Personal exposure to ultrafine particles in multiple microenvironments among adolescents.

BACKGROUND: Experimental studies suggest ultrafine particles (UFPs), the smallest size fraction of particulate matter, may be more toxic than larger particles, however personal sampling studies in children are lacking. OBJECTIVE: The objective of this analysis was to examine individual, housing, and neighborhood characteristics associated with personal UFP concentrations as well as the differences in exposures that occur within varying microenvironments. METHODS: We measured weekly personal UFP concentrations and GPS coordinates in 117 adolescents ages 13-17 to describe exposures across multiple microenvironments. Individual, home, and neighborhood characteristics were collected by caregiver completed questionnaires. RESULTS: Participants regularly exposed to secondhand tobacco smoke had significantly higher indoor concentrations of UFPs compared to participants who were not. We observed that the 'home' microenvironment dominated the relative contribution of overall UFP concentrations and sampling time, however, relative proportion of integrated UFP exposure were higher in 'other' environments. IMPACT STATEMENT: In this study, we employed a novel panel study design, involving real-time measurement of UFP exposure within the multiple microenvironments of adolescents. We found a combination of personal sampling and detailed activity patterns should be used in future studies to accurately describe exposure-behavior relationships.

Long-Term Neurobehavioral and Functional Outcomes of Pediatric Extracorporeal Membrane Oxygenation Survivors.

There are limited reports of neurobehavioral outcomes of children supported on extracorporeal membrane oxygenation (ECMO). This observational study aims to characterize the long-term (≥1 year) neurobehavioral outcomes, identify risk factors associated with neurobehavioral impairment, and evaluate the trajectory of functional status in pediatric ECMO survivors. Pediatric ECMO survivors ≥1-year postdecannulation and ≥3 years of age at follow-up were prospectively enrolled and completed assessments of adaptive behavior (Vineland Adaptive Behavior Scales, Third Edition [Vineland-3]) and functional status (Functional Status Scale [FSS]). Patient characteristics were retrospectively collected. Forty-one ECMO survivors cannulated at 0.0-19.8 years (median: 2.4 [IQR: 0.0, 13.1]) were enrolled at 1.3-12.8 years (median: 5.5 [IQR: 3.3, 6.5]) postdecannulation. ECMO survivors scored significantly lower than the normative population in the Vineland-3 Adaptive Behavior Composite (85 [IQR: 70, 99], P < 0.001) and all domains (Communication, Daily Living, Socialization, Motor). Independent risk factors for lower Vineland-3 composite scores included extracorporeal cardiopulmonary resuscitation, electrographic seizures during ECMO, congenital heart disease, and premorbid developmental delay. Of the 21 patients with impaired function at discharge (FSS ≥8), 86% reported an improved FSS at follow-up. Pediatric ECMO survivors have, on average, mild neurobehavioral impairment related to adaptive functioning years after decannulation. Continued functional recovery after hospital discharge is likely.

Engaging students in a genetics course-based undergraduate research experience utilizing Caenorhabditis elegans in hybrid learning to explore human disease gene variants.

Genetic analysis in model systems using bioinformatic approaches provides a rich context for a concrete and conceptual understanding of gene structure and function. With the intent to engage students in research and explore disease biology utilizing the nematode Caenorhabditis elegans model, we developed a semester-long course-based undergraduate research experience (CURE) in a hybrid (online/in-person) learning environment-the gene-editing and evolutionary nematode exploration CURE (GENE-CURE). Using a combination of bioinformatic and molecular genetic tools, students performed structure-function analysis of disease-associated variants of uncertain significance (VUS) in human orthologs. With the aid of a series of workshop-style research sessions, students worked in teams of two to six members to identify a conserved VUS locus across species and design and test a polymerase chain reaction-based assay for targeted editing of a gene in the nematode and downstream genotyping. Research session discussions, responsible conduct of research training, electronic laboratory notebook, project reports, quizzes, and group poster presentations at a research symposium were assessed for mastery of learning objectives and research progress. Self-reflections were collected from students to assess engagement, science identity, and science efficacy. Qualitative analysis of these reflections indicated several gains suggesting that all students found many aspects of the GENE-CURE rewarding (learning process of research, self-confidence in research and science identity, and personal interest) and challenging (iterative research and failure, time management, COVID-19 pandemic, and life issues).

