Patient and navigator experiences with the opioid use disorder treatment system in Philadelphia, PA.

BACKGROUND: In 2022, 1413 people in Philadelphia died of an unintentional drug overdose. Addressing the complex challenges within the opioid use disorder (OUD) treatment system requires a comprehensive grasp of multiple system-level siloes from the perspective of patients who are accessing services and certified recovery specialists. Identifying facilitators and barriers to treatment entry and retention are critical. METHODS: We conducted 13 focus groups with 70 people with a history of opioid use in Philadelphia, Pennsylvania. The study recruited participants from non-profit organizations, OUD treatment programs, and street intercept. Certified Recovery Specialists (CRS), people with experience in residential, outpatient, methadone, and buprenorphine programs in Philadelphia, identity-specific groups with Black women, Black men, and Latino men, pregnant and parenting people, and people accessing harm reduction services participated in focus groups. Focus group guides varied by group, but the overarching focus remained on understanding participants' experiences in navigating the OUD treatment system. The research team summarized and edited CRS focus groups and coded all other focus groups for thematic analysis. RESULTS: Most focus group participants (mean age = 45.1 years; 52.9 % men, 40 % Black) had a history with multiple treatment types and reported experiences with different modalities. Salient themes that emerged from analysis included frustrations with the assessment process; reflections on facilitators and barriers by treatment type (residential, methadone, and buprenorphine); and recommendations across treatment modalities. Assessment centers, rather than being easy points of treatment entry, were identified as a major barrier to OUD treatment initiation; issues discussed included length of assessment, limited operating hours, and inadequate withdrawal management. DISCUSSION: The data from the present study were used to develop recommendations for policymakers and other stakeholders of OUD treatment programs to improve care across the spectrum of services. Expansion of residential programs that can support patients with complex comorbid conditions and wounds is needed to prevent delays for patients deemed ineligible for lower levels of care. Housing and income were identified as significant deterrents to initiating drug treatment and greater resources are needed. Greater investment in the OUD workforce is needed, especially expanding staff with lived experience. Findings can enhance OUD treatment programs elsewhere.

Scarce perinatal social support for women with OUD: Opportunities for doula services.

PROBLEM: Persons with opioid use disorder (OUD) often lack social support, which is associated with improved recovery outcomes. BACKGROUND: In the last two decades, the rate of opioid use disorder (OUD) among pregnant people has quadrupled. QUESTION: This study aimed to describe the prenatal and postpartum social support networks and needs of persons with OUD and assess perceived acceptability of community-based social supports such as doulas. METHODS: This mixed methods study utilized quantitative and qualitative data to understand social support structures and needs. Data was collected through surveys -demographics and social mapping; Adverse Childhood Experiences (ACE) tool; Connor Davidson Resilience 25-item (CDRS-25) scale- and a semi-structured interview. A total of 34 participants from a single urban opioid treatment program consented to participate. FINDINGS: Participants were on average 34.9 years old, White (64.7%), and unemployed (91.2%). Participants described small perinatal social support networks, which decreased in size from the prenatal to postpartum period. Only half (52.9%) reported adequate prenatal and postpartum social support. Doulas and peer recovery support specialists were perceived as valuable in perinatal health, social support, and recovery domains, with interest in doulas seen particularly amongst those with fewer reported supports. DISCUSSION: The scarcity of prenatal and postpartum social support among persons with OUD is critical to address, given the increased risk of relapse during the postpartum period which has implications for the maternal child dyad. CONCLUSION: Due to multiple disparities in prenatal and postpartum social support (small networks, inadequate support), doulas represent a trusted community-based support to be integrated into healthcare teams to address maternal morbidity/mortality associated with opioid use.

Refining the Universal, School-Based OurFutures Mental Health Program to Be Trauma Informed, Gender and Sexuality Diversity Affirmative, and Adherent to Proportionate Universalism: Mixed Methods Participatory Design Process.

