You Gotta Walk the Walk to Talk the Talk: Happy Older Latino Adults (HOLA) as a pilot health promotion and prevention program for older HIV-positive Latino men


 Background

Older Latinos with HIV have been disproportionately affected by the epidemic and experience compounded health disparities that have deepened over time. These health disparities are largely related to lifestyle and are either preventable or amenable to early detection or intervention. Despite existing resources to deliver an intervention to reduce this compounded health disparity, there is little information on the effects of health promotion interventions on indices of cardiometabolic risk in midlife and older Latinos with HIV. The Happy Older Latinos are Active (HOLA) intervention is an innovative health promotion program that is uniquely tailored to meet the diverse needs and circumstances of older Latinos with HIV. The goal of this pilot study is to evaluate the feasibility and acceptability of HOLA among Latinos aged 50 and older with HIV.
Methods/Design:

HOLA, which is informed by Behavioral Activation and Social Learning theory is a community health worker (CHW)-led, multicomponent, health promotion intervention consisting of: (1) a social and physical activation session; (2) a moderately intense group walk led by a CHW for 45 minutes, 3x/week for 16 weeks; (3) pleasant events scheduling. The proposed pilot study will recruit and enroll 18 community dwelling Latinos with HIV aged 50+. Participants will be assessed at three time points (baseline, post intervention, and 3 months post intervention) on measures of cardiometabolic risk factors (waist circumference, dyslipidemia, hypertension, and glucose), psychosocial functioning, and health-related quality of life.
Conclusions

If HOLA can be delivered successfully by CHWs, then the scalability, accessibility, and potential for dissemination is increased. Additionally, the results of this pilot study have far reaching implications in regard to the health and welfare of other at-risk, under resourced populations. This pilot study will inform feasibility and identify modifications needed in the design of a larger hypothesis testing study.


Abstract Background
Older Latinos with HIV have been disproportionately affected by the epidemic and experience compounded health disparities that have deepened over time.
These health disparities are largely related to lifestyle and are either preventable or amenable to early detection or intervention. Despite existing resources to deliver an intervention to reduce this compounded health disparity, there is little information on the effects of health promotion interventions on indices of cardiometabolic risk in midlife and older Latinos with HIV. The Happy Older Latinos are Active (HOLA) intervention is an innovative health promotion program that is uniquely tailored to meet the diverse needs and circumstances of older Latinos with HIV. The goal of this pilot study is to evaluate the feasibility and acceptability of HOLA among Latinos aged 50 and older with HIV.
Methods/Design: HOLA, which is informed by Behavioral Activation and Social Learning theory is a community health worker (CHW)-led, multicomponent, health promotion intervention consisting of: (1) a social and physical activation session; (2) a moderately intense group walk led by a CHW for 45 minutes, 3x/week for 16 weeks; (3) pleasant events scheduling. The proposed pilot study will recruit and enroll 18 community dwelling Latinos with HIV aged 50+. Participants will be assessed at three time points (baseline, post intervention, and 3 months post intervention) on measures of cardiometabolic risk factors (waist circumference, dyslipidemia, hypertension, and glucose), psychosocial functioning, and health-related quality of life.

Conclusions
If HOLA can be delivered successfully by CHWs, then the scalability, accessibility, and potential for dissemination is increased. Additionally, the results of this pilot study have far reaching implications in regard to the health and welfare of other at-risk, under resourced populations. This pilot study will inform feasibility and identify modi cations needed in the design of a larger hypothesis testing study.

