Outcomes of substance use and sexual power among adolescent girls and young women in Cape Town: Implications for structural and cultural differences.

Adolescent girls and young women (AGYW) in South Africa experience contextual barriers to HIV risk reduction including incomplete schooling, unintended pregnancy, substance use, and gender-based violence. A cluster randomised trial in Cape Town allocated 24 Black and Coloured communities to a gender-focused HIV risk-reduction intervention or HIV testing, with 500 AGYW total enrolled. We evaluated intervention efficacy by comparing mean differences overall, by community population group (Black and Coloured) and among those with structural barriers based on neighbourhood, education, and employment (n = 406). Both arms reported reductions in alcohol, cannabis, and condomless sex, with no intervention efficacy overall. Among AGYW with barriers, intervention participants reported fewer days of methamphetamine use at 6 months (t(210) = 2·08, p = ·04). In population group analysis, we found intervention effects on alcohol and sexual communication. Intervention participants in Black communities had fewer days of alcohol use at 12 months (t(136) = 2·10, p = ·04). Sexual discussion (t(147) = -2·47, p = ·02) and condom negotiation (t(146) = -2·51, p = ·01) increased for intervention participants at 12 months in Coloured communities. Gender-focused interventions must address population group differences and intersecting barriers to decrease substance use and increase education, skills, and sexual health protection.

Assessing Differences in mHealth Usability and App Experiences Among Young African American Women: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND: In North Carolina, HIV continues to disproportionately affect young African American women. Although mobile health (mHealth) technology appears to be a tool capable of making public health information more accessible for key populations, previous technology use and social determinants may impact users' mHealth experiences. OBJECTIVE: The objective of this study was to evaluate mHealth usability, assessing differences based on previous technology use and social determinants among a sample of African American women in emerging adulthood. METHODS: As part of a National Institute on Drug Abuse-funded randomized controlled trial with African American women (aged 18-25 years), counties were assigned to receive an evidence-based HIV risk reduction intervention through mHealth and participants were asked to complete usability surveys at 6- and 12-month follow-ups. Participants' first survey responses were analyzed through 2-tailed t tests and linear regression models to examine associations with previous technology use and social determinants (P<.05). RESULTS: The mean System Usability Scale (SUS) score was 69.2 (SD 17.9; n=159), which was higher than the threshold of acceptability (68.0). Participants who had previously used a tablet indicated higher usability compared to participants without previous use (mean 72.9, SD 18.1 vs mean 57.6, SD 11.4; P<.001), and participants with previous smartphone use also reported higher usability compared to participants without previous use (mean 71.9, SD 18.3 vs mean 58.0, SD 10.7; P<.001). Differences in SUS scores were observed among those reporting homelessness (mean 58.3, SD 19.0 vs mean 70.8, SD 17.2; P=.01), unemployment (mean 65.9, SD 17.2 vs mean 71.6, SD 18.1; P=.04), or current school enrollment (mean 73.2, SD 18.5 vs mean 65.4, SD 16.5; P=.006). Statistically significant associations were not observed for food insecurity (mean 67.3, SD 18.6 vs mean 69.9, SD 17.7; P=.45). CONCLUSIONS: Although above-average usability was observed overall, these findings demonstrate differences in mHealth usability based on past and current life experiences. As mHealth interventions become more prevalent, these findings may have important implications for ensuring that mHealth apps improve the reach of evidence-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02965014; https://clinicaltrials.gov/study/NCT02965014. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12889-018-5796-8.

Binge drinking and condom negotiation behaviours among adolescent girls and young women living in Cape Town, South Africa: sexual control and perceived personal power.