BACKGROUND: Mental disorders are the leading cause of disease burden among youth. Effective prevention of mental disorders during adolescence is a critical public health strategy to reduce both individual and societal harms. Schools are an important setting for prevention; however, existing universal school-based mental health interventions have shown null, and occasionally iatrogenic, effects in preventing symptoms of common disorders, such as depression and anxiety. OBJECTIVE: This study aims to report the adaptation process of an established, universal, school-based prevention program for depression and anxiety, OurFutures Mental Health. Using a 4-stage process; triangulating quantitative, qualitative, and evidence syntheses; and centering the voices of young people, the revised program is trauma-informed; lesbian, gay, bisexual, transgender, nonbinary, queer, questioning, and otherwise gender and sexuality diverse (LGBTQA+) affirmative; relevant to contemporary youth; and designed to tailor intervention dosage to those who need it most (proportionate universalism). METHODS: Program adaptation occurred from April 2022 to July 2023 and involved 4 stages. Stage 1 comprised mixed methods analysis of student evaluation data (n=762; mean age 13.5, SD 0.62 y), collected immediately after delivering the OurFutures Mental Health program in a previous trial. Stage 2 consisted of 3 focus groups with high school students (n=39); regular meetings with a purpose-built, 8-member LGBTQA+ youth advisory committee; and 2 individual semistructured, in-depth interviews with LGBTQA+ young people via Zoom (Zoom Video Communications) or WhatsApp (Meta) text message. Stage 3 involved a clinical psychologist providing an in-depth review of all program materials with the view of enhancing readability, improving utility, and normalizing emotions while retaining key cognitive behavioral therapy elements. Finally, stage 4 involved fortnightly consultations among researchers and clinicians on the intervention adaptation, drawing on the latest evidence from existing literature in school-based prevention interventions, trauma-informed practice, and adolescent mental health. RESULTS: Drawing on feedback from youth, clinical psychologists, and expert youth mental health researchers, sourced from stages 1 to 4, a series of adaptations were made to the storylines, characters, and delivery of therapeutic content contained in the weekly manualized program content, classroom activities, and weekly student and teacher lesson summaries. CONCLUSIONS: The updated OurFutures Mental Health program is a trauma-informed, LBGTQA+ affirmative program aligned with the principles of proportionate universalism. The program adaptation responds to recent mixed findings on universal school-based mental health prevention programs, which include null, small beneficial, and small iatrogenic effects. The efficacy of the refined OurFutures Mental Health program is currently being tested through a cluster randomized controlled trial with up to 1400 students in 14 schools across Australia. It is hoped that the refined program will advance the current stalemate in universal school-based prevention of common mental disorders and ultimately improve the mental health and well-being of young people in schools.

Project Safe Guard: Evaluating a Lethal Means Safety Intervention to Reduce Firearm Suicide in the National Guard.

INTRODUCTION: The purpose of this paper is to examine a scalable secure firearm storage intervention in the U.S. National Guard (NG) in preventing firearm injury and suicide. A study among firearm-owning members of the Mississippi NG testing Project Safe Guard (PSG), a 10 to 15 min lethal means counseling intervention, found that PSG increased self-reported secure firearm storage practices. Here, we sought to examine a "real world" rollout of a modified PSG program in the NG in which NG members were trained to understand the importance of lethal means safety and to deliver PSG to Guardsmen peers within their units. MATERIALS AND METHODS: The PSG team collaborated with the NG to identify 4 states for the rollout; for each state, the NG was responsible for identifying key personnel ("facilitators") who would receive the training. Team members provided in-person training at 5 locations across 4 states (AZ, GA, IA, and NV) from January to April 2023. Attendees were provided with combination trigger locks or cable locks and evaluation instructions. Questionnaires were administered to training attendees via REDCap at pre-training and post-training. We conducted descriptive and comparison statistics of questionnaire data. RESULTS: A total of 186 facilitators were trained at 5 in-person training locations across 4 states (AZ, GA, IA, and NV) from January to April 2023; data collection concluded in August 2023. There were 137 pre-training responses (74% pre-survey response rate) and 88 post-training responses (64% response rate from those who took the pre-training survey). Findings demonstrate increases in self-reported knowledge, attitudes, and beliefs regarding firearm injury and suicide and a reported desire to store personal firearms more securely. CONCLUSION: The adapted version of PSG shows promise as a relevant and acceptable intervention among Guardsmen to enhance knowledge and attitudes regarding firearm suicide, increase secure firearm storage practices, and normalize conversations about firearm suicide prevention among peers. This intervention seeks to frame firearm suicide prevention within a culture of safety, complementary to the existing prevention methods and training within the NG.

"Because I Am a Female": Stigma and Safety Perspectives from Racially/Ethnically Diverse Women with Serious Mental Illnesses.

