PURPOSE: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. METHODS: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. RESULTS: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E-12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. CONCLUSION: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

CONTEXT: Digital video-based behavioral interventions are effective tools for improving HIV care and treatment outcomes. OBJECTIVE: To assess the costs of the Positive Health Check (PHC) intervention delivered in HIV primary care settings. DESIGN, SETTING, AND INTERVENTION: The PHC study was a randomized trial evaluating the effectiveness of a highly tailored, interactive video-counseling intervention delivered in 4 HIV care clinics in the United States in improving viral suppression and retention in care. Eligible patients were randomized to either the PHC intervention or the control arm. Control arm participants received standard of care (SOC), and intervention arm participants received SOC plus PHC. The intervention was delivered on computer tablets in the clinic waiting rooms. The PHC intervention improved viral suppression among male participants. A microcosting approach was used to assess the program costs, including labor hours, materials and supplies, equipment, and office overhead. PARTICIPANTS: Persons with HIV infection, receiving care in participating clinics. MAIN OUTCOME MEASURES: The primary outcome was the number of patients virally suppressed, defined as having fewer than 200 copies/mL by the end of their 12-month follow-up. RESULTS: A total of 397 (range across sites [range], 95-102) participants were enrolled in the PHC intervention arm, of whom 368 participants (range, 82-98) had viral load data at baseline and were included in the viral load analyses. Of those, 210 (range, 41-63) patients were virally suppressed at the end of their 12-month follow-up visit. The overall annual program cost was $402 274 (range, $65 581-$124 629). We estimated the average program cost per patient at $1013 (range, $649-$1259) and the cost per patient virally suppressed at $1916 (range, $1041-$3040). Recruitment and outreach costs accounted for 30% of PHC program costs. CONCLUSIONS: The costs of this interactive video-counseling intervention are comparable with other retention in care or reengagement interventions.

BACKGROUND: To determine whether Positive Health Check, a highly tailored video doctor intervention, can improve viral suppression and retention in care. SETTING: Four clinics that deliver HIV primary care. METHODS: A hybrid type 1 effectiveness-implementation randomized trial design was used to test study hypotheses. Participants (N = 799) who were not virally suppressed, were new to care, or had fallen out of care were randomly assigned to receive Positive Health Check or the standard of care alone. The primary endpoint was viral load suppression, and the secondary endpoint was retention in care, both assessed at 12 months, using an intention-to-treat approach. A priori subgroup analyses based on sex assigned at birth and race were examined as well. RESULTS: There were no statistically significant differences between Positive Health Check (N = 397) and standard of care (N = 402) for either endpoint. However, statistically significant group differences were identified from a priori subgroup analyses. Male participants receiving Positive Health Check were more likely to achieve suppression at 12 months than male participants receiving standard of care adjusted risk ratio [aRR] [95% confidence interval (CI)] = 1.14 (1.00 to 1.29), P = 0.046}. For retention in care, there was a statistically significant lower risk for a 6-month visit gap in the Positive Health Check arm for the youngest participants, 18-29 years old [aRR (95% CI) = 0.55 (0.33 to 0.92), P = 0.024] and the oldest participants, 60-81 years old [aRR (95% CI) = 0.49 (0.30 to 0.81), P = 0.006]. CONCLUSIONS: Positive Health Check may help male participants with HIV achieve viral suppression, and younger and older patients consistently attend HIV care. REGISTRY NAME: Positive Health Check Evaluation Trial. Trial ID: 1U18PS004967-01. URL: https://clinicaltrials.gov/ct2/show/NCT03292913.

BACKGROUND: Positive Health Check (PHC) is an evidenced-based video doctor intervention developed for improving the medication adherence, retention in care, and viral load suppression of people with HIV receiving clinical care. SETTING: Four HIV primary care clinics within the United States. METHODS: As part of a type 1 hybrid trial, a mixed-methods approach was used to longitudinally assess the following 3 key implementation constructs over a 23-month period: innovation-values fit (ie, the extent to which staff perceive innovation use will foster the fulfillment of their values), organizational readiness for change (ie, the extent to which organizational members are psychologically and behaviorally prepared to implement organizational change), and implementation climate (ie, the extent to which implementation is expected, supported, and rewarded). Quantitative mixed-effects regression analyses were conducted to assess changes over time in these constructs. Qualitative analyses were integrated to help provide validation and understanding. RESULTS: Innovation-values fit and organizational readiness for change were found to be high and relatively stable. However, significant curvilinear change over time was found for implementation climate. Based on the qualitative data, implementation climate declined toward the end of implementation due to decreased engagement from clinic champions and differences in priorities between research and clinic staff. CONCLUSIONS: The PHC intervention was found to fit within HIV primary care service settings, but there were some logistical challenges that needed to be addressed. Additionally, even within the context of an effectiveness trial, significant and nonlinear change in implementation climate should be expected over time.