BACKGROUND: Condom use among young people in South Africa has declined in recent years and adolescent girls and young women continue to bear the highest incidence of HIV in the country. Young women who have dropped out of school may be more at risk because of traditional gender norms that create substantial power imbalances and a lack of power to negotiate condom use with their male partners, especially when using alcohol and other drugs. METHODS: This study presents an analysis of baseline data provided by 500 adolescent girls and young women (AGYW) from Cape Town communities between November 2016 and November 2018 who were reached for a cluster-randomised trial conducted to assess the efficacy of an evidence-based, young woman-focused intervention seeking to reduce HIV risk and substance use behaviours. The analysis focuses on associations between binge drinking, condom use, and sexual negotiation, including impaired sex (any substance use at last sex). RESULTS: AGYW who reported frequent condom negotiation with their partners were 8.92 times (95% CI: [4.36, 18.24]) as likely to use a condom when alcohol or other drugs were not used at last sex and 5.50 times (95% CI: [2.06, 14.72]) as likely when alcohol or other drugs were used at last sex (p < 0.05). AGYW who reported frequent binge drinking in the past month (n = 177) had significantly reduced odds of condom use at last sex, irrespective of whether the sex was impaired (OR 0.60, 95% CI: [0.49, 0.73]) or not impaired (OR 0.69, 95% CI: [0.60, 0.81]). DISCUSSION: The findings highlight the need for interventions that reach AGYW in South Africa by specifically aiming to educate AGYW about the effect of binge drinking on negotiating power in their relationships, thus providing them with the knowledge and skills to increase agency regarding condom use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02974998 (recruitment completed). 29/11/2016.

Stigma in the health clinic and implications for PrEP access and use by adolescent girls and young women: conflicting perspectives in South Africa.

BACKGROUND: Globally, an urgent need exists to expand access to HIV prevention among adolescent girls and young women (AGYW), but the need is particularly acute in sub-Saharan Africa. Oral pre-exposure prophylaxis (PrEP) offers an effective HIV prevention method. In many countries, however, accessing PrEP necessitates that AGYW visit their local health clinic, where they may face access challenges. Some countries have implemented youth-friendly services to reduce certain challenges in local health clinics, but barriers to access persist, including clinic stigma. However, evidence of clinic stigma toward AGYW, particularly with respect to PrEP service delivery, is still limited. This mixed methods study explores stigma toward AGYW seeking clinic services, in particular PrEP, from the perspective of both clinic staff (clinical and nonclinical) and AGYW who seek services at clinic sites in Tshwane province, South Africa. METHODS: Six focus group discussions were conducted with AGYW (43 total participants) and four with clinic staff (42 total participants) and triangulated with survey data with AGYW (n = 449) and clinic staff (n = 130). Thematic analysis was applied to the qualitative data and descriptive statistics were conducted with the survey data. RESULTS: Four common themes emerged across the qualitative and quantitative data and with both AGYW and clinic staff, although with varying degrees of resonance between these two groups. These themes included (1) clinic manifestations of stigma toward AGYW, (2) concerns about providing PrEP services for AGYW, (3) healthcare providers' identity as mothers, and (4) privacy and breaches of confidentiality. An additional theme identified mainly in the AGYW data pertained to stigma and access to healthcare. CONCLUSION: Evidence is needed to inform strategies for addressing clinic stigma toward AGYW, with the goal of removing barriers to PrEP services for this group. While awareness has increased and progress has been achieved around the provision of comprehensive, youth-friendly sexual and reproductive health services, these programs need to be adapted for the specific concerns of young people seeking PrEP services. Our findings point to the four key areas noted above where programs seeking to address stigma toward AGYW in clinics can tailor their programming.

Gender and Context Matter: Behavioral and Structural Interventions for People Who Use Alcohol and Other Drugs in Africa.

Heavy alcohol consumption and other drug use are prominent across Africa and increase the risk of exposure to violence, HIV acquisition, and other life-threatening injuries. This review synthesizes evidence on alcohol and other drug (AOD) interventions in Africa; evaluates the differences between interventions that do and do not specifically target populations that use AODs; and highlights the impact of comprehensive vs. brief interventions and those that address syndemic issues from a gender and contextualized lens. Literature searches were conducted to identify research outcomes of randomized interventions published between January 2010 and May 2022 that address AOD use in Africa. Thirty-five full-text articles were included in this review. Most of the identified research studies were concentrated in a few countries. Most studies were conducted in South Africa. Many of the studies comprised brief interventions. However, the most comprehensive interventions were the most effective for AOD outcomes. Several studies indicated the importance of addressing AOD use alongside gender-based violence, mental health needs, gender roles, and other social determinants that affect health outcomes. Intervening on AOD use and addressing social determinants from a gender and contextually relevant perspective is essential to ensuring the long-term health and well-being of people in Africa.