Individuals with serious mental illnesses (SMIs) face safety risks related to their mental health conditions that are often compounded by experiences of trauma, victimization, residence in impoverished neighborhoods, and histories of homelessness. Stigma and safety challenges significantly impact community integration for individuals with SMIs, particularly women, who often bear a disproportionate burden of vulnerability, gender-based stigma, violence, and other inequalities. This study investigates how women with SMIs engage in the meaning-making of their safety and stigma experiences that, in turn, influence their community integration. From a large multi-site study exploring community experiences of racially/ethnically diverse participants with SMIs, a subsample of 28 cis and trans-gender women, who reported experiencing gendered stigma and a lack of safety, were chosen for the current study. The interviews were analyzed using modified principles of Interpretive Phenomenological Analysis (IPA) to understand how women with SMIs made meaning of their safety and stigma encounters in their families, communities, and neighborhoods. IPA analysis resulted in the emergence of themes within a broad category of safety that represented participants' meaning-making about their physical safety and stigma experiences. Specifically, we used the broad themes from an existing framework of safety called 'Navigating Safety' model as sensitizing concepts for our analysis. Physical and psychological aspects of safety for this study were experienced in tandem whereby the women made sense of how their experiences of a lack of physical safety in multiple contexts shaped their sense of self, internalized stigma, and their social relationships. Within the broad theme of physical safety, participants described unsafe neighborhoods, exposure to domestic and intimate partner violence, and vulnerability to sexual violence. Additionally, under psychological safety, we identified how gender-based norms, race and ethnicity, sources of stigma (internalized, familial, and societal), and social isolation contributed to their mental health and social relationships (particularly with family). These findings highlight how the compounding influence of the intersection of multiple stigmatized identities exerts safety challenges on the lives and community experiences of women with SMIs. Focusing on access and affordability of appropriate gender-responsive resources for women, including trauma-informed care, could reduce hospitalizations, mental health symptoms, and stigma so they can safely integrate into their communities.

Improving Data-Driven Decision Making for Primary Prevention: Providing Data Interpretation Resources to Schools and Communities in Colorado.

Communities are increasingly interested in primary prevention efforts to reduce health inequities. However, few communities can access local data on social determinants of health and many do not have the skills or training to interpret data to inform decision making on appropriate strategies that impact social determinants of health. A population-based youth health survey administered to middle and high school students, such as exists in most states in the United States, can assess health behaviors and risk and protective factors. The schools and school districts that participate are provided with reports of results and data interpretation resources that support their understanding of risk and protective factors to inform local decision making and action. Other states can similarly provide local data and resources on risk and protective factors to help communities collaborate on primary prevention efforts that achieve health equity.

The Fulfillment Center Intervention Study: Protocol for a group-randomized control trial of a participatory workplace intervention.

Warehousing and storage is an economically vital industry, with 1.2 million workers in 2020. The Fulfillment Center Intervention Study focuses on workers in fulfillment centers in the e-commerce segment of this industry. Fulfillment centers are a growing yet understudied work environment which provides a unique setting to further examine how working conditions and worker voice influence health. The Study involves a group-randomized controlled trial comparing participants in worksites randomized to launch the participatory intervention (Health and Well-Being Committees, or HaWCs) with participants working for the same firm in control sites. HaWCs serve as a new formal voice channel where a small group of frontline workers and supervisors solicit workers' concerns and ideas about safety (e.g., physical hazards), the psychosocial environment (e.g., how workers feel about their treatment at work), and work organization (e.g., workflow, training opportunities, scheduling) and then develop and implement improvement projects in response. The primary objectives of the study are to evaluate the efficacy of the HaWC intervention and its effect on mental health outcomes and changes in the conditions of work within fulfillment centers, and to conduct a process evaluation of key contextual factors that support effective intervention implementation and sustained engagement. To our knowledge, this will be the first trial of a participatory intervention within a fulfillment center setting. Anticipated challenges include competing demands and company initiatives that may limit management support and high turnover. Should the intervention be shown to be feasible, the outcomes from this study will inform future randomized controlled trials of participatory interventions. Trial registration: This trial is registered with the ClinicalTrials.gov registry (NCT05199415) and approved by the Institutional Review Board (IRB) at the Massachusetts Institute of Technology (Protocol: 200800024).

