Optimising motor development in the hospitalised infant with CHD: factors contributing to early motor challenges and recommendations for assessment and intervention.

BACKGROUND: Neurodevelopmental challenges are the most prevalent comorbidity associated with a diagnosis of critical CHD, and there is a high incidence of gross and fine motor delays noted in early infancy. The frequency of motor delays in hospitalised infants with critical CHD requires close monitoring from developmental therapies (physical therapists, occupational therapists, and speech-language pathologists) to optimise motor development. Currently, minimal literature defines developmental therapists' role in caring for infants with critical CHD in intensive or acute care hospital units. PURPOSE: This article describes typical infant motor skill development, how the hospital environment and events surrounding early cardiac surgical interventions impact those skills, and how developmental therapists support motor skill acquisition in infants with critical CHD. Recommendations for healthcare professionals and those who provide medical or developmental support in promotion of optimal motor skill development in hospitalised infants with critical CHD are discussed. CONCLUSIONS: Infants with critical CHD requiring neonatal surgical intervention experience interrupted motor skill interactions and developmental trajectories. As part of the interdisciplinary team working in intensive and acute care settings, developmental therapists assess, guide motor intervention, promote optimal motor skill acquisition, and support the infant's overall development.

Virtual Peer Groups Reduce HbA1c and Increase Continuous Glucose Monitor Use in Adolescents and Young Adults with Type 1 Diabetes.

Background: Adolescents and young adults (AYA) from diverse and marginalized backgrounds with type 1 diabetes (T1D) generally have higher hemoglobin A1c (HbA1c) levels and less frequent continuous glucose monitor (CGM) use than AYA from more privileged backgrounds. Further, scant data address the impact of virtual peer groups (VPG) on health-related outcomes for ethnically and racially diverse AYA with T1D. Methods: CoYoT1 to California was a 15-month randomized controlled trial for AYA aged 16-25 years. In this study, AYA were randomized to receive standard care (n = 28), or CoYoT1 care (n = 40), which consisted of person-centered provider visits and bimonthly VPG. VPG were AYA-driven discussions. AYA completed the Diabetes Distress Scale (DDS), Center for Epidemiologic Studies Depression (CES-D), and Diabetes Empowerment Scale-Short Form (DES-SF) scales at baseline and all study visits. Results: Participants were 50% Latinx and 75% publicly insured. Among CoYoT1 care participants, 19 attended at least 1 VPG session (VPG attendees) and 21 did not attend any VPG sessions. VPG attendees participated in 4.1 VPG sessions on average. VPG attendees had a relative reduction in HbA1C (treatment effect -1.08%, effect sizes values [ES] = -0.49, P = 0.04) and increase in CGM use (treatment effect +47%, ES = 1.00, P = 0.02) compared to standard care. VPG participation was not associated with statistically significant changes in DDS, CES-D, and DES-SF scores. Conclusions: In a 15-month randomized controlled trial, AYA with T1D who participated in VPG reported significant improvements in HbA1c and CGM use. Peer interactions may support unmet needs of AYA with T1D from diverse and marginalized backgrounds. ClinicalTrials.gov Identifier: NCT03793673.

Greater Telehealth Use Results in Increased Visit Frequency and Lower Physician Related-Distress in Adolescents and Young Adults With Type 1 Diabetes.

BACKGROUND: Type one diabetes (T1D) management is challenging for adolescents and young adults (AYAs) due to physiological changes, psychosocial challenges, and increasing independence, resulting in increased diabetes distress and hemoglobin A1c (HbA1c). Alternative care models that engage AYAs and improve diabetes-related health outcomes are needed. METHODS: A 15-month study evaluated an adaptation of the Colorado Young Adults with T1D (CoYoT1) Care model. CoYoT1 Care includes person-centered care, virtual peer groups, and physician training delivered via telehealth. AYAs (aged 16-25 years) were partially randomized to CoYoT1 or standard care, delivered via telehealth or in-person. As the study was ending, the COVID-19 pandemic forced all AYAs to transition to primarily telehealth appointments. This secondary analysis compares changes in clinic attendance, T1D-related distress, HbA1c, and device use between those who attended more than 50% of diabetes clinic visits via telehealth and those who attended more sessions in-person throughout the course of the study. RESULTS: Out of 68 AYA participants, individuals (n = 39, 57%) who attended most (>50%) study visits by telehealth completed more diabetes care visits (3.3 visits) than those (n = 29, 43%) who primarily attended visits in-person (2.5 visits; P = .007). AYAs who primarily attended visits via telehealth maintained stable physician-related distress, while those who attended more in-person visits reported increases in physician-related distress (P = .03). CONCLUSIONS: Greater usage of telehealth improved AYA engagement with their care, resulting in increased clinic attendance and reduced physician-related diabetes distress. A person-centered care model delivered via telehealth effectively meets the needs of AYAs with T1D.