Background
Due to the changing landscape of HIV, older adults are living with HIV at rates higher than ever before. In 2018, the prevalence of diagnosed HIV infection in the United States (U.S.) was 374.6 per 100,000 population with an increased number of estimated cases affecting older Americans over the age of 50. 1 Even though HIV is no longer a death sentence due to the development of effective antiretroviral therapy (ART) and other HIV focused therapeutics, signi cant disparities in treatment outcomes persist among certain demographics. In general, HIV continues to not only affect racial/ethnic minorities at higher rates, but also gay, bisexual, and men who have sex with men (MSM) compared to their cis-gender heterosexual white counterparts. 2 Therefore, research must look to the intersections of age, race, ethnicity, and sexual identity in developing interventions that may best support those most at risk for poor HIV-related treatment outcomes.
Signi cantly more people with HIV (PWH) are living into older adulthood demonstrating a growing need for HIV-focused research and treatment examined through an aging lens. According to 2018 CDC data, more than half of PWH in the U.S. are over the age of 50 years 1 with predictions that by the start of 2021 almost 70% of PWH in the United States will be at least 50 years old. 3 Older adults are often diagnosed with HIV much later (~ 4.5 years after infection) indicating more advanced disease progression associated with the epidemic among this age group. 1 Additionally, for PWH in the United States aged 55 and above, while 90% knew their HIV status, only 64% were virally suppressed and barely more than half (57%) were actively engaged in care, suggesting that the "90-90-90" goals towards ending the HIV epidemic 4 are currently out of reach among older adults with HIV (OAWH). 1 Latinos have been disproportionately affected by HIV since the origins of the epidemic, and that increased vulnerability has deepened over time. Despite representing less than 20% of the entire U.S. population, Latinos make up 27% of new HIV diagnoses and account for over 20% of the national prevalence. 5 More speci cally, Latino sexual minority men (LSMM) are responsible for almost 25% of new HIV infections among all gay, bisexual, and MSM identi ed individuals 2 despite Latino men making up less than 9% of the entire U.S. population. 6 These disparities persist beyond just HIV incidence with Latino identi ed PWH facing additional challenges with their HIV treatment care due to suboptimal rates of viral suppression 7,8 and ART adherence 9 compared to their non-Latino SMM peers.
Unsurprisingly, these racial/ethnic disparities become signi cantly more observable among older adults. Older Latinos in the U.S. are slightly more than 5 times more likely to acquire HIV 10 and are more likely to have an AIDS diagnosis, detectable viral load, and poorer treatment adherence compared to their age-matched white non-Latino counterparts. 11,12 Additionally, older Latinos seem to exhibit mild to moderate cognitive impairment in learning, memory, and processing speed compared to their non-Latino white peers. 12,13 It is likely that these intersecting social determinants (i.e. age, race/ethnicity, sexual identity) will continue as the HIV population ages and that many of these poor health outcomes will be felt most intensely by older Latinos.
Older Latinos with HIV experience various physical health disparities due to their intersecting minority status that must be considered. In general, OAWH face increased rates of age-related comorbidities due to a phenomenon called accelerated aging. 14,15 Data from a large observational cohort study of OAWH reported that over 77% of participants reported suffering from two or more health comorbidities in addition to HIV 16 with the average number of physical comorbidities per participants landing at three. 17 In particular, older HIV-positive Latino individuals are disproportionately affected with cardiometabolic diseases including metabolic syndrome (MetS), a precursor to diabetes, as well as cardiometabolic risk factors such as obesity and hypertension compared to their non-Latino older white peers. 18,19,20 Moreover, older Latinos with HIV are more likely to be sedentary and not as actively engaged in pursuing changes in their physical activity compared to their non-Latino white counterparts. 21 Despite evidence of the "Hispanic Paradox" 22 , this lack of physical activity in combination with possible issues connected to ART medication and Hepatitis-C co-infection make older Latino adults with HIV more likely to suffer from other complicating physical conditions like nonalcoholic fatty liver disease 23,24 and cardiovascular issues compared to their non-Latino white counterparts.
Older Latinos with HIV face elevated rates of mental health concerns in addition to these physical comorbidities. More generally, OAWH have documented rates of major depressive episodes anywhere between 18 and 52% 17,26,27 , signi cantly higher than the 1-8% documented rates of depression among older adults in the general population. 28 Rates of social isolation in the general aging public (60 years or older) are estimated to be anywhere between 33% and 50% 29 with evidence suggesting that OAWH face social isolation more often than their age matched peers in the general population. 30,31 Similarly, there is strong evidence to suggest that loneliness exponentially increases with age and one could predict OAWH bear even a greater amount of loneliness due to reduced social networks and ostracism. 32,33 Additionally, loneliness and social isolation have been correlated with levels of morbidity and mortality comparable to more established biopsychosocial risk factors like obesity, sedentary behavior, smoking, and hypertension. 29,34,35 For OAWH, one of the biggest contributing factors to loneliness and social isolation is that of co-occurring stigma. While exact estimates of HIV stigma and age-related stigma in the U.S. are hard to calculate, OAWH must often navigate the dueling stigmas of HIV stigma, ageism, and stigma resulting from other possible marginalized identities. [36][37][38] It is possible that rates of stigma and loneliness seem to skyrocket in OAWH due to the increased likelihood that OAWH live along and have limited and often inconsistent social networks. 26,38 OAWH can face ostracism from the larger LGBTQ + community and stigma due to the intersection of their age and HIV status compared to their non-infected peers which may in turn contribute to the increased levels of depression among this already vulnerable population. 39 Additionally, since familism and social cohesion are strong hallmarks of Latino culture, 40,41 Latino OAWH may experience the harmful effects of co-morbid stigma and social isolation more intensely than their non-Latino HIV-positive peers due to societal expectation that they be more connected to family as they age; however, more research must be conducted to determine the veracity of such a hypothesis.
As outlined above, compounded health disparities place older Latinos with HIV at particularly high risk for diminished quality of life due to physical and mental health morbidity. These data underscore the public health importance of increased efforts to address the multiplicative and unequal burden of HIV, MetS, and diabetes shouldered by older Latinos. Therefore, based on this gap in the literature, there is a compelling need to develop and disseminate interventions that promote healthy living, combat social isolation, and improve HIV-related health outcomes among older Latinos with HIV. Since this is a pilot study, researchers are focused on establishing feasibility and acceptability of a potential intervention rather than testing speci c hypotheses. Also, in accordance with recommendations from biostatistical workgroups funded by NIH, 42 this pilot study is not powered to test a hypothesis. Rather, this pilot study serves as an initial step in establishing feasibility and acceptability of an innovative application of an already established health promotion intervention titled HOLA. 43 The speci c aims of this pilot study are: 1. To evaluate the feasibility of recruitment, assessment procedures, retention, acceptability, and implementation of HOLA in a sample of midlife and older Latinos with HIV.
2. To identify modi cations needed in the design of a larger, con rmatory randomized controlled trial.
3. To explore changes in cardiometabolic risk factors (waist circumference, dyslipidemia, hypertension, and glucose), psychosocial functioning (depression and anxiety severity, social support), and health-related quality of life in a sample of midlife and older Latinos with HIV enrolled in the HOLA health promotion intervention.