Theory Analysis: The Health Promotion Model and Motivation in Physical Activity.

Background: The health promotion model (HPM) depicts numerous factors impacting health-promoting behavior. Variables of the HPM including experiences, self-efficacy, and the influences affecting health choices portray a comprehensive picture of a person's values and barriers to health behavior change. Perceived harm of inaction is weighed against the perceived benefits of action within the HPM. Physical inactivity is a worldwide concern with deleterious consequences. Strategies are needed to increase physical activity participation to mitigate the impacts. The HPM has not been previously analyzed in the context of adult physical activity. Purpose: Analyze the HPM, apply it to the concept of adult motivation for physical activity, display the utility of theory application in practice, and demonstrate the vital role of nursing in connecting theory to practice. Methods: Theory analysis was conducted using Walker and Avant's method with a focus on motivation for physical activity among adults. Evaluation of the origins, meaning, logical adequacy, usefulness, generalizability, parsimony, and testability of the HPM adds depth to understanding the theory and its application in clinical practice. Results: The HPM is logical, generalizable, and has been broadly applied and tested. Adaptations were made to the HPM to reflect updated knowledge and for application to adult motivation for physical activity. Implications for practice and future research: Thorough evaluation of the HPM facilitates application to clinical practice to impact physical activity health behavior change. Examining motivation for physical activity through the lens of the HPM can guide nursing engagement and interventions to enhance behavior changes.

Participant engagement to develop report-back materials for personal air monitoring.

Background: Studies that measure environmental exposures in biological samples frequently provide participants their results. In contrast, studies using personal air monitors do not typically provide participants their monitoring results. The objective of this study was to engage adolescents who completed personal air sampling and their caregivers to develop understandable and actionable report-back documents containing the results of their personal air sampling. Methods: Adolescents and their caregivers who previously completed personal air sampling participated in focus groups to guide the development of report-back materials. We conducted thematic analyses of focus group data to guide the design of the report-back document and convened experts in community engagement, reporting study results, and human subjects research to provide feedback. Final revisions to the report-back document were made based on follow-up focus group feedback. Results: Focus groups identified critical components of an air-monitoring report-back document to include an overview of the pollutant being measured, a comparison of individual personal sampling data to the overall study population, a guide to interpreting results, visualization of individual data, and additional information on pollution sources, health risks, and exposure reduction strategies. Participants also indicated their desire to receive study results in an electronic and interactive format. The final report-back document was electronic and included background information, participants' results presented using interactive maps and figures, and additional material regarding pollution sources. Conclusion: Studies using personal air monitoring technology should provide research participants their results in an understandable and meaningful way to empower participants with increased knowledge to guide exposure reduction strategies.

Disorientation effects, circulating small ribonucleic acid, and genetic susceptibility on static postural stability.

Background: Motion Sickness increases risk of performance deficits and safety of flight concerns. The etiology of motion sickness is poorly understood. Here, we attempted to quantify the physiological effects of motion sickness on static balance and determine the genetic predictors associated with these effects. Methods: 16 subjects underwent a disorientation stimulus to induce motion sickness. Motion sickness susceptibility was identified using the Motion Sickness Susceptibility Questionnaire. Postural balance outcomes were measured using two tasks, and small ribonucleic acid profiles were assessed with blood draws before motion sickness stimulus. Differences in postural sway before and after the stimulus as well as effect modification of susceptibility were assessed. A random forest followed by regression tree analysis was constructed for each postural sway variable to determine top genetic and covariate predictors. Findings: Significant differences existed in mean postural balance responses between before and after stimulus. Individuals with longer stimulus survival experienced a greater (but insignificant) perception of sway, even if not displaying increased sway for all conditions. Circulation small ribonucleic acids were differentially expressed between individuals with long and short stimulus survival, many of these microRNA have purported targets in genes related to vestibular disorders. Interpretation: We found motion sickness produces transient motor dysfunction in a healthy military population. Small ribonucleic acids were differentially expressed between subjects with long and short stimulus survival times.

Radiation Therapy and Indigenous Peoples in Canada and Australia: Building Paths Toward Reconciliation in Cancer Care Delivery.