A Scoping Review of Computer-Based and Telecommunication Technology Interventions to Address Drug and Alcohol Misuse and Smoking in Women.

BACKGROUND: Computer-based and telecommunication technology has become increasingly common to address addiction among women. This review assessed the effect of technology-based interventions on substance misuse, alcohol use, and smoking outcomes among women. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews (PRISMA-ScR) guideline was used to conduct the scoping review. Four databases (PubMed, Web of Science, PsycINFO, and Scopus) were used to search for peer-reviewed articles published in English on computer-based and telecommunication technology use to address substance misuse, alcohol use, and smoking among women. RESULTS: A total of 30 articles were selected after the final full-text review from the U.S., England, Japan, and the Netherlands. The types of technology used in the interventions included computer software (standalone or web-based), mobile applications, video calling, phone, and text messaging. Intervention outcomes included alcohol and other substance misuse reduction as polysubstance misuse (n = 5), smoking cessation (n = 10), substance misuse reduction only (n = 6), and alcohol use reduction only (n = 9). The populations reached included women who were pregnant (n = 13), postpartum (n = 4), or non-pregnant (n = 14) ranging from adolescent to adulthood. Interventions that targeted polysubstance misuse showed statistically significant reductions (p < .05). CONCLUSION: Although effective in reducing alcohol and other substance misuse, mixed findings were identified for other outcomes targeting a single substance. Technology-based interventions might maximize their effects by targeting polysubstance misuse and addressing associated contextual issues in the form of a computer-delivered module(s).

An Evidence-Based HIV Risk-Reduction Intervention for Young African American Women in the US South Using mHealth: Adaptation and Development Study.

BACKGROUND: Young African American women have higher rates of sexually transmitted infections, including HIV, than those of young women of other racial and ethnic groups. Gender-, culture-, and age-specific interventions are needed to end the HIV epidemic. The Women's CoOp (WC) is an HIV risk-reduction intervention that is proven to be efficacious in various face-to-face formats. OBJECTIVE: This study aims to adapt the delivery method of an evidence-based intervention, the WC, from an in-person format to a self-guided mobile health (mHealth) format while ensuring that core elements are maintained for intervention comparability and fidelity. METHODS: Several adaptation phases were conducted by using the Personal Health Informatics and Intervention Toolkit (PHIT) as a guiding point to create the mobile app version of the WC. Throughout 5 phases, we established the implementation groundwork for the app; conducted formative research activities to test the initial draft of the app and obtain feedback; applied the PHIT toolkit programming structure to produce the mHealth version of the WC intervention; conducted usability testing and pretesting with interested parties, followed by in-house testing by WC interventionists and PHIT developers; and deployed the app to tablets and distributed it to study participants. The app underwent regular maintenance updates during the study. RESULTS: The team converted the seven elements of the WC as accurately as possible for comparability to determine efficacy in a mobile app format while changing little about the basic delivery methods. For instance, cue card presentations of the materials delivered by the intervention staff were presented within the app but with voice-over narration and in a self-guided format rather than being led by a staff member. Other aspects of the intervention did not lend themselves to such straightforward adaptation, such as hands-on condom proficiency practice and one-on-one goal-setting activities. In these cases, the subject matter experts and app developers worked together to find comparable analogs to be used within the app. Once developed, tested, and finalized, the mHealth WC app was deployed into local health departments as part of a randomized trial. CONCLUSIONS: This systematic adaptation process created an accurate mHealth equivalent of an existing, in-person behavioral health intervention. Although participants' reception of the app during the formative developmental phase was overall positive, maintaining fidelity to the in-person delivery compromised the natural capabilities of a mobile app, such as further gamification, different types of interactivity, and integrated notifications and messaging, which could be helpful for participants' adherence to the intervention schedule. Given the development and implementation of the app, the next step is to examine the impact of the app and its efficacy in HIV and substance use risk-reduction.

"Because all mothers is not the same": The development and implementation of an in loco parentis informed consent procedure to enroll adolescent girls and young women to participate in HIV research.