Methods
All study methods and protocols were approved by the university's Internal Review Board (IRB ID: 20181032).

Participants
This pilot study will enroll 18 Latino older (aged 50+) men with HIV to three speci c cohorts of the HOLA intervention. Despite the small sample size, 18 participants should be large enough to observe meaningful differences in primary outcomes of interest and establish feasibility of the intervention in a population of older Latino men with HIV. Additionally, this sample size is consistent with similar pilot studies focused on physical activity among older adults. 44,45 Informed consent was obtained from each participant prior to enrollment and all enrollees were provided with an initial verbal summary of the study. Payments were graduated so participants received $15 on the rst visit, $25 on the second visit, and $35 on the third visit (total of honoraria = $75). For a detailed description of the inclusion/exclusion criteria, see Table 1. Have an acute or severe medical illness that precludes them from safely participating in a health promotion intervention (e.g. progressive, degenerative neurologic disease, such as Parkinson's Disease, multiple sclerosis, ALS; severe arthritis or orthopedic condition that would prevent participation in a physical activity program; lung disease requiring either oral or injected steroids, or the use of supplemental oxygen; New York Heart Association Class III or IV congestive heart failure, clinically signi cant aortic stenosis, history of cardiac arrest, use of a cardiac de brillator, or uncontrolled angina; renal disease requiring the use of dialysis; cancer being actively treated with radiation or chemotherapy; myocardial infarction, CABG, or valve replacement within the past 6 months; serious conduction disorder, such as 3rd degree heart block; uncontrolled arrhythmia; pulmonary embolism or deep venous thrombosis within past 6-months; uncontrolled diabetes with recent weight loss, diabetic coma or frequent insulin reactions; stroke, hip fracture, hip or knee replacement, or spinal surgery in the past 6 months; receiving physical therapy for gait, balance, or other lower extremity training; severe, uncontrolled hypertension -systolic blood pressure > 200 mmHg and/or diastolic blood pressure > 110 mmHg) Are currently taking antidepressant medications in doses indicated for weight reduction.