BACKGROUND: Video is a versatile and popular medium for digital health interventions. As mobile device and app technology advances, it is likely that video-based interventions will become increasingly common. Although clinic waiting rooms are complex and busy environments, they offer the opportunity to facilitate engagement with video-based digital interventions as patients wait to see their providers. However, to increase efficiency in public health, leverage the scalability and low cost of implementing digital interventions, and keep up with rapidly advancing technology and user needs, more design and development guidance is needed for video-based tailored interventions. OBJECTIVE: We provide a tutorial for digital intervention researchers and developers to efficiently design and develop video-based tailored digital health interventions. We describe the challenges and solutions encountered with Positive Health Check (PHC), a hybrid app used to deliver a brief, interactive, individually tailored video-based HIV behavioral counseling intervention. PHC uses video clips and multimedia digital assets to deliver intervention content, including interactive tailored messages and graphics, a repurposed animated video, and patient and provider handouts generated in real time by PHC. METHODS: We chronicle multiple challenges and solutions for the following: (1) using video as a medium to enhance user engagement, (2) navigating the complexity of linking a database of video clips with other digital assets, and (3) identifying the main steps involved in building an app that will seamlessly deliver to users individually tailored messages, graphics, and handouts. RESULTS: We leveraged video to enhance user engagement by featuring "video doctors," full-screen video, storyboards, and streamlined scripts. We developed an approach to link the database of video clips with other digital assets through script coding and flow diagrams of algorithms to deliver a tailored user experience. We identified the steps to app development by using keyframes to design the integration of video and digital assets, using agile development methods to gather iterative feedback from multidisciplinary teams, and creating an intelligent data-driven back-end solution to tailor message delivery to individual users. CONCLUSIONS: Video-based digital health interventions will continue to play an important role in the future of HIV prevention and treatment, as well as other clinical health practices. However, facilitating the adoption of an HIV video intervention in HIV clinical settings is a work in progress. Our experience in designing and developing PHC presented unique challenges due to the extensive use of a large database of videos tailored individually to each user. Although PHC focuses on promoting the health and well-being of persons with HIV, the challenges and solutions presented in this tutorial are transferable to the design and development of video-based digital health interventions focused on other areas of health.

For people with HIV, important transmission prevention strategies include early initiation and adherence to antiretroviral therapy and retention in clinical care with the goal of reducing viral loads as quickly as possible. Consequently, at this point in the HIV epidemic, innovative and effective strategies are urgently needed to engage and retain people in health care to support medication adherence. To address this gap, the Positive Health Check Evaluation Trial uses a type 1 hybrid randomized trial design to test whether the use of a highly tailored video doctor intervention will reduce HIV viral load and retain people with HIV in health care. Eligible and consenting patients from four HIV primary care clinical sites are randomly assigned to receive either the Positive Health Check intervention in addition to the standard of care or the standard of care only. The primary aim is to determine the effectiveness of the intervention. A second aim is to understand the implementation potential of the intervention in clinic workflows, and a third aim is to assess the costs of intervention implementation. The trial findings will have important real-world applicability for understanding how digital interventions that take the form of video doctors can be used to decrease viral load and to support retention in care among diverse patients attending HIV primary care clinics.

We used the 1-month pilot implementation of Positive Health Check, a brief web-based video counseling intervention that supports patients with HIV attending HIV primary care clinics, to exemplify how studying implementation strategies earlier in the evidence-generation process can improve implementation outcomes in later pragmatic trials. We identified how implementation strategies were operationalized and the barriers and facilitators these strategies addressed using multiple data sources, including adapted implementation procedures and weekly structured interviews conducted with 9 key stakeholders in 4 HIV primary care clinics. Nineteen of 73 discrete implementation strategies for clinical innovations were used in the pilot implementation of Positive Health Check. Clinic staff reported 17 barriers and facilitators related to the clinic environment, patient population, intervention characteristics, and training and technical assistance. Identifying the link between strategies, barriers, and facilitators helped plan for a subsequent larger multisite pragmatic trial.