Assessment and management of feeding difficulties for infants with complex CHD.

Early surgical intervention in infants with complex CHD results in significant disruptions to their respiratory, gastrointestinal, and nervous systems, which are all instrumental to the development of safe and efficient oral feeding skills. Standardised assessments or treatment protocols are not currently available for this unique population, requiring the clinician to rely on knowledge based on neonatal literature. Clinicians need to be skilled at evaluating and analysing these systems to develop an appropriate treatment plan to improve oral feeding skill and safety, while considering post-operative recovery in the infant with complex CHD. Supporting the family to re-establish their parental role during the hospitalisation and upon discharge is critical to reducing parental stress and oral feeding success.

Equity in Medical Care for People Living With Diabetes.

Disparities and inequities exist for individuals with diabetes in marginalized communities of color, especially among people with low socioeconomic status. Although these barriers are apparent, only a few care models have been designed for and examined in racially and ethnically diverse individuals. This article reviews models that have been developed and examined in a variety of different populations and focuses on how to implement elements from these programs in clinical practice. Health equity-promoting ideas and approaches that can be applied throughout the life span (children to seniors) are also included. As diabetes health care providers, researchers, educators, policymakers, and advocates, we must now combine our efforts and focus on historically excluded populations to bridge the gap to essential diabetes care.

The Economic Evaluation of Team Clinic-Group Approach to a Care Model of Early Adolescents With Type 1 Diabetes.

INTRODUCTION: Glycemic control is challenging for adolescents with type 1 diabetes (T1D). Team Clinic, a shared medical appointment model, has improved psychosocial outcomes in middle school patients with T1D. We aimed to evaluate the costs of delivering Team Clinic. METHOD: Participants were randomized into Team Clinic (n = 44) or usual care (n = 42) groups. RESULTS: We found no significant difference in 6-month total costs per subject ($3,204 [intervention] vs. $3,476 [control]. No significant differences were found in health care use, test strip use, or continuous glucose monitoring and/or pump. The intervention had more clinic visits (2.41 vs. 1.52 times) and a longer length of visit (2.34 vs. 0.74 hr, but no difference in provider time per patient per visit (median, 0.67 vs. 0.68 hr). DISCUSSION: The Team Clinic care model may help young adolescents with T1D improve psychosocial outcomes and increase completion of clinical visits without increasing costs.

Clinical Intervention to Reduce Dietary Sugar Does Not Affect Liver Fat in Latino Youth, Regardless of PNPLA3 Genotype: A Randomized Controlled Trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) among Latinos is partially attributed to a prevalent C>G polymorphism in the patatin-like phospholipase 3 (PNPLA3) gene. Cross-sectional analyses in Latino children showed the association between dietary sugar and liver fat was exacerbated by GG genotype. Pediatric feeding studies show extreme sugar restriction improves liver fat, but no prior trial has examined the impact of a clinical intervention or whether effects differ by PNPLA3 genotype. OBJECTIVES: We aimed to test effects of a clinical intervention to reduce dietary sugar compared with standard dietary advice on change in liver fat, and secondary-endpoint changes in liver fibrosis, liver enzymes, and anthropometrics; and whether effects differ by PNPLA3 genotype (assessed retrospectively) in Latino youth with obesity (BMI ≥ 95th percentile). METHODS: This parallel-design trial randomly assigned participants (n = 105; mean baseline liver fat: 12.7%; mean age: 14.8 y) to control or sugar reduction (goal of ≤10% of calories from free sugar) for 12 wk. Intervention participants met with a dietitian monthly and received delivery of bottled water. Changes in liver fat, by MRI, were assessed by intervention group via general linear models. RESULTS: Mean free sugar intake decreased in intervention compared with control [11.5% to 7.3% compared with 13.9% to 10.7% (% energy), respectively; P = 0.02], but there were no significant effects on liver outcomes or anthropometrics (Pall > 0.10), and no PNPLA3 interactions (Pall > 0.10). In exploratory analyses, participants with whole-body fat mass (FM) reduction (mean ± SD: -1.9 ± 2.4 kg), irrespective of randomization, had significant reductions in liver fat compared with participants without FM reduction (median: -2.1%; IQR: -6.5% to -0.8% compared with 0.3%; IQR: -1.0% to 1.1%; P < 0.001). CONCLUSIONS: In Latino youth with obesity, a dietitian-led sugar reduction intervention did not improve liver outcomes compared with control, regardless of PNPLA3 genotype. Results suggest FM reduction is important for liver fat reduction, confirming clinical recommendations of weight loss and a healthy diet for pediatric NAFLD.This trial was registered at clinicaltrials.gov as NCT02948647.

