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Abstract Background Hypertension is the most common cardiovascular disease in Peru despite the availability of cost-effective, evidence-based treatment. Here we describe the rationale and study design for a hybrid type 2 randomized controlled trial to test the implementation and effectiveness of a community health worker (CHW)-led hypertension control program within the national primary care system in Puno, Peru. Methods We will recruit 1068 adult participants with hypertension aged ≥ 18 years in Puno, Peru, via facility-based enrollment and community health fairs. Participants will be individually randomized (1:1) to either continue with usual care or participate in a 12-month CHW-led home-based hypertension control program consisting of blood pressure monitoring, medication adherence support, and healthy lifestyle counseling. Outcome development and reporting are guided by the Consolidated Framework for Implementation Research (CFIR), the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, and the Proctor et al. framework. Clinical effectiveness outcomes include mean change in systolic blood pressure (primary outcome), diastolic blood pressure, and HbA1C. Implementation outcomes include fidelity (i.e., CHW protocol adherence and dose), reach, adoption, sustainability, acceptability, and cost-effectiveness. Discussion The ANDES trial is testing the first CHW-led multicomponent strategy for hypertension and type 2 diabetes management in Peru. This type 2 hybrid trial will provide critical insights into the individual, community, and system-level factors necessary for successful implementation and effectiveness. These data can inform the future adaptation and scaling of the ANDES strategy in Peru and other LMICs, as well as influence policies at the system level to support this transition. Furthermore, by addressing both hypertension and diabetes, the ANDES strategy supports integrated care approaches advocated by the WHO HEARTS technical package, ultimately enhancing health outcomes and reducing morbidity and mortality in the region. Trial registration ClinicalTrials.gov, ID: NCT05524987 , Addressing Hypertension and Diabetes through Community-Engaged Systems in Puno, Peru (ANDES study), prospectively registered on September 1, 2021.

Abstract Background While TB-related mortality in the US declined four-fold from 1990 to 2019, country-level estimates of TB burden obscure within-state racial heterogeneity and changes in TB burden over time. In sixteen US Southern States and Washington DC, the effects of health inequities engendered by Jim-Crow laws enacted from the late 1800s to the 1960s have not been evaluated for TB-related mortality. We, therefore, sought to compare TB mortality rates and annualized rate of change (AROC) between 1990 and 2019 in former Jim-Crow vs. non-Jim-Crow states to help guide response efforts and inform resource prioritization to improve racial equity. Methods We evaluated whether TB-related mortality varied over time, from 1990 to 2019, between states that have a history of enacting Jim-Crow laws vs. states with no such history using estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019). TB mortality per 100,000 population and bootstrap 95% uncertainty intervals (UIs) were modeled using the Cause of Death Ensemble model (CODEm) framework with varying combinations of predictive covariates. For changes over time, we present age-standardized AROC as the percent difference in the natural logarithm of the rate in 1990 and 2019 divided by 30 (i.e., 100*[ln(2019 Rate/1990 Rate)/(30)) and the corresponding 95% UIs. Results TB-related mortality in all US states declined between 1990 and 2019. From 1990 to 2019, most former Jim-Crow states had higher mortality rates than states that did not enact Jim-Crow laws. The most significant decline in TB mortality was in Washington DC, with a six-fold decline from 2.69 (2.46–2.96) per 100,000 population in 1990 to 0.45(0.37–0.55) in 2019, corresponding to an AROC of -0.83% (-0.86;-0.79). The lowest decline was in Iowa, from 0.30 (0.27–0.33) to 0.09 (0.07–0.11) (AROC: -0.70% (-0.76; -0.63)). Eleven of the 16 states and Washington DC in the third tertile of TB mortality rate in 1990 (range 0.81–2.69) had a history of Jim-Crow laws, whereas none of the 17 states in the first tertile (range 0.30–0.51) had such history. Conversely, mortality decreased relatively slowly in former Jim-Crow states than in non-Jim-Crow states. Conclusions Even though the 1964 Civil Rights Act dismantled Jim-Crow statutes, racial inequities in TB burden experienced by past generations may still be felt in subsequent generations. Understanding the role of structural racism at the intersection of science and medicine shows the complex ways historical laws, such as Jim-Crow laws, continue to negatively impact health outcomes and warn of future dangers, such as COVID-19, to avoid.

