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Physiologically based pharmacokinetic (PBPK) models for chemicals in food animals are a useful tool in estimating chemical tissue residues and withdrawal intervals. Physiological parameters such as organ weights and blood flows are an important component of a PBPK model. The objective of this study was to compile PBPK-related physiological parameter data in food animals, including cattle and swine. Comprehensive literature searches were performed in PubMed, Google Scholar, ScienceDirect, and ProQuest. Relevant literature was reviewed and tables of relevant parameters such as relative organ weights (% of body weight) and relative blood flows (% of cardiac output) were compiled for different production classes of cattle and swine. The mean and standard deviation of each parameter were calculated to characterize their variability and uncertainty and to allow investigators to conduct population PBPK analysis via Monte Carlo simulations. Regression equations using weight or age were created for parameters having sufficient data. These compiled data provide a comprehensive physiological parameter database for developing PBPK models of chemicals in cattle and swine to support animal-derived food safety assessment. This work also provides a basis to compile data in other food animal species, including goats, sheep, chickens, and turkeys.

PURPOSE:: Quantitative end points for uveitis are needed. Here we quantify the rate of ellipsoid zone (EZ) recovery on optical coherence tomography (OCT) and correlate it with visual acuity (VA) improvement in patients with acute posterior multifocal placoid pigmented epitheliopathy (APMPPE). We use automated and manually graded EZ area analysis to assess EZ recovery in APMPPE. METHODS:: We performed a retrospective review of 9 APMPPE cases (18 eyes) that had characteristic clinical examination and fluorescein angiography findings, outer retinal disruption on spectral-domain OCT, and treatment with systemic steroids after an unambiguous laboratory workup. The EZ was delineated using custom software to perform automated analysis and manual grading by 2 independent physicians. Quantitation of EZ changes was performed in ImageJ (National Institutes of Health). EZ maps were compared with equivalent findings from EZ en face OCT segmentation. RESULTS:: The 9 cases in our study were followed for an average of 198 days. Symptomatic improvement occurred in all eyes. VA recovery occurred in 83% of eyes and depended on presenting foveal involvement. Positive slopes of EZ area over time demonstrated recovery. EZ recovery profiles determined by manual and automated software demonstrated high Pearson correlation coefficients (0.78-0.94). Slab en face EZ analysis demonstrated moderate agreement. CONCLUSIONS:: EZ recovery correlates with symptomatic and VA recovery. Automated EZ analysis shows strong agreement with manually graded EZ analysis in APMPPE. EZ recovery in patients with APMPPE provides a biomarker for recovery and may be applied to other diseases affecting the outer retina.

Con el objetivo de priorizar políticas públicas para disminuir el consumo de bebidas azucaradas en Argentina, Brasil, El Salvador y Trinidad y Tobago e identificar las necesidades de información relacionadas con la carga de enfermedad atribuible a su consumo se realizó un diálogo de políticas en el que participaron miembros de gobierno, organizaciones de la sociedad civil, investigadores y comunicadores de países de Latinoamérica y el Caribe. Se llevaron a cabo exposiciones y talleres deliberativos utilizándose herramientas de recolección de datos semiestructuradas y discusiones grupales facilitadas. Las intervenciones priorizadas fueron el incremento de impuestos, el etiquetado frontal, la restricción de la publicidad, promoción y patrocinio y las modificaciones del entorno escolar. La principal barrera percibida fue la interferencia de la industria alimentaria. La realización de este diálogo de decisores permitió la identificación de las políticas públicas prioritarias para disminuir el consumo de bebidas azucaradas en la región.

Abstract Pelvic floor muscle (PFM) injury during childbirth is a key risk factor for pelvic floor disorders that affect millions of women worldwide. Muscle stem cells (MuSCs), supported by the fibro-adipogenic progenitors (FAPs) and immune cells, are indispensable for the regeneration of injured appendicular skeletal muscles. However, almost nothing is known about their role in PFM regeneration following birth injury. To elucidate the role of MuSCs, FAPs, and immune infiltrate in this context, we used radiation to perturb cell function and followed PFM recovery in a validated simulated birth injury (SBI) rat model. Non-irradiated and irradiated rats were euthanized at 3,7,10, and 28 days post-SBI (dpi). Twenty-eight dpi, PFM fiber cross-sectional area (CSA) was significantly lower and the extracellular space occupied by immune infiltrate was larger in irradiated relative to nonirradiated injured animals. Following SBI in non-irradiated animals, MuSCs and FAPs expanded significantly at 7 and 3 dpi, respectively; this expansion did not occur in irradiated animals at the same time points. At 7 and 10 dpi, we observed persistent immune response in PFMs subjected to irradiation compared to non-irradiated injured PFMs. CSA of newly regenerated fibers was also significantly smaller following SBI in irradiated compared to non-irradiated injured PFMs. Our results demonstrate that the loss of function and decreased expansion of MuSCs and FAPs after birth injury lead to impaired PFM recovery. These findings form the basis for further studies focused on the identification of novel therapeutic targets to counteract postpartum PFM dysfunction and the associated pelvic floor disorders.