Indigenous peoples represent approximately 5% of the world's population and reside in over 90 countries worldwide. They embody a rich diversity of cultures, traditions, languages and relationships with the land that are shared through many generations and that are distinct from those of the settler societies within which they now live. Many Indigenous peoples have a shared experience of discrimination, trauma, and violation of rights, rooted in complex sociopolitical relationships with settler societies that are still ongoing. This results in continuing social injustices and pronounced disparities in health for many Indigenous peoples around the globe. Indigenous peoples exhibit a significantly higher cancer incidence, mortality, and poorer survival compared to non-Indigenous peoples. Cancer services, including radiotherapy, have not been designed to support the specific values and needs of Indigenous populations, resulting in poorer access to cancer services for Indigenous peoples globally across the entire cancer care spectrum. Specific to radiotherapy, available evidence demonstrates disparities in radiotherapy uptake between Indigenous and non-Indigenous patients. Radiotherapy centres are also located disparately further away from Indigenous communities. Studies are limited by a lack of Indigenous-specific data to help inform effective radiotherapy delivery. Recent Indigenous-led partnerships and initiatives have helped to address existing gaps in cancer care, and radiation oncologists play an important role in supporting such efforts. In this article, we present an overview of access to radiotherapy for Indigenous peoples in Canada and Australia, with a focus on strengthening cancer care delivery through education, partnerships, and research.

Aesthetic Knowing: Cut-Ups and Haiku Poems.

Enhancing course design and pedagogy to encourage engagement and creativity is fundamental in doctoral education. Using poetry is an innovative way to enrich nursing education through aesthetic knowing. The authors in this paper aim to describe an educational exercise utilizing the Cut-Up Method to create haiku poems. PhD nursing students used the Cut-Up Method to produce haiku poems describing the meaning of nursing science. Themes from the haiku poems include relationship building, caring and caring relationships, and the evolution of nursing. Learning activities promote aesthetic knowing to facilitate engagement, creativity, and collaboration. The Cut-Up Method and haikus are creative ways of developing aesthetic knowing.

RNA virus-mediated changes in organismal oxygen consumption rate in young and old Drosophila melanogaster males.

Aging is accompanied by increased susceptibility to infections including with viral pathogens resulting in higher morbidity and mortality among the elderly. Significant changes in host metabolism can take place following virus infection. Efficient immune responses are energetically costly, and viruses divert host molecular resources to promote their own replication. Virus-induced metabolic reprogramming could impact infection outcomes, however, how this is affected by aging and impacts organismal survival remains poorly understood. RNA virus infection of Drosophila melanogaster with Flock House virus (FHV) is an effective model to study antiviral responses with age, where older flies die faster than younger flies due to impaired disease tolerance. Using this aged host-virus model, we conducted longitudinal, single-fly respirometry studies to determine if metabolism impacts infection outcomes. Analysis using linear mixed models on Oxygen Consumption Rate (OCR) following the first 72-hours post-infection showed that FHV modulates respiration, but age has no significant effect on OCR. However, the longitudinal assessment revealed that OCR in young flies progressively and significantly decreases, while OCR in aged flies remains constant throughout the three days of the experiment. Furthermore, we found that the OCR signature at 24-hours varied in response to both experimental treatment and survival status. FHV-injected flies that died prior to 48- or 72-hours measurements had a lower OCR compared to survivors at 48-hours. Our findings suggest the host's metabolic profile could influence the outcome of viral infections.

Postpyloric vs gastric enteral nutrition in critically ill children: A single-center retrospective cohort study.

BACKGROUND: We aimed to describe enteral nutrition (EN) delivery in patients receiving postpyloric EN (PPEN) vs gastric EN (GEN). METHODS: Single-center retrospective study including patients aged <21 years admitted to an intensive care unit in a pediatric quaternary care hospital for ≧48 h who received PPEN or GEN as a first approach, as guided by a nutrition algorithm. PPEN patients were 1:1 propensity score matched to GEN patients on demographics, clinical characteristics, and disease severity. Days to EN initiation from admission, percentage of EN adequacy (delivered EN volume/prescribed EN volume) on days 1-3 and 7 after EN initiation, and time to achieving 60% of prescribed EN volume were compared between the two groups using Wilcoxon Mann-Whitney tests and a Cox proportional hazards model. Data are presented as median (IQR1, IQR3). RESULTS: Forty-six PPEN and 46 GEN patients were matched. Median time to EN initiation was 3.25 (2, 6.8) days for PPEN and 4.15 (1.5, 7.1) days for GEN (P = 0.6). Percentage of EN adequacy was greater for PPEN than GEN patients (day 1 PPEN 59.4% [18.8, 87.5] vs GEN 21.1% [7.8, 62.8], day 2 PPEN 54.3% [16.7, 95.8] vs GEN 24% [5.4, 56.7], day 3 PPEN 65.4% [14.7, 100] vs GEN 16% [0, 64.6], day 7 PPEN 77.8% [11.1, 100] vs GEN 13.8% [0, 74.5]; P < 0.05). PPEN patients had greater likelihood of achieving 60% of their prescribed EN volume than GEN patients (hazard ratio 1.84, 95% CI 1.07-3.15; P = 0.028). CONCLUSION: PPEN was associated with greater EN delivery compared with GEN.