INTRODUCTION: South Africa has one of the highest incidences of HIV among adolescent girls and young women (AGW), ages 15-24, and recent research has focused on developing interventions for HIV prevention. However, the South African National Health Act requires those under 18 years of age to obtain a guardian's permission to participate in research. Limiting research enrolment to AGYW who can obtain guardian consent may lead to non-representative findings. Therefore, innovative, inclusive consent approaches that protect AGYW from the risks of research are needed. METHODS: This report details the development and implementation of an approach called the in loco parentis (in place of parent) consent procedure. In loco parentis consent provides a vehicle for adolescent participation that protects adolescents from potential social harms. The in loco parentis consent procedure does not seek to obtain independent minor consent but seeks to obtain permission for the minor to participate in research from a trusted adult who is not a minor's parent or legal guardian. This report also qualitatively explores the experiences of 31 AGYW who were recruited into a behavioral HIV prevention study using this method. RESULTS: Findings suggest that the in loco parentis consent procedure is a feasible and acceptable method to inclusively AGYW in HIV research. CONCLUSIONS: The in loco parentis procedure may provide a more inclusive strategy to recruit AGYW for HIV research to increase the generalizability of findings.

Current Interventions for People Living with HIV Who Use Alcohol: Why Gender Matters.

PURPOSE OF REVIEW: Alcohol is the most misused substance in the world. For people living with HIV (PLWH), alcohol misuse may impact ART adherence and viral suppression. This review of the most recently published alcohol intervention studies with PLWH examines how these studies considered gender in the samples, design, and analyses. RECENT FINDINGS: Three searches were conducted initially, and 13 intervention studies fit our criteria with alcohol outcomes. In general, most studies did not consider gender and had used small samples, and few demonstrated significant efficacy/effectiveness outcomes. Five studies considered gender in their samples or analyses and/or were woman-focused with larger samples and demonstrated significant outcomes. It is essential for women who misuse alcohol to not only be well represented in alcohol and HIV research but also for studies to consider the barriers to reaching them and their contextual demands and/or co-occurring issues that may affect participation and outcomes in intervention research.

The PrEPARE Pretoria Project: protocol for a cluster-randomized factorial-design trial to prevent HIV with PrEP among adolescent girls and young women in Tshwane, South Africa.

BACKGROUND: Despite increased prevention efforts, HIV remains the leading cause of death among adolescent girls and young women in South Africa. Although research indicates important determinants of HIV acquisition at the individual and interpersonal levels, structural-level stigma and discrimination continue to be critical barriers to reaching and retaining this key population for HIV prevention and sexual and reproductive health services. Innovative and multilevel interventions are needed that can address the intersectional structural and gender issues that young women face, including stigma, alcohol and drug use, gender-based violence, and other risk factors when seeking health services. Oral pre-exposure prophylaxis (PrEP) taken daily has been found to be an effective biomedical HIV prevention tool. Testing a comprehensive gender-focused biobehavioral HIV prevention intervention that is inclusive of social ecological determinants, such as stigma and discrimination reduction in clinics, is critical for reducing HIV among adolescent girls and young women. METHODS: This project involves both a Community Collaborative Board and a Youth Advisory Board in helping to adapt the Young Women's Health CoOp intervention and the Health Policy Project (HPP) Stigma and Discrimination (S&D) reduction training curriculum to the setting and population. This study uses a two-by-two factorial design with stratified randomization of 12 clinics, each with distinct catchment areas. The Young Women's Health CoOp addresses substance use, sexual risk, violence prevention and sexual negotiation, condom demonstration, and problem solving with the following additions: knowledge of PrEP, the importance of PrEP adherence, and sexual and reproductive health. Adolescent girls and young women will be assessed with behavioral and biological measures at baseline, 3-, 6- and 9-month follow-up. The S&D reduction training is provided for all staff in the clinics randomized to this condition. Clinic staff will be surveyed at baseline, 4- and 8-month follow-up. We will recruit 900 AGYW from communities in the 12 clinic catchment areas. DISCUSSION: The study findings, if efficacious across the outcomes, will be incorporated into the gender-focused HIV prevention intervention toolkit and disseminated to inform multilevel prevention approaches. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT04048551 (Recruiting). Registered: August 7, 2019 (Retrospectively registered).

Addressing the nexus of risk: Biobehavioral outcomes from a cluster randomized trial of the Women's Health CoOp Plus in Pretoria, South Africa.