Diabetes Technology Experiences Among Latinx and Non-Latinx Youth with Type 1 Diabetes.

BACKGROUND: Diabetes technologies, such as insulin pumps and continuous glucose monitors (CGM), have been associated with improved glycemic control and increased quality of life for young people with type 1 diabetes (T1D); however, few young people use these devices, especially those from minority ethnic groups. Current literature predominantly focuses on white patients with private insurance and does not report experiences of diverse pediatric patients with limited resources. METHODS: To explore potential differences between Latinx and non-Latinx patients, English- and Spanish-speaking young people with T1D (n = 173, ages 11-25 years) were surveyed to assess attitudes about and barriers to diabetes technologies using the Technology Use Attitudes and Barriers to Device Use questionnaires. RESULTS: Both English- and Spanish-speaking participants who identified as Latinx were more likely to have public insurance (P = .0001). English-speaking Latinx participants reported higher Hemoglobin A1c values (P = .003), less CGM use (P = .002), and more negative attitudes about technology (generally, P = .003; and diabetes-specific, P < .001) than either non-Latinx or Spanish-speaking Latinx participants. Barriers were encountered with equivalent frequency across groups. CONCLUSIONS: Latinx English-speaking participants had less positive attitudes toward general and diabetes technology than Latinx Spanish-speaking and non-Latinx English-speaking peers, and differences in CGM use were associated with socioeconomic status. Additional work is needed to design and deliver diabetes interventions that are of interest to and supportive of patients from diverse ethnic and language backgrounds.

Virtual Group Appointments Reduce Distress and Improve Care Management in Young Adults with Type 1 Diabetes.

PURPOSE: The purpose of this study was to analyze the impact of virtual group appointments (VGA) on self-reported health-related outcomes and care activities for young adults (YA) with type 1 diabetes (T1D). METHODS: Fifty-three YA (ages 18-25 years) with T1D participated in a randomized controlled trial (RCT) of the Colorado Young Adults with T1D (CoYoT1) Clinic intervention, encompassing telehealth (TH) with or without VGA. Both new patients (n = 32) and those who participated in a pilot phase (n = 26) were randomized to CoYoT1 Clinic (TH+VGA; n = 23) or TH-only (n = 35) and followed for 1 year. YA completed the Diabetes Distress Scale (DDS), Diabetes Strengths and Resilience (D-STAR), Self-Efficacy in Diabetes (SED), Self-Management of Type 1 Diabetes in Adolescence (SMOD-A), Center for Epidemiologic Studies Depression (CES-D), and EuroQol (EQ-5D) scales at baseline and study end. RESULTS: YA were 67% female, 84% white, 10% Latinx, and the mean age was 20.4 years old. At study end, participants in CoYoT1 Clinic reported significantly reduced diabetes distress compared to those in TH-only, who reported increased levels [Effect Size (ES) = -0.40, P = .02]. Specifically, CoYoT1 Clinic participants reported relative reductions in Physician (ES = -2.87, P = .02) and Regimen-related distress (ES = -0.35, P = .01). In addition, participants in CoYoT1 Clinic reported improved self-management of T1D-related problem solving (ES = 0.47, P = .051) and communication with care providers (ES = 0.39, P = .07). CONCLUSIONS: Virtual group attendance in CoYoT1 Clinic was associated with significant improvements in diabetes-related distress. Long-term exposure to VGA should be investigated in YA with T1D and other pediatric chronic conditions.

