assumption of a univariate continuous or binary outcome variable. However, multivariate outcomes, especially beyond the case of bivariate binary responses, remain underexplored. This paper introduces an approach based on a generalized joint regression framework exploiting the Gaussian copula. Compared to existing methods, our approach accommodates various outcome variable scales, such as continuous, binary, categorical, and ordinal, including mixed outcomes in multi-dimensional spaces. We demonstrate the validity of this approach through a simulation study and an efficacy-toxicity case study, hence highlighting its practical relevance.

Cervical orthosis does not improve postoperative pain following posterior cervical fusion: a randomized controlled trial.

PURPOSE: To determine whether postoperative neck pain in the first 4 weeks following multi-level posterior cervical fusion (PCF) with orthosis is equivalent to multi-level PCF without orthosis. METHODS: Patients were randomly assigned in a 1:1 ratio to postoperative orthosis (CO) for 6 weeks or no orthosis (NO). Randomization was stratified by indication (traumatic vs. degenerative), and preoperative opioid use. A model of longitudinal regression for repeated measures was used. The two-sided 95% confidence interval (CI) was used to test equivalence. If the CI lay between the pre-determined margin of equivalence (-2.0 to + 2.0 pain score) the two groups were considered equivalent. A multiple imputation procedure was used to replace missing data. RESULTS: Thirty-one patients were enrolled in each group. At baseline, the CO group had more neck pain (5.3 vs. 3.2, p = 0.013). The Four week post-operative neck pain intensity score was 4.6 ± 0.3 for the CO group vs. 4.9 ± 0.3 for the NO group. The 95% confidence interval (-1.2 to 0.6) was within the pre-determined equivalence margin. Neck Disability Index, quality-of-life scores, and arm pain were similar. Eleven patients in the CO group and 12 patients in the NO group had an adverse event. The CO group had reduced range of motion at 6 weeks. CONCLUSION: Pain scores over the first 4 weeks after surgery were equivalent for patients undergoing multi-level PCF treated with or without a cervical orthosis. Our findings do not support the routine use of a postoperative cervical orthosis for postoperative pain control. Clinical Trials Registration Number NCT04308122, April 22, 2020.