BACKGROUND: HIV prevalence has increased among South African women who use alcohol and other drugs (AOD). However, HIV prevention and treatment efforts have not focused on this population. This study presents the efficacy of the Women's Health CoOp Plus (WHC+) in a cluster-randomized trial to reduce AOD use, gender-based violence, and sexual risk and to increase linkage to HIV care among women who use AODs, compared with HIV counseling and testing alone. METHODS: Black African women (N = 641) were recruited from 14 geographic clusters in Pretoria, South Africa, and underwent either an evidence-based gender-focused HIV prevention intervention that included HIV counseling and testing (WHC+) or HIV counseling and testing alone. Participants were assessed at baseline, 6-months, and 12-months post enrollment. RESULTS: At 6-month follow-up, the WHC+ arm (vs. HCT) reported more condom use with a main partner and sexual negotiation, less physical and sexual abuse by a boyfriend, and less frequent heavy drinking (ps < 0.05). At 12-month follow-up, the WHC+ arm reported less emotional abuse (p < 0.05). Among a subsample of women, the WHC+ arm was significantly more likely to have a non-detectable viral load (measured by dried blood spots; p = 0.01). CONCLUSION: The findings demonstrate the WHC+'s efficacy to reduce HIV risk among women who use AODs in South Africa. Substance abuse rehabilitation centers and health centers that serve women may be ideal settings to address issues of gender-based violence and sexual risk as women engage in substance use treatment, HIV testing, or HIV care.

mHealth versus face-to-face: study protocol for a randomized trial to test a gender-focused intervention for young African American women at risk for HIV in North Carolina.

BACKGROUND: Disparities in the prevalence of HIV persist in the southern United States, and young African American women have a disproportionate burden of HIV as compared with young women of other racial/ethnic backgrounds. As a result, engaging young African American women in the HIV care continuum through HIV testing is imperative. This study is designed to reach this key population at risk for HIV. The study seeks to test the efficacy of two formats of a gender-focused, evidence-based, HIV-risk reduction intervention-the Young Women's CoOp (YWC)-relative to HIV counseling and testing (HCT) among young African American women between the ages of 18 and 25 who use substances and have not recently been tested for HIV. METHODS: Using a seek-and-test framework, this three-arm cross-over randomized trial is being conducted in three county health departments in North Carolina. Each county is assigned to one of three study arms in each cycle: in-person (face-to-face) YWC, mobile Health (mHealth) YWC, or HCT. At study enrollment, participants complete a risk behavior survey via audio computer-assisted self-interview, and drug, alcohol, and pregnancy screening tests, and are then referred to HIV, gonorrhea, and chlamydia testing through their respective health departments. Participants in either of the YWC arms are asked to return approximately 1 week later to either begin the first of two in-person individual intervention sessions or to pick up the mHealth intervention preloaded on a tablet after a brief introduction to using the app. Participants in all arms are asked to return for a 6-month follow-up and 12-month follow-up, and repeat the survey and biological testing from baseline. DISCUSSION: The findings from this study will demonstrate which delivery format (mHealth or face-to-face) is efficacious in reducing substance use and sexual risk behaviors. If found to be efficacious, the intervention has potential for wider dissemination and reach. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02965014 . Registered November 16, 2016.

The Young Women's Health CoOp in Cape Town, South Africa: Study protocol for a cluster-randomised trial for adolescent women at risk for HIV.