Telehealth for Young Adults With Diabetes: Addressing Social Determinants of Health.

Type 1 diabetes is a challenging chronic condition and can lead to diabetes-related distress and disengagement. Historically disadvantaged, racially and ethnically diverse young adults (YAs) with type 1 diabetes experience higher blood glucose levels and encounter more barriers to care than their White counterparts. Current research shows that telehealth may provide a route for improving psychosocial issues and diabetes care among YAs.

Risk of Micronutrient Inadequacy among Hispanic, Lactating Mothers: Preliminary Evidence from the Southern California Mother's Milk Study.

Micronutrients are dietary components important for health and physiological function, and inadequate intake of these nutrients can contribute to poor health outcomes. The risk of inadequate micronutrient intake has been shown to be greater among low-income Hispanics and postpartum and lactating women. Therefore, we aimed to determine the risk of nutrient inadequacies based on preliminary evidence among postpartum, Hispanic women. Risk of micronutrient inadequacy for Hispanic women (29-45 years of age) from the Southern California Mother's Milk Study (n = 188) was assessed using 24 h dietary recalls at 1 and 6 months postpartum and the estimated average requirement (EAR) fixed cut-point approach. Women were considered at risk of inadequate intake for a nutrient if more than 50% of women were consuming below the EAR. The Chronic Disease Risk Reduction (CDRR) value was also used to assess sodium intake. These women were at risk of inadequate intake for folate and vitamins A, D, and E, with 87.0%, 93.4%, 43.8%, and 95% of women consuming less than the EAR for these nutrients, respectively. Lastly, 71.7% of women consumed excess sodium. Results from this preliminary analysis indicate that Hispanic women are at risk of inadequate intake of important micronutrients for maternal and child health.

PNPLA3 Genotype, Arachidonic Acid Intake, and Unsaturated Fat Intake Influences Liver Fibrosis in Hispanic Youth with Obesity.

Non-alcoholic fatty liver disease impacts 15.2% of Hispanic adolescents and can progress to a build-up of scared tissue called liver fibrosis. If diagnosed early, liver fibrosis may be reversible, so it is necessary to understand risk factors. The aims of this study in 59 Hispanic adolescents with obesity were to: (1) identify potential biological predictors of liver fibrosis and dietary components that influence liver fibrosis, and (2) determine if the association between dietary components and liver fibrosis differs by PNPLA3 genotype, which is highly prevalent in Hispanic adolescents and associated with elevated liver fat. We examined liver fat and fibrosis, genotyped for PNPLA3 gene, and assessed diet via 24-h diet recalls. The prevalence of increased fibrosis was 20.9% greater in males, whereas participants with the GG genotype showed 23.7% greater prevalence. Arachidonic acid was associated with liver fibrosis after accounting for sex, genotype, and liver fat (ß = 0.072, p = 0.033). Intakes of several dietary types of unsaturated fat have different associations with liver fibrosis by PNPLA3 genotype after accounting for sex, caloric intake, and liver fat. These included monounsaturated fat (ßCC/CG = -0.0007, ßGG = 0.03, p-value = 0.004), polyunsaturated fat (ßCC/CG = -0.01, ßGG = 0.02, p-value = 0.01), and omega-6 (ßCC/CG = -0.0102, ßGG = 0.028, p-value = 0.01). Results from this study suggest that reduction of arachidonic acid and polyunsaturated fatty acid intake might be important for the prevention of non-alcoholic fatty liver disease progression, especially among those with PNPLA3 risk alleles.

Neurodevelopmental and psychosocial interventions for individuals with CHD: a research agenda and recommendations from the Cardiac Neurodevelopmental Outcome Collaborative.