Abstract Background HIV clinical guidelines recommend hypertension detection and management to lower cardiovascular disease risk, but these have not been effectively implemented for people living with HIV (PWH). Addressing this implementation gap requires community-engaged implementation studies focused on addressing implementation barriers specific to the HIV care context. Methods This protocol describes a type 2 effectiveness-implementation hybrid study conducted in nine primary care clinics in Johannesburg. The study will evaluate the effect of implementation strategies on guideline-recommended blood pressure assessment and management in HIV clinics and the effects of assessment/management on patient blood pressure. A stepped-wedge, cluster randomized study design was used to randomize clinics to the time at which they receive the implementation strategies and patient intervention. The implementation strategies tested include identifying and preparing care champions, changing record systems, conducting ongoing training, providing audit and feedback, and changing the physical structure/equipment. The patient intervention tested includes detection of elevated blood pressure, educational materials, lifestyle modification advice, and medication where needed. Implementation outcomes include adoption, fidelity (co-primary outcome), cost, and maintenance of the blood pressure assessment protocol in participating clinics, while patient outcomes include reach, effectiveness (co-primary outcome), and long-term effects of the intervention on patient blood pressure. These will be assessed via direct observation, study records, staff logs, medical chart reviews, and patient and healthcare worker surveys. To examine effects on the implementation (intervention fidelity) and effectiveness (patient blood pressure changes) co-primary outcomes, we will use the standard Hussey and Hughes model for analysis of stepped-wedge designs which includes fixed effects for both interventions and time periods, and a random effect for sites. Finally, we will examine the costs for the implementation strategies, healthcare worker time, and patient-facing intervention materials, as well as the cost-effectiveness and cost-utility of the intervention using study records, patient surveys, and a time and motion assessment. Discussion This study will address knowledge gaps around implementation of cardiovascular disease preventive practices in HIV care in South Africa. In doing so, it will provide a dual opportunity to promote evidence-based care in the South African HIV care context and help refine implementation research methods to better serve HIV populations globally. Trial registration ClinicalTrials.gov: NCT05846503. Registered on May 6, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05846503 .

Abstract Background The impact of both implementation strategies (IS) and evidence-based interventions (EBI) can vary across contexts, and a better understanding of how and why this occurs presents fundamental but challenging questions that implementation science as a field will need to grapple with. We use causal epidemiologic methods to explore the mechanisms of why sharp distinctions between implementation strategies (IS) and efficacy of an evidence-based intervention (EBI) may fail to recognize that the effect of an EBI can be deeply intertwined and dependent on the context of the IS leading to its uptake. Methods We explore the use of instrumental variable (IV) analyses as a critical tool for implementation science methods to isolate three relevant quantities within the same intervention context when exposure to an implementation strategy is random: (1) the effect of an IS on implementation outcomes (e.g., uptake), (2) effect of EBI uptake on patient outcomes, and (3) overall effectiveness of the IS (i.e., ~ implementation*efficacy). We discuss the mechanisms by which an implementation strategy can alter the context, and therefore effect, of an EBI using the underlying IV assumptions. We illustrate these concepts using examples of the implementation of new ART initiation guidelines in Zambia and community-based masking programs in Bangladesh. Results Causal questions relevant to implementation science are answered at each stage of an IV analysis. The first stage assesses the effect of the IS (e.g., new guidelines) on EBI uptake (e.g., same-day treatment initiation). The second stage leverages the IS as an IV to estimate the complier average causal effect (CACE) of the EBI on patient outcomes (e.g., effect of same-day treatment initiation on viral suppression). The underlying assumptions of CACE formalize that the causal effect of EBI may differ in the context of a different IS because (1) the mechanisms by which individuals uptake an intervention may differ and (2) the subgroup of individuals who take up an EBI may differ. IV methods thus provide a conceptual framework for how IS and EBIs are linked and that the IS itself needs to be considered a critical contextual determinant. Moreover, it also provides rigorous methodologic tools to isolate the effect of an IS, EBI, and combined effect of the IS and EBI. Discussion Leveraging IV methods when exposure to an implementation strategy is random helps to conceptualize the context-dependent nature of implementation strategies, EBIs, and patient outcomes. IV methods formalize that the causal effect of an EBI may be specific to the context of the implementation strategy used to promote uptake. This integration of implementation science concepts and theory with rigorous causal epidemiologic methods yields novel insights and provides important tools for exploring the next generation of questions related to mechanisms and context in implementation science.