Engineering xylose induction in Vibrio natriegens for biomanufacturing applications.

Xylose is an abundant, inexpensive and readily available carbohydrate common in minimally processed feedstocks such as seaweed and algae. While a wide variety of marine microbes have evolved to utilize seaweed and algae, only a few currently have the requisite characteristics and genetic engineering tools necessary to entertain the use of these underutilized feedstocks. The rapidly growing Gram-negative halophilic bacterium Vibrio natriegens is one such chassis. In this study, we engineered and tested xylose induction in V. natriegens as a tool for scalable bioproduction applications. First, we created a sensing construct based on the xylose operon from Escherichia coli MG1665 and measured its activity using a fluorescent reporter and identified that cellular import plays a key role in induction strength and that expression required the XylR transcription factor. Next, we identified that select deletions of the promoter region enhance gene expression, limiting the effect of carbohydrate repression when xylose is used as an inducer in the presence of industrially relevant carbon sources. Lastly, we used the optimized constructs to produce the biopolymer melanin using seawater mimetic media. One of these formulations utilized a nori-based seaweed extract as an inducer and demonstrated melanin yields comparable to previously optimized methods using a more traditional and costly inducer. Together, the results demonstrate that engineering xylose induction in V. natriegens can provide an effective and lower cost option for timed biosynthesis in scalable biomanufacturing applications using renewable feedstocks.

Relief in Gastrointestinal Symptoms with Medical Marijuana Over 1 Year.

Introduction: Subjective improvement in gastrointestinal (GI) symptoms was assessed among patients using medical marijuana (MMJ). Methods: Participants completed surveys at 0 days, 30 days, 6 months, and 12 months with questions about the severity of their GI symptoms on a scale from 1 (mild) to 3 (severe). Results: In each survey, participants reported a significant decrease in GI symptom severity when using MMJ versus when not using MMJ (p < 0.05). The most common self-reported side effects from using MMJ were increased appetite (12-21.4%), fatigue (6-16.7%), anxiety (4-11.9%), cough (4-11.9%), headache (6-7.9%), and dry mouth (4-7.1%). Conclusion: In patients with chronic GI symptoms, MMJ may provide persistent symptom severity improvement. Limited product availability and mild to moderate side effects are factors to consider before trialing MMJ.

Exploring the Wilderness within: An Integrative Metabolomics and Transcriptomics Study on Near-Wild and Colonized Aedes aegypti.

This study examines the phenotypic differences between wild-derived F2 Central Valley mosquitoes and the insecticide-susceptible Rockefeller (Rock) lab strain of Ae. aegypti. Given the rarity of wild pyrethroid-susceptible populations, the focus of this work is to develop an understanding of the resistance physiology in this invasive mosquito population and explore the potential of metabolites as diagnostic biomarkers for metabolic resistance. This study utilizes metabolomic, gene expression, and lifespan data for a comparison between strains. The findings indicate that wild-derived mosquitoes with greater metabolic resistance have a lifespan sensitivity to restricted larval nutrition. In terms of metabolism and gene expression, Central Valley mosquitoes show increased activity in oxidoreductase, glutathione metabolism, and the pentose phosphate pathway. Conversely, Rock mosquitoes display signs of metabolic inefficiency and mitochondrial dysregulation, likely tolerated due to the consistency and nutritional abundance of a controlled lab environment. The study also examines Ae. aegypti P450 and GSTE profiles in relation to other insecticide-resistant groups. While metabolomic data can differentiate our study groups, the challenges in biomarker development arise from few detected markers meeting high fold change thresholds.

Effect of Education on Adherence to Recommended Prenatal Practices among Indigenous Ngäbe-Buglé Communities of Panama.