In 2018, the Neurodevelopmental and Psychosocial Interventions Working Group of the Cardiac Neurodevelopmental Outcome Collaborative convened through support from an R13 grant from the National Heart, Lung, and Blood Institute to survey the state of neurodevelopmental and psychosocial intervention research in CHD and to propose a slate of critical questions and investigations required to improve outcomes for this growing population of survivors and their families. Prior research, although limited, suggests that individualised developmental care interventions delivered early in life are beneficial for improving a range of outcomes including feeding, motor and cognitive development, and physiological regulation. Interventions to address self-regulatory, cognitive, and social-emotional challenges have shown promise in other medical populations, yet their applicability and effectiveness for use in individuals with CHD have not been examined. To move this field of research forward, we must strive to better understand the impact of neurodevelopmental and psychosocial intervention within the CHD population including adapting existing interventions for individuals with CHD. We must examine the ways in which dedicated cardiac neurodevelopmental follow-up programmes bolster resilience and support children and families through the myriad transitions inherent to the experience of living with CHD. And, we must ensure that interventions are person-/family-centred, inclusive of individuals from diverse cultural backgrounds as well as those with genetic/medical comorbidities, and proactive in their efforts to include individuals who are at highest risk but who may be traditionally less likely to participate in intervention trials.

Psychosocial outcomes in young adolescents with type 1 diabetes participating in shared medical appointments.

For youth with type 1 diabetes (T1D), the early adolescent period is associated with worsening diabetes management and high rates of negative psychosocial issues, including depressive symptoms and family conflict. Alternative clinical models may help improve both diabetes and psychosocial outcomes. Our study aims to investigate whether Team Clinic, a shared medical appointment model developed specifically for adolescents with T1D, will improve psychosocial outcomes for middle school-aged youth. Youth with T1D, 11-13 years of age, and their caregivers, participated in a randomized controlled trial comparing Team Clinic to traditional clinic visits (control group). Diabetes characteristics were obtained at every visit. Participants and caregivers completed depression screening and family conflict questionnaires at baseline and end of study. Changes in mean scores on clinical and psychosocial outcomes from baseline to end of study were compared between groups using linear mixed-effects models. Eighty-six youth (51% female; 74% White; 10% Hispanic) completed at least one visit during the 12-month study period. At the end of the study, control group participants reported increases in Emotional Problems compared to Team Clinic participants, including higher levels of Negative Mood/Physical Symptoms (p = 0.02). Team Clinic participants reported reduced family conflict surrounding diabetes at study end, compared to control group participants (p = 0.03). Caregivers did not report change in depressive symptoms or family conflict during the study. Hemoglobin A1C levels did not change over time in either group. Participation in Team Clinic was associated with improved psychosocial outcomes in middle school-aged participants with T1D.

Disruptions in the development of feeding for infants with congenital heart disease.

Congenital heart disease (CHD) is the most common birth defect for infants born in the United States, with approximately 36,000 affected infants born annually. While mortality rates for children with CHD have significantly declined, there is a growing population of individuals with CHD living into adulthood prompting the need to optimise long-term development and quality of life. For infants with CHD, pre- and post-surgery, there is an increased risk of developmental challenges and feeding difficulties. Feeding challenges carry profound implications for the quality of life for individuals with CHD and their families as they impact short- and long-term neurodevelopment related to growth and nutrition, sensory regulation, and social-emotional bonding with parents and other caregivers. Oral feeding challenges in children with CHD are often the result of medical complications, delayed transition to oral feeding, reduced stamina, oral feeding refusal, developmental delay, and consequences of the overwhelming intensive care unit (ICU) environment. This article aims to characterise the disruptions in feeding development for infants with CHD and describe neurodevelopmental factors that may contribute to short- and long-term oral feeding difficulties.

Lactose-reduced infant formula with added corn syrup solids is associated with a distinct gut microbiota in Hispanic infants.

Infant formula feeding, compared with human milk, has been associated with development of a distinct infant gut microbiome, but no previous study has examined effects of formula with added sugars. This work examined differences in gut microbiota among 91 Hispanic infants who consumed human milk [at breast (BB) vs. pumped in bottle (BP)] and 2 kinds of infant formula [(traditional lactose-based (TF) vs. lactose-reduced with added sugar (ASF)]. At 1 and 6 months, infant stool was collected to characterize gut microbiota. At 6 months, mothers completed 24-hour dietary recalls and questionnaires to determine infant consumption of human milk (BB vs. BP) or formula (TF vs. ASF). Linear regression models were used to determine associations of milk consumption type and microbial features at 6 months. Infants in the formula groups exhibited a significantly more 'mature' microbiome than infants in the human milk groups with the most pronounced differences observed between the ASF vs. BB groups. In the ASF group, we observed reduced log-normalized abundance of Bifidobacteriaceae (TF-BB Mean Difference = -0.71, ASF-BB Mean Difference = -1.10), and increased abundance of Lachnospiraceae (TF-BB Mean Difference = +0.89, ASF-BB Mean Difference = +1.20). We also observed a higher Community Phenotype Index of propionate, most likely produced by Lachnospiraceae, in the ASF group (TF-BB Mean Difference = +0.27, ASF-BB Mean Difference = +0.36). This study provides the first evidence that consumption of infant formula with added sugar may have a stronger association than birth delivery mode, infant caloric intake, and maternal BMI on the infant's microbiome at 6 months of age.