Recruitment
Participants will be recruited through two consent-to-contact databases with over 1200 participants each -one of people with HIV (recruited from the university-a liated adult HIV clinic) and another of people at risk for acquiring HIV (recruited from the community). Data in these databases include contact information, demographic information and data associated with HIV-related risk factors such as homelessness and psychological distress.

Intervention
Happy Older Latino Adults (HOLA) is a multi-component health promotion intervention for midlife and older Latinos. 43 The conceptual model which serves as the foundation for the intervention (Fig. 1) was crafted to address comorbid depression and anxiety symptoms as well as both physical and psychosocial functioning of older Latinos. Grounded in theory, HOLA addresses the goals mentioned above through two interconnected mechanisms, Social Learning Theory (SLT) 46 and Behavioral Activation (BA). 47 BA is used to engage participants in both a physical activity routine and pleasant events scheduling to combat incident and recurrent episodes of depression and anxiety disorders as well as subdue symptom intensity. 47 As a complement, SLT's tenets of reinforcement, observational learning, and enhanced self-e cacy are utilized to bolster participant engagement and success in the intervention. 46 Additionally, using a task-shifting approach the intervention is delivered by a community health worker (CHW) who capitalizes on the unique relationship they have with participants to model, encourage, and promote consistent health behavior change. 48 increase the sheer number of participants' social activities; (d) recognize possible challenges that may prevent participants' from successfully engaging with the intervention; and (e) problem solve ways to overcome these obstacles. After week 8, participants again meet one-on-one with the CHW for the second session so that they may discuss their own individual progress in relation to their physical and social activity goals.
The second core tenet of HOLA is centered around a group walk meant to facilitate both physical activity and social interaction between participants. This moderately intense group walk meets for 45 minutes, three times a week, for a total of 16 weeks. Moderate intensity is de ned as a rating between 11 and 13 on the Borg Scale of Perceived Exertion. 50 The group walk component was designed with interval training in mind and gradually increases in workload (de ned by intensity, volume, and work/recovery cycle) over the course of the intervention. Each group walk begins with 10 minutes of stretching and warm up, followed by 30 minutes of walking, and ends with 5 minutes of stretching/cool down. Each group walk is led by the CHW and is composed of six bilingual and monolingual Spanish-speaking participants (one cohort).
A third component of HOLA centers on scheduling pleasant events in participants' daily routines. In addition to stretching, the cool down phase will feature a quick discussion led by the CHW in which they ask each participant to identify a pleasant event that they intend to do with another person prior to the next walk session. Activities mentioned may be done alongside other members in the group, or in conjunction with family and friends outside the intervention.
The CHW will be adept at utilizing problem solving skills (i.e. brainstorming) to assist participants should they struggle to commit to a pleasant event. Each subsequent session will begin with a quick recap where participants report back to the group on how successful they were in executing their pleasant event plan while their peers and CHW provide encouragement, positive feedback, and constructive feedback. Overall, this component is meant to not only generalize the intervention into the participants' everyday lives and relationships, but also to provide positive feedback so that participants can build selfe cacy as they engage with the program.
The fourth and nal component of HOLA in the context of this pilot study centers around a maintenance phase to reinforce behavior change gleaned during intervention. Participants will engage in "booster" walking sessions, twice a month for three months post intervention so to capitalize on bene cial physical and mental health effects gained during the 16-week program. Encouraged by the prior literature, this maintenance phase was added to this pilot study with the hopes of cultivating more sustained treatment effects over time. [51][52][53]

COVID-19 Adaptations
Due to COVID-19, the protocol has been amended to conduct all intervention-related activities over the telephone. Participants would conference call with the CHW and the other members of their group at the time of their regularly scheduled walk, and they would walk around their respective neighborhoods with the CHW leading them.

Measures and Analysis
This quasi-experimental pilot study of a health promotion intervention will primarily examine feasibility of recruitment, assessment procedures, retention, acceptability, and implementation of HOLA in a sample of older Latinos with HIV. In keeping with guidance from NIH funded biostatistical workgroups, this pilot study was not designed to be powered to test a hypothesis. 42 Additionally, the proposed analysis of feasibility data parallels a similar structure employed in the rst HOLA trial and comparable pilot trials. 54,55 For this study, recruitment was de ned as a success should 100% percent of the targeted sample (N = 18) be enrolled and less than 20% of eligible subjects refusing to participate. Additionally, adequate retention was characterized as 85% or more of enrolled participants completing all post-intervention assessments while acceptability was de ned as subjects' attending at least 80% of sessions. Finally, with goals of scaling up the intervention in the future, an established project evaluation questionnaire developed by investigators at the University of Miami will be used to pinpoint any modi cations needed for the design of a larger, con rmatory randomized control trial. The questionnaire is made up of a series of closed ended yes/no questions, rating scales, and open-ended questions that allow for more qualitative data regarding participants' opinions of the speci c components of the overall intervention. Study measures will be administered at baseline, end of intervention, and 3 months post intervention.
Trained research assistants (RA) will administer all of the assessments.