Background and Objectives: The primary objective of this study was to assess the adherence of Ngäbe-Buglé women to WHO-recommended prenatal practices. The secondary objective was to compare adherence levels between women who received prenatal education from official medical providers and those educated through traditional or community-based sources within Ngäbe-Buglé communities. Materials and Methods: An eight-question survey was verbally administered to 137 Ngäbe-Buglé women at clinics set up by the non-profit NGO Floating Doctors in eight communities. A two-sided Fisher's Exact test with a p = 0.05 was used to compare the results of mothers who received prenatal education from evidence-based sources to other groups. Results: Out of the 137 surveyed women, 65 reported taking prenatal vitamins, 21 had prenatal check-ups, 136 avoided alcohol, 31 increased caloric intake, and 102 maintained their activity levels. Significant differences were observed in prenatal vitamin adherence between those educated by official sources versus unofficial sources (p = 0.0029) and official sources compared to those with no prenatal education (p < 0.0001). The difference was also significant for education from an unofficial source versus no education (p = 0.0056). However, no significant differences were found in other prenatal practices based on education sources. Conclusions: Our findings highlight deficiencies in both prenatal education and adherence to recommended practices among Ngäbe-Buglé women. Prenatal education significantly improved adherence to taking prenatal vitamins, suggesting its effectiveness as an intervention. Future interventions should prioritize culturally competent prenatal education and address barriers to accessing prenatal healthcare in Ngäbe-Buglé communities.

Firearm businesses as partners in suicide prevention: a cross-sectional study of the Gun Shop Project in Colorado, USA.

BACKGROUND: The Gun Shop Project aims to reduce firearm suicide and is widely implemented in the USA, yet little is known about the core firearm business practices and behaviours that might contribute to preventing firearm suicide. METHODS: Owners or managers of all firearm businesses identified as participants in Colorado's Gun Shop Project were invited to respond to a questionnaire. Data collection occurred from March to May 2021. Analyses included unweighted descriptive statistics with CIs and Pearson χ2 tests for categorical associations. RESULTS: 54 firearm businesses participated (response rate: 28%). Under half reported practices that are Gun Shop Project core aspects (range: 14%-45%). 22% of businesses frequently engaged customers on the importance of safe firearm storage in suicide prevention while 26% had denied a firearm sale and 14% had assisted with temporary secure storage in the past year with customers perceived to be in suicidal crisis. However, high proportions reported willingness to engage in these behaviours if a customer was in crisis: 74% were willing to refuse a sale of a firearm or ammunition, 70% were willing to discuss temporary secure storage options and 70% were willing to direct customers to mental health services. CONCLUSIONS: This study suggests that efforts to continue educating and involving firearm businesses may have an impact on the adoption of organisational suicide prevention practices and behaviours. Ongoing efforts are needed to understand core components of Gun Shop Project to inform standardised recommendations for effective firearm business practices that prevent firearm suicide.

Regulatory Intensity on Private Forestland and its Relationship with State Characteristics in the United States.

Though the federal government impacts private forest management across the United States through legislation such as the Clean Water Act, state-level regulations applied to private forest landowners vary remarkably. Despite this diversity of policies, little is known about how variations in regulatory intensity (defined here as number of forestry regulations) correlate with state-level political and socioeconomic characteristics. In this study, we use a quantitative approach to explore the intensity of regulation on forest practices impacting private landowners across all 50 states. We quantified intensity by tabulating the number of regulated forest practices, then used a quasi-Poisson regression to estimate the relationship between regulatory intensity and state-level characteristics, including forestland ownership types, the economic importance of the forest industry, and measures of state environmentalism. Results indicated a positive association between regulatory intensity and the percent of private corporate land, environmental voting records of elected officials, and direct democracy. Foresters and landowners may learn from these relationships, consider how to influence different policies, and build or achieve greater levels of public trust. This study starts to help us explain why state-level forestry policies differ, not just how they differ.

The long-term effectiveness of a personality-targeted substance use prevention program on aggression from adolescence to early adulthood.

BACKGROUND: Addressing aggressive behavior in adolescence is a key step toward preventing violence and associated social and economic costs in adulthood. This study examined the secondary effects of the personality-targeted substance use preventive program Preventure on aggressive behavior from ages 13 to 20. METHODS: In total, 339 young people from nine independent schools (M age = 13.03 years, s.d. = 0.47, range = 12-15) who rated highly on one of the four personality traits associated with increased substance use and other emotional/behavioral symptoms (i.e. impulsivity, anxiety sensitivity, sensation seeking, and negative thinking) were included in the analyses (n = 145 in Preventure, n = 194 in control). Self-report assessments were administered at baseline and follow-up (6 months, 1, 2, 3, 5.5, and 7 years). Overall aggression and subtypes of aggressive behaviors (proactive, reactive) were examined using multilevel mixed-effects analysis accounting for school-level clustering. RESULTS: Across the 7-year follow-up period, the average yearly reduction in the frequency of aggressive behaviors (b = -0.42; 95% confidence interval [CI] -0.64 to -0.20; p < 0.001), reactive aggression (b = -0.22; 95% CI 0.35 to -0.10; p = 0.001), and proactive aggression (b = -0.14; 95% CI -0.23 to -0.05; p = 0.002) was greater for the Preventure group compared to the control group. CONCLUSIONS: The study suggests a brief personality-targeted intervention may have long-term impacts on aggression among young people; however, this interpretation is limited by imbalance of sex ratios between study groups.