A pragmatic parallel arm randomized-controlled trial of a multi-pronged electronic health record-based clinical decision support tool protocol to reduce low-value antipsychotic prescriptions among older adults with Alzheimer's and related dementias.

Among patients with Alzheimer's disease and its related dementias (ADRD) with behavioral disturbances, antipsychotic prescriptions have limited efficacy and increase the risk of death. Yet, physicians continue to routinely prescribe low-value antipsychotic medications for behavioral disturbances among patients with ADRD. We designed a pragmatic randomized-controlled trial to measure the impact of a behavioral economic electronic health record (EHR) clinical decision support (CDS) intervention to reduce physician prescriptions of new antipsychotic medications among patients with ADRD. Utilizing a pragmatic parallel arm randomized-controlled trial design, the study will randomize eligible physicians from a large academic health system to either receive a EHR CDS intervention or not (control) when they prescribe a new antipsychotic medication during visits with patients with ADRD. The intervention will include three components: 1) alerts prescribers that antipsychotic prescriptions increase mortality risk (motivating physicians' intrinsic desire for non-malfeasance); 2) offers non-pharmacological behavioral resources for caregivers; 3) auto-defaults the prescription to contain the lowest dose and number of pill-days (n = 30) without refills if the prescriber does not cancel the order (appealing to default bias). Over 1 year, we will compare the cumulative total of new antipsychotic pill-days prescribed (primary outcome) by physicians in the intervention group versus in the control group. The study protocol meets international SPIRIT guidelines. Behavioral economics, or the study of human behavior as a function of more than rational incentives, considering a whole host of cognitive and social psychological preferences, tendencies, and biases, is increasingly recognized as an important conceptual framework to improve physician behavior. This pragmatic trial is among the first to combine two distinct behavioral economic principles, a desire for non-malfeasance and default bias, to improve physician prescribing patterns for patients with ADRD. We anticipate this trial will substantially advance understanding of how behavioral-economic informed EHR CDS tools can potentially reduce harmful, low-value care among patients with ADRD.

Labour induction for termination of pregnancy with severe fetal anomalies after 24 weeks' gestation: a case series and systematic review of the literature.

PURPOSE: Under some circumstances, individuals choose to undergo pregnancy termination for foetal anomalies in the second half of pregnancy. This report provides objective information on the clinical management of such cases and a systematic review of the literature on labour induction outcomes for third-trimester abortion using mifepristone-misoprostol. MATERIALS AND METHODS: The study is a case series describing outcomes for labour induction abortion for foetal anomalies, at gestational age 24 weeks and beyond. A systematic review was performed, searching PubMed, Embase, and Cochrane databases. Two independent authors reviewed and quality assessed the data from the articles. RESULTS: During a two-year period, 15 patients met inclusion criteria. Fourteen patients received mifepristone and misoprostol, and one received oxytocin. All delivered vaginally. Thirteen patients delivered within 24 hours of the first misoprostol dose, and half delivered within 12 hours. The average interval from misoprostol initiation to foetal expulsion was 15.5 hours in our series. The systematic review identified nine articles for inclusion, all retrospective studies. Labour induction protocols for mifepristone-misoprostol, reporting of gestational age, and key comparisons varied greatly. CONCLUSIONS: The case series illustrates successful termination of pregnancy primarily using combined mifepristone-misoprostol. Certainty of current evidence is low, based on the GRADE framework. Future research is necessary on third-trimester outcomes with mifepristone-misoprostol.