Implementing Telehealth in Pediatric Type 1 Diabetes Mellitus.

Management of type 1 diabetes mellitus for pediatric and young adult patients is well suited for telehealth. Diabetes management requires frequent communication with health care providers as well as the interpretation of many types of data that can be measured in the home and shared virtually to the provider by the patient. Telehealth technologies allow for a safe alternative and/or addition to in-person care for youth with diabetes. Telehealth increases access to health care, saves time and money, and results in improvements in rates of appointment adherence, patient satisfaction, and quality of life.

Defining an Essential Clinical Dataset for Admission Patient History to Reduce Nursing Documentation Burden.

BACKGROUND: Documentation burden, defined as the need to complete unnecessary documentation elements in the electronic health record (EHR), is significant for nurses and contributes to decreased time with patients as well as burnout. Burden increases when new documentation elements are added, but unnecessary elements are not systematically identified and removed. OBJECTIVES: Reducing the burden of nursing documentation during the inpatient admission process was a key objective for a group of nurse experts who collaboratively identified essential clinical data elements to be documented by nurses in the EHR. METHODS: Twelve health care organizations used a data-driven process to evaluate inpatient admission assessment data elements to identify which elements were consistently deemed essential to patient care. Processes used for the twelve organizations to reach consensus included identifying: (1) data elements that were truly essential, (2) which data elements were explicitly required during the admission process, and (3) data elements that must be documented by a registered nurse (RN). RESULT: The result was an Admission Patient History Essential Clinical Dataset (APH ECD) that reduced the amount of admission documentation content by an average of 48.5%. Early adopters experienced an average reduction of more than two minutes per admission history documentation session and an average reduction in clicks of more than 30%. CONCLUSION: The creation of the essential clinical dataset is an example of combining evidence from nursing practice within the EHR with a set of predefined guiding principles to decrease documentation burden for nurses. Establishing essential documentation components for the adult admission history and intake process ensures the efficient use of bedside nurses' time by collecting the right (necessary) information collected by the right person at the right time during the patient's hospital stay. Determining essential elements also provides a framework for mapping components to national standards to facilitate shareable and comparable nursing data.

Adapting home telehealth group appointment model (CoYoT1 clinic) for a low SES, publicly insured, minority young adult population with type 1 diabetes.

As more individuals from diverse backgrounds are diagnosed with Type 1 Diabetes (T1D), the need to address resulting disparities in diabetes outcomes among these populations also escalates. Although young adulthood proves challenging for all patients with diabetes, young adults (YA) from racial/ethnic minorities and low socioeconomic backgrounds face even greater T1D management obstacles. The poorer outcomes in these populations drive an urgent need for alternative care models to improve YA's engagement in their T1D clinical care and address barriers to improved health outcomes. Previous telemedicine initiatives for T1D have yielded positive diabetes care results, especially in YA, offering one promising way to reach this high-risk population. To serve these patients better, an established and successful home telehealth group appointment model, "CoYoT1 Clinic" (Colorado Young Adults with T1D), was adapted to provide care to YA with T1D at a large urban children's hospital in Southern California. At this location, ~70% of patients have public/no insurance, and 85% are racial/ethnic minorities. In this paper, we report the process of adapting the CoYoT1 Clinic model and designing a randomized controlled trial (RCT) to evaluate its efficacy. The adapted model uses meticulous study-design methods that incorporate patient advisors, quantitative and qualitative data collection, collaboration with local stakeholders, intervention development, and patient randomization into a factorial design analyzing telemedicine versus in-person and patient-centered versus standard care. The new model addresses the needs of high-risk YA in Southern California, with the goal of increasing access to care, improving follow-up frequency, and strengthening patient and provider satisfaction. The study is registered with ClinicalTrials.gov (Clinical Trials Number: NCT03793673).