Improved Resolution and Image Quality of Musculoskeletal Magnetic Resonance Imaging using Deep Learning-based Denoising Reconstruction: A Prospective Clinical Study.

OBJECTIVE: To prospectively evaluate a deep learning-based denoising reconstruction (DLR) for improved resolution and image quality in musculoskeletal (MSK) magnetic resonance imaging (MRI). METHODS: Images from 137 contrast-weighted sequences in 40 MSK patients were evaluated. Each sequence was performed twice, first with the routine parameters and reconstructed with a routine reconstruction filter (REF), then with higher resolution and reconstructed with DLR, and with three conventional reconstruction filters (NL2, GA43, GA53). The five reconstructions (REF, DLR, NL2, GA43, and GA53) were de-identified, randomized, and blindly reviewed by three MSK radiologists using eight scoring criteria and a forced ranking. Quantitative SNR, CNR, and structure's full width at half maximum (FWHM) for resolution assessment were measured and compared. To account for repeated measures, Generalized Estimating Equations (GEE) with Bonferroni adjustment was used to compare the reader's scores, SNR, CNR, and FWHM between DLR vs. NL2, GA43, GA53, and REF. RESULTS: Compared to the routine REF images, the resolution was improved by 47.61% with DLR from 0.39 ± 0.15 mm2 to 0.20 ± 0.06 mm2 (p < 0.001). Per-sequence average scan time was shortened by 7.93% with DLR from 165.58 ± 21.86 s to 152.45 ± 25.65 s (p < 0.001). Based on the average scores, DLR images were rated significantly higher in all image quality criteria and the forced ranking (p < 0.001). CONCLUSION: This prospective clinical evaluation demonstrated that DLR allows approximately two times finer resolution and improved image quality compared to the standard-of-care images.

Feasibility of precision smoking treatment in a low-income community setting: results of a pilot randomized controlled trial in The Southern Community Cohort Study.

BACKGROUND: The feasibility of precision smoking treatment in socioeconomically disadvantaged communities has not been studied. METHODS: Participants in the Southern Community Cohort Study who smoked daily were invited to join a pilot randomized controlled trial of three smoking cessation interventions: guideline-based care (GBC), GBC plus nicotine metabolism-informed care (MIC), and GBC plus counseling guided by a polygenic risk score (PRS) for lung cancer. Feasibility was assessed by rates of study enrollment, engagement, and retention, targeting > 70% for each. Using logistic regression, we also assessed whether feasibility varied by age, sex, race, income, education, and attitudes toward precision smoking treatment. RESULTS: Of 92 eligible individuals (79.3% Black; 68.2% with household income < $15,000), 67 (72.8%; 95% CI 63.0-80.9%) enrolled and were randomized. Of these, 58 (86.6%; 95% CI 76.4-92.8%) engaged with the intervention, and of these engaged participants, 43 (74.1%; 95% CI 61.6-83.7%) were retained at 6-month follow-up. Conditional on enrollment, older age was associated with lower engagement (OR 0.83, 95% CI 0.73-0.95, p = 0.008). Conditional on engagement, retention was significantly lower in the PRS arm than in the GBC arm (OR 0.18, 95% CI 0.03-1.00, p = 0.050). No other selection effects were observed. CONCLUSIONS: Genetically informed precision smoking cessation interventions are feasible in socioeconomically disadvantaged communities, exhibiting high enrollment, engagement, and retention irrespective of race, sex, income, education, or attitudes toward precision smoking treatment. Future smoking cessation interventions in this population should take steps to engage older people and to sustain participation in interventions that include genetic risk counseling. TRIAL REGISTRATION: ClinicalTrials.gov No. NCT03521141, Registered 27 April 2018, https://www. CLINICALTRIALS: gov/study/NCT03521141.