Mental and Physical Stress Responses to Personal Ultrafine Particle Exposure in Adolescents.

Incidence rates of mental health disorders among adolescents is increasing, indicating a strong need for effective prevention efforts at a population level. The etiology of mental health disorders includes genetic, social, and environmental factors. Ultrafine particles (UFPs; particles less than 0.1 µm in diameter) have been shown to exert neurotoxic effects on the brain; however, epidemiologic evidence on the relationship between UFPs and childhood mental health outcomes is unclear. The objective of this study was to determine if exposure to UFPs was associated with symptoms of mental health in adolescents. Adolescents completed personal UFP monitoring for one week as well as a series of validated Patient-Reported Outcomes Measurement Information System (PROMIS) assessments to measure five domains of mental and physical stress symptoms. Multivariable linear regression models were used to estimate the association between PROMIS domain T-scores and median weekly personal UFP exposure with the inclusion of interactions to explore sex differences. We observed that median weekly UFP exposure was significantly associated with physical stress symptoms (ß: 5.92 per 10-fold increase in UFPs, 95% CI [0.72, 11.13]) but no other measured domains. Further, we did not find effect modification by sex on any of the PROMIS outcomes. The results of this study indicate UFPs are associated with physical symptoms of stress response among adolescents, potentially contributing to mental health disorders in this population.

Motion sickness decreases low back function and changes gene expression in military aircrew.

BACKGROUND: Motion sickness and low back disorders are prevalent and debilitating conditions that affect the health, performance, and operational effectiveness of military aircrews. This study explored the effects of a motion sickness stimulus on biomechanical and genetic factors that could potentially be involved in the causal pathways for both disorders. METHODS: Subjects recruited from a military population were exposed to either a mild (n = 12) or aggressive (n = 16) motion sickness stimulus in a Neuro-Otologic Test Center. The independent variable of interest was the motion sickness stimulus exposure (before vs. after), though differences between mild and aggressive stimuli were also assessed. Dependent measures for the study included motion sickness exposure duration, biomechanical variables (postural stability, gait function, low back function, lumbar spine loading), and gene expression. FINDINGS: Seven of twelve subjects experiencing the mild motion sickness stimulus endured the full 30 min in the NOTC, whereas subjects lasted an average of 13.2 (SD 5.0) minutes in the NOTC with the aggressive motion sickness stimulus. Mild motion sickness exposure led to a significant decrease in the postural stability measure of sway area, though the aggressive motion sickness exposure led to a statistically significant increase in sway area. Both stimuli led to decreases in low back function, though the decrease was only statistically significant for the mild protocol. Both stimuli also led to significant changes in gene expression. INTERPRETATION: Motion sickness may alter standing balance, decrease low back function, and lead to changes in the expression of genes with roles in osteogenesis, myogenesis, development of brain lymphatics, inflammation, neuropathic pain, and more. These results may provide preliminary evidence for a link between motion sickness and low back disorders.

Impact of Personal, Subhourly Exposure to Ultrafine Particles on Respiratory Health in Adolescents with Asthma.

Rationale: Ultrafine particle (UFP; particles <0.1 µm in diameter) concentrations exhibit high spatiotemporal variability; thus, individual-level exposures and health risks are difficult to estimate. Objectives: To determine the effects of recent UFP exposures on respiratory health outcomes in children and to determine if children with asthma are at increased risk. Methods: Personal sampling of UFPs was completed by adolescents in combination with repeated personal spirometry measurements and ecological momentary assessment of respiratory symptoms (wheeze, cough, and/or shortness of breath). We assessed the association between UFP exposures every 30 minutes up to 150 minutes before measuring forced expiratory volume in 1 second (FEV1), peak expiratory flow, and respiratory symptoms using mixed-effects models and interaction with asthma diagnosis. Results: Participants (N = 105; 43% with asthma) completed an average of 11 spirometry measurements and 16 symptom responses throughout sampling. After adjustments (maternal education, physical activity, season, and distance to nearest roadway), a 10-fold increase in UFP exposure was significantly associated with a 0.04-L decrease (95% confidence interval [CI], -0.07 to -0.001) in FEV1 90 minutes later. Asthma status modified this association in which participants with asthma had significantly lower FEV1 values in response to UFP exposures 30 minutes earlier than participants without asthma. We found a significant increase in the odds of reporting a respiratory symptom 30 minutes after increased UFP exposure (odds ratio, 1.8; 95% CI, 1.00 to 3.00). Conclusions: Greater UFP exposure conferred deleterious effects on lung function and respiratory symptoms within 90 minutes of exposure and was more pronounced among participants with asthma.