BACKGROUND: South Africa remains the global epicentre of HIV infection, and adolescent women have the highest incidence of HIV in the country. South Africa also has high rates of alcohol and other drug (AOD) use, violence, and gender inequality. Violence converges with AOD use, gender inequities and other disparities, such as poverty, to increase sexual risk and poor educational attainment for adolescent women. This study seeks to test the efficacy of peer recruitment and cofacilitation of the Young Women's Health CoOp (YWHC), a comprehensive gender-focused intervention to reduce HIV risk behaviours and increase the uptake of HIV counselling and testing (HCT) among out-of-school, adolescent women who use AODs. The YWHC is facilitated by local research staff and supported by peers. METHODS: This cluster-randomised trial is enrolling participants into two arms: a control arm that receives standard HCT, and an intervention arm that receives the YWHC. Participants are enrolled from 24 economically disadvantaged communities in Cape Town, South Africa. These geographically distinct communities serve as clusters that are the units of randomisation. This study uses adolescent peer role models and research field staff to recruit marginalised adolescent women. At baseline, participants complete a questionnaire and biological testing for HIV, recent AOD use, and pregnancy. The core intervention is delivered in the month following enrollment, with linkages to health services and educational programmes available to participants throughout the follow-up period. Follow-up interviews and biological testing are conducted at 6 and 12 months post enrollment. DISCUSSION: The study findings will increase knowledge of the efficacy of a comprehensive HCT, gender-focused programme in reducing AOD use, victimisation, and sexual risk behaviour and increase uptake services for out-of-school, adolescent women who use AODs. The trial results could lead to wider implementation of the YWHC for vulnerable adolescent women, a key population often neglected in health services. TRIAL REGISTRATION: Trial registration no: NCT02974998 , November 29, 2016.

Condom Use, Multiple Rounds of Sex, and Alcohol Use Among South African Women Who Use Alcohol and Other Drugs: An Event-Level Analysis.

BACKGROUND: High rates of alcohol and other drug use contribute to the ongoing generalized human immunodeficiency virus epidemic in South Africa. Despite the general link between alcohol use and condomless sex, findings from event-level studies of the relationship between alcohol use and condomless sex during the same encounter have been inconsistent. METHODS: We conducted event-level analyses of the most recent sexual encounter reported by 636 women who use substances in Pretoria. Data were collected via a questionnaire that included questions about the number of rounds of vaginal and anal sex and condom use during each round. We used multiple logistic regression analyses to model the associations between alcohol use by both partners and having multiple rounds of sex, and alcohol use and condom use during all rounds of sex. RESULTS: Over 50% of encounters involved multiple rounds of vaginal or anal sex. Encounters that involved multiple rounds of sex were associated with inconsistent condom use. Encounters in which both partners drank alcohol were more likely to involve condomless sex, as compared with encounters in which one or neither partner drank alcohol. CONCLUSIONS: These findings raise the possibility that prior event-level studies, which do not ask about multiple rounds of sex, may underestimate the prevalence of condomless sex. The association between alcohol use by both partners and condomless sex may partially explain inconsistent associations between alcohol use and condom use in event-level studies that did not assess the number of partners drinking.

Barriers and facilitators to implementing an evidence-based woman-focused intervention in South African health services.

BACKGROUND: Since the beginning of the HIV epidemic, numerous behavior change, risk-reduction, and biomedical interventions have been developed and tested. While some of these interventions have shown to be efficacious in randomized trials, it often takes almost two decades for an intervention to be translated into practice. Meanwhile, South Africa continues to have among the highest prevalence of HIV globally, with women of childbearing age bearing the burden of the epidemic. Given the urgency of the HIV epidemic among vulnerable women in South Africa, it is imperative that evidence-based interventions be implemented rapidly into practice. This study presents a first step toward examining the acceptability and feasibility of implementing the Women's Health CoOp (WHC) in clinics and substance abuse rehab settings in Cape Town, South Africa. METHODS: We conducted focus group discussions with women who use substances and with service providers, we also conducted in-depth interviews with health service planners. Our goal was to examine implementation and clinical outcomes associated with delivery of the WHC across clinics and substance abuse rehab programs. RESULTS: All participants agreed on the need for the WHC. Perceived facilitators to implementing the WHC included the recognizable need for programs to empower women and to build the capacity of staff to address issues of substance use, sexual risk, and intimate partner violence. Participants also identified potential barriers to women engaging with this program, including the stigma women experience when seeking services and the lack of person-centered care at healthcare facilities. CONCLUSIONS: In a country with the largest number of women of childbearing age living with HIV, an evidence-based woman-focused intervention that comprehensively addresses women's risk for suboptimal antiretroviral adherence may be essential for reducing HIV incidence. However, potential barriers to implementing the WHC successfully must be addressed before the program can be fully integrated into the services delivered by healthcare facilities. TRIAL REGISTRATION: Clinical trials NCT02733003 . Date of Registration: January 21, 2016, registered retroactively after participant enrollment.