Study Measures
In the full-scale trial, the primary outcomes of this study will be changes in (a) cardiometabolic risk factors as de ned by dyslipidemia, glucose level, hypertension, and waist circumference; (b) psychosocial functioning as characterized by depression severity, anxiety severity, and social support; and (c) health related quality of life. A three-pronged screening process was conducted to identify eligible participants. Based on our exclusion criteria, participants completed the Mini Mental Status Exam (MMSE) to recognize potential subjects with dementia or severe cognitive abnormalities. 56 Second, to establish baseline walking ability, eligible participants were required to complete the 10-meter walk test which has been shown to have not only excellent reliability when used in older adult populations, but also be comparable in validity with other longer measures. 57 Participants' viral load was ascertained to determine viral suppression which is de ned as < 200 copies/mL. 58 Finally, potential participants self-con rmed safe participation by not having an acute or severe medical illness.

Cardiometabolic Measurements
Just prior to baseline, blood draws were completed at the university a liated adult HIV outpatient clinic from which participant recruitment will take place.
These blood draws yielded baseline data on participants' levels of HDL-C, LDL-C, triglycerides, insulin, and HbA1c. Fasting blood samples were drawn via venipuncture and stored at 4ºC until analysis could be completed. Insulin resistance was de ned by calculating a participants' homeostatic model assessment (HOMA) score. All the samples were evaluated by commercial laboratory services using commercially available enzyme-linked immunosorbent assays. Simultaneously, participant physical characteristics such as blood pressure and hip-to-waist circumference will be collected to complement the measures of glucose, insulin resistance, and blood lipid pro le mentioned prior. All of these measurements of cardiometabolic risk will be collected immediately post intervention, and 3 months post-intervention as well.

Psychosocial Functioning
Measures of psychosocial functioning will be collected at all three timepoints as well -baseline, post-intervention, and three-months post intervention. To measure depression symptom severity, participants will complete the Center for Epidemiologic Scale of Depression 59 , nine item Patient Health Questionnaire 60 , the Perceived Stress Scale 61 , and the seven-item Generalized Anxiety Disorder scale to ascertain anxiety symptom intensity. 62 Finally, participants' perceived social support will be measured by the frequently used and validated Multidimensional Scale of Perceived Social Support. 63

Additional Measures
Additional measures will be administered to participants to gain more insight on factors of acculturation, physical activity, stigma, quality of life, and overall patient satisfaction. At baseline, participants will complete a demographics form, provide a list of current medications, and respond to the Bidimensional Acculturation Scale. 64 Additionally, at all three time points -baseline, post-intervention, and three-months post intervention -subjects will be asked to complete the Global Physical Activity Questionnaire, 65 the 12-item Short Form health survey, 66 and the HIV Stigma Scale 67 to measure their overall physical activity levels, general health-related quality of life, and HIV-related stigma participants face on a day-to-day basis. Finally, participants will complete a project evaluation questionnaire developed by the investigators to indicate individual satisfaction in the intervention.

Analysis
Before analyzing the pilot data collected, all electronic data will be stripped of identi ers and will be stored in password-protected les. Speci cally, for each data le, a code number will be assigned, and the master list, linking code numbers with names, will be stored separately. As per IRB protocol, collected data will be stored on password protected, network computer hard drives, which will only be accessible to the Principal Investigator to maintain patient privacy and con dentiality.
Overall, the purpose of this pilot study is not to test hypotheses, but rather generate them. The main goal of this study is to explore possible hypotheses concerning the intervention's effects on cardiometabolic risk factors, psychosocial functioning, and health-related quality of life in a sample of older Latinos with HIV. After data collection, all data will be exported to SPSS for analysis. A one-way ANOVA will be used to illustrate the change in scores from baseline to post-intervention in all the outcome measures used. Since this is a pilot study without a control group, a repeated measures ANOVA is appropriate to explore the intervention effects on cardiometabolic risk factors, psychosocial functioning, and health-related quality of life given that this type of analysis is often used in studies that investigate either changes in mean scores over three or more time points. 68 For exploratory analyses, we will incorporate a number of covariates including age, socioeconomic status, and years of education. Similarly, changes in current medications or dosage levels will be controlled for during the exploratory analysis. Methodologically, covariates will be tested as moderators of treatment response.