Intrinsic motivation in exercise: A concept analysis.

AIM: To explore the concept of intrinsic motivation in exercise as it pertains to nursing. BACKGROUND: Exercise is an integral part of treating and preventing chronic diseases, and yet the vast majority of adults do not adequately meet endorsed exercise recommendations. Evaluating motivation for exercise assists in the effort to promote sustained exercise participation. Intrinsic motivation speaks to the innate drive for an action or behavior. Intrinsic motivation has previously been evaluated in various disciplines including nursing, education, exercise science, medicine, and psychology. The combination of intrinsic motivation and exercise can be applied in the nursing discipline to evaluate, predict, and impact behavior change. DESIGN: Concept analysis using Walker and Avant (2019) methodology. DATA SOURCE: PubMed, CINAHL, and PsychINFO. Articles from the years 2011 to 2020 were included. REVIEW METHODS: Literature from multiple disciplines was synthesized to explore the concept of intrinsic motivation in the context of exercise. RESULTS: Characteristics of intrinsic motivation, their attributes, antecedents, and consequences were identified. The concept analysis represents a consensus of the identified literature providing a concise description of intrinsic motivation with exercise. Four vital attributes were identified in the literature and became the basis of the concept analysis; self-efficacy, competence, self-determination, and satisfaction. CONCLUSION: This concept analysis provides a foundation from which to create nursing interventions aimed at fostering intrinsic motivation for exercise. Expansion of our knowledge of intrinsic motivation, in the context of exercise, has the potential to enhance approaches used by nurses and nurse providers to affect healthy behavior changes.

Pediatric anxiety and daily fine particulate matter: A longitudinal study.

Daily variations in ambient fine particulate matter (PM2.5) could contribute to the morbidity of anxiety disorders in children and adolescents, but has not yet been studied longitudinally at a daily level. We tested this association using repeated weekly measures of anxiety symptom severity in a group of 23 adolescents with generalized anxiety disorder. After estimating ambient PM2.5 concentrations using a validated model, we found that increased concentrations were significantly associated with increased anxiety symptom severity and frequency two, three, and four days later. PM2.5 may be a novel, modifiable exposure that could inform population level interventions to decrease psychiatric morbidity.

Protocol for pragmatic randomised trial: integrating electronic health record-based behavioural economic 'nudges' into the electronic health record to reduce preoperative testing for patients undergoing cataract surgery.

INTRODUCTION: Robust randomised trial data have shown that routine preoperative (pre-op) testing for cataract surgery patients is inappropriate. While guidelines have discouraged testing since 2002, cataract pre-op testing rates have remained unchanged since the 1990s. Given the challenges of reducing low-value care despite strong consensus around the evidence, innovative approaches are needed to promote high-value care. This trial evaluates the impact of an interdisciplinary electronic health record (EHR) intervention that is informed by behavioural economic theory. METHODS AND ANALYSIS: This pragmatic randomised trial is being conducted at UCLA Health between June 2021 and June 2022 with a 12-month follow-up period. We are randomising all UCLA Health physicians who perform pre-op visits during the study period to one of the three nudge arms or usual care. These three nudge alerts address (1) patient harm, (2) increased out-of-pocket costs for patients and (3) psychological harm to the patients related to pre-op testing. The nudges are triggered when a physician starts to order a pre-op test. We hypothesise that receipt of a nudge will be associated with reduced pre-op testing. The primary outcome will be the change in the percentage of patients undergoing pre-op testing at 12 months. Secondary outcomes will include the percentage of patients undergoing specific categories of pre-op tests (labs, EKGs, chest X-rays (CXRs)), the efficacy of each nudge, same-day surgery cancellations and cost savings. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review board of the University of California, Los Angeles as well as a nominated Data Safety Monitoring Board. If successful, we will have created a tool that can be disseminated rapidly to EHR vendors across the nation to reduce inappropriate testing for the most common low-risk surgical procedures in the country. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT04104256.