BACKGROUND: Web-based interventions can help people living with HIV achieve better clinical outcomes and behaviors, but integrating them into clinical practice remains challenging. There is a gap in understanding the feasibility of implementing these interventions in HIV clinic settings from the clinicians' perspective. OBJECTIVE: The goal of the research was to determine whether Positive Health Check (PHC)-a Web-based, tailored video counseling tool focused on increasing patient adherence and retention in care and reducing HIV risk among HIV-positive patients-was acceptable, appropriate, and feasible for HIV primary care clinic staff to implement in clinic workflows. METHODS: A multiple-case study design was used to evaluate the pilot implementation. Four primary care clinics located in the southeastern United States implemented PHC over a 1-month period. Nine clinic staff across the clinics participated in structured interviews before, during, and after the implementation. In total, 54 interviews were conducted. We used a framework analysis approach to code the data and identify themes related to implementation outcomes, including acceptability, appropriateness, and feasibility. We also analyzed patient intervention use metrics (n=104) to quantify patient intervention completion rates (n=68). RESULTS: Overall, clinicians viewed PHC as acceptable and appropriate. Themes that emerged related to these implementation outcomes include the ability for PHC to increase provider-patient communication and its ability to engage patients due to the tailored and interactive design. While generally feasible to implement, challenges to the clinic workflow and physical environment were areas that clinics needed to manage to make PHC work in their clinics. CONCLUSIONS: Findings from this pilot implementation suggest that clinical staff viewed PHC as acceptable and appropriate, especially as more patients used the intervention over the pilot period. Feasibility of implementation was challenging in some cases, and lessons learned from this pilot implementation can provide information for larger scale tests of the intervention that include assessment of both implementation outcomes and clinical outcomes.

Digital health interventions use technologies such as mobile phones and tablets to influence health-related behaviors.1 Widespread access and use of digital technologies have contributed to the increased adoption of digital health interventions. According to the Pew Research Center, 90% of American adults have a cell phone and 68% have a smartphone.2 Cell phone ownership is similarly high across various demographic groups such as race/ethnicity, education levels, income, and community type.2 Digital health technologies are being used for human immunodeficiency virus (HIV) prevention and treatment as well as for other health arenas such as cardiovascular disease, physical activity, and smoking cessation.3–8 The adoption of digital health interventions is changing the intervention landscape and may impact intervention design, formation of project teams, and regulatory issues such as data security and patient privacy surrounding implementation of these interventions.

HIV prevention efforts are increasingly aimed at engaging people living with HIV (PLWH) in healthcare to enhance treatment adherence and retention in care. Clinics need evidence-based interventions to support these goals and guidance on how to successfully implement these interventions in clinical settings. We describe the development of Positive Health Check (PHC) digital health intervention to support adherence and retention in care as well as a pilot implementation to determine feasibility. We developed PHC using input from seven HIV primary care providers. Over 15 months, providers gave feedback on the development of PHC by participating in nine inquiries, via online methods or webinars, addressing topics related to intervention development and implementation. After a 1-month pilot test, four providers shared their impressions of PHC implementation via a structured, open-ended interview. Providers’ comments resulted in script revisions, feedback on the filming of four virtual doctors (actors) balanced by race and gender, a user-friendly visual design, and more engaging messaging. Implementation feedback informed protocols to increase privacy and strategies to gain buy-in from clinics. Providers responded positively after using the final version of PHC, and again after the 1-month pilot implementation. Using a collaborative development approach with healthcare providers is a viable method for developing clinic-based interventions to support clinical encounters for PLWH. Intervention development should include strategies to support integrating mobile interventions into clinic workflows. © 2017 Informa UK Limited, trading as Taylor & Francis Group

BACKGROUND: The public health literature documents the efficacy-effectiveness gap between research and practice resulting from the research priority of demonstrating efficacy at the expense of testing for effectiveness. PURPOSE: The Safe in the City video-based HIV/sexually transmitted infection (STI) prevention intervention designed for sexually transmitted disease (STD) clinic waiting rooms is presented as a case study to demonstrate the application of a new framework to bridge efficacy and effectiveness. The goal of the study is to determine the extent to which clinics are implementing the intervention. METHODS: As part of the case study, data were collected from a convenience sample of 81 publicly funded STD clinics during program implementation to determine whether clinics were showing the video. A baseline telephone survey was administered to clinic directors from November to December 2008, and a follow-up was conducted from March to May 2009. Data analysis was completed in 2009. RESULTS: At baseline, 41% of STD clinics were showing Safe in the City, which increased to 58% at follow-up. None reported previous implementation of behavioral interventions delivered in waiting rooms. Almost one fourth of clinics adapted the intervention by showing the video on laptop computers in examination rooms or in other venues with different audiences. CONCLUSIONS: The Safe in the City intervention was implemented by the majority of STD clinics and adapted for implementation. The framework for HIV/STI prevention intervention illustrates how measures of effectiveness were increased in the development, evaluation, dissemination, implementation and sustainability phases of research and program.

The HIV/AIDS epidemic in the United States continues despite several recent, noteworthy advances in HIV prevention. Contemporary approaches to HIV prevention involve implementing combinations of biomedical, behavioral and structural interventions in novel ways to achieve high levels of impact on the epidemic. Methods are needed to develop optimal combinations of approaches for improving efficiency, effectiveness and scalability. This paper argues that operational research offers promise as a valuable tool for addressing these issues. We define operational research relative to domestic HIV prevention, identify and illustrate how operational research can improve HIV prevention, and pose a series of questions to guide future operational research. Operational research can help achieve national HIV prevention goals of reducing new infections, improving access to care and optimization of health outcomes of people living with HIV, and reducing HIV-related health disparities.