Discussion
As the population of PWH increasingly ages, high comorbidity between HIV and cardiometabolic diseases make older Latinos a high-risk population for whom innovative, scalable health promotion intervention could make a signi cant and lasting public health impact. 19 Despite the fact that older Latinos with HIV experience high levels of cardiometabolic disease due to issues associated with accelerated aging or potential adverse effects of ART medication, there is still a considerable dearth of relevant information on the effects of positive health promotion interventions in older Latinos living with HIV and comorbid cardiometabolic illness. This study will generate evidence as to whether or not an already established health promotion intervention, HOLA, can be adapted for older Latino men with HIV to improve physical health, psychosocial functioning, and health-related quality of life in the midst of a rapid demographic transition.
The HOLA intervention is a multifaceted, innovative health promotion program that is uniquely tailored to meet the diverse needs and circumstances of older Latinos with HIV. Since many older adults who identify as racial/ethnic minorities hold stigmatizing views of mental health services, 69,70 HOLA builds on prior research and incorporates culturally relevant strategies to health promotion/behavior change as way of reducing mental and physical health risk factors among older Latinos with HIV. 71 Speci cally, the use of a CHW to deliver a dual mental/physical health promotion intervention is an innovative approach to minimize disease burden in a population with high exposure to risk factors (in addition to HIV) and established disparities in both access to and engagement in bene cial mental and physical health services. 70,72,73 We believe that such an approach will appeal to older Latinos with HIV at risk for cardiometabolic disorders and psychological distress because of its non-stigmatizing presentation and the incorporation of cultural values/beliefs that promote the varying sociocultural in uences contributing to the health of Latinos. Essentially, if HOLA can be delivered successfully by CHWs, then the scalability, accessibility, and potential for dissemination is increased and HOLA becomes an optimal choice to address a signi cant medical and public health issue.

Conclusions
To our knowledge, HOLA is the rst health promotion trial whose central focus is on improving both physical and mental health among older Latinos with HIV. As the literature suggests, increased physical activity and the incorporation of pleasant events into daily routine are both effective strategies in treating geriatric anxiety and depression.47,74.75 Therefore, the integrated (mental and physical health) nature of this health promotion intervention bolsters its novelty and potential clinical impact. Additionally, the results of this pilot study have far reaching implications in regard to the health and welfare or other atrisk, under resourced populations. Since, the intervention is culturally tailored and contains features that will enable easy adaptation to different Latino subgroups, there's potential for further modi cation to other disadvantaged groups like older African-Americans with HIV or older sexual minorities with HIV. Like older Latino adults with HIV, older African-Americans with HIV report low utilization of mental health services,76 high rates of physical and mental health comorbidities,77 and signi cant experiences of ageism and HIV related stigma78 demonstrating just how impactful a program like HOLA may be when implemented within the community. Overall, the dissemination of a health promotion intervention like HOLA in a population of older Latino adults with HIV can serve to tackle multiple disparities (both health and service utilization related) among vulnerable adults at the crux of multiple marginalized communities (racial/ethnic, age, and HIV-status).

Declarations
Ethics approval and consent to participate All study methods and protocols were approved by the University of Miami's Internal Review Board (IRB ID: 20181032).

Consent for publication
Not applicable Availability of data and materials Not applicable

Competing interests
The authors declare that they have no competing interests.

Funding
This research was supported by grants R01 MD012610 and U54 MD002266 from the National Institute on Minority Health and Health Disparities and RO1 AG053163 from the National Institute on Aging. Dr. Batsis is supported by K23-AG051681 from the National Institute on Aging.
Authors' contributions DJ is the study principal investigator and contributed to the theoretical background and conceptualization of the study, intervention and study design, writing, and editing. EW and JB contributed to writing and editing. All authors read and approved the nal manuscript.