BackgroundThe introduction of self-administered injectable contraception presents an opportunity to address the unmet need for family planning. As ministries of health scale up self-administered injectable contraception, there is a scarcity of knowledge on the implementation practices and contextual conditions that help and hinder these efforts. The World Health Organization has launched the “enhancing self-administered family planning through embedded research project” (EASIER) to address this challenge. ObjectiveEASIER’s objectives are to: (1) assess the coverage of self-injectable contraception, and the readiness of health systems to integrate it into the contraceptive method mix; (2) document strategies used to introduce and scale up self-injectable contraception and understand practices that have led to success and challenges; (3) identify the contextual factors that affect the adoption and implementation of self-injectable contraception throughout health systems; (4) understand whether implementation addresses users’ preferences and needs; (5) strengthen collaboration between decision makers, researchers, and implementers; support and build capacity to use evidence. MethodsEASIER developed a global protocol that implementation research (IR) teams in Burkina Faso, Ghana, and Kenya adapted into country-level embedded IR projects. In all countries (1) at the national level, IR teams evaluate the policy environment for scaling up by conducting a desk review and in-depth interviews; (2) at the local level, IR teams implement quantitative questionnaires on structural and organizational readiness to integrate self-injection into the method mix; (3) in “case study” localities, IR teams conduct in-depth interviews and focus group discussions with implementers, method users, and community members; and (4) IR teams use participatory action research to elicit stakeholder participation and translate findings into programmatic decisions. ResultsEASIER has been launched in all 3 countries. Preliminary findings are available from Burkina Faso and Kenya. In Burkina Faso, IR teams identified the need to strengthen health worker training approaches to ensure that family planning providers at primary health care facilities are adequately oriented to depo-medroxyprogesterone acetate subcutaneous (DMPA-SC) and self-injection and capacitated to initiate women to the method. In addition, they report the need for service communication strategies that reach potential users of the method with knowledge about self-injection and how to initiate the practice. In Kenya, the findings illuminate the need for practice guidelines that county health teams can use to coordinate the rollout of self-administered DMPA-SC. In addition, Kenya’s findings underscore the importance of addressing logistical bottlenecks to help avoid stock-outs. ConclusionsEASIER presents a strategy to embed IR in contraceptive method introduction and scale-up, address local knowledge needs, devise ways to maximize the impact of new technologies in health systems, and build capacity for using evidence in programmatic decisions. Adaptation and implementation of country-level IR studies will advance the use of IR to strengthen family planning programs. Trial RegistrationAustralia New Zealand Clinical Trials Registry ACTRN12622001228774; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384534&isReview=true International Registered Report Identifier (IRRID)DERR1-10.2196/44222

BackgroundIn addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.MethodsWe conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.ResultsAll sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.ConclusionsWe confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

Abstract Rapid earth surface evolution is discrete in nature, with short‐duration extreme events having a widespread impact on landscapes despite occurring relatively infrequently. Here, we exploit a unique opportunity to identify the broad, process‐based, controls on sediment production and export during extreme rainfall‐runoff events through a multi‐catchment analysis. A 3 hr extreme rainfall event generated significantly different impacts across three catchments, ranging from (a) sediment export exceeding two orders of magnitude more than the typical long term average to (b) a minimal impact, with this variability primarily controlled by catchment steepness and the presence of reach‐scale morphological transitions caused by postglacial landscape adjustment. In any catchment worldwide where populations are at risk, we highlight the importance of combining topographic analysis with detailed mapping of channel bed material (e.g., presence of transitions between process domains) and identification of sediment sources within morphological transition zones for accurately predicting the impact of extreme events.

Population change impacts almost every aspect of global change from land use, to greenhouse gas emissions, to biodiversity conservation, to the spread of disease. Data on spatial patterns of population density help us understand patterns and drivers of human settlement and can help us quantify the exposure we face to natural disasters, pollution, and infectious disease. Human populations are typically recorded by national or regional units that can vary in shape and size. Using these irregularly sized units and ancillary data related to population dynamics, we can produce high-resolution gridded estimates of population density through intelligent dasymetric mapping (IDM). The gridded population density provides a more detailed estimate of how the population is distributed within larger units. Furthermore, we can refine our estimates of population density by specifying uninhabited areas which have impacts on the analysis of population density such as our estimates of human exposure. In this study, we used various geospatial datasets to expand the existing specification of uninhabited areas within the United States (US) Environmental Protection Agency's (EPA) EnviroAtlas Dasymetric Population Map for the conterminous United States (CONUS). When compared to the existing definition of uninhabited areas for the EnviroAtlas dasymetric population map, we found that IDM's population estimates for the US Census Bureau blocks improved across all states in the CONUS. We found that IDM performed better in states with larger urban areas than in states that are sparsely populated. We also updated the existing EnviroAtlas Intelligent Dasymetric Mapping toolbox and expanded its capabilities to accept uninhabited areas. The updated 30 m population density for the CONUS is available via the EPA's Environmental Dataset Gateway (Baynes et al., 2021, https://doi.org/10.23719/1522948) and the EPA's EnviroAtlas (https://www.epa.gov/enviroatlas, last access: 15 June 2022; Pickard et al., 2015).

Per- and polyfluoroalkyl substances (PFAS) are found in a variety of places including cosmetics, rain jackets, dust, and water. PFAS have also been applied to occupational gear to protect against water and oils. However, PFAS have been identified as immunosuppressants and perfluorooctanoic acid (PFOA), a specific PFAS, has been identified as carcinogenic. Since there is a risk for dermal exposure to these compounds, there is a need to characterize their dermal absorption. Using in vitro flow-through diffusion, skin permeabilities were determined for 14C-labeled perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA), and perfluorobutanoic acid (PFBA) using porcine skin. Tests were conducted over 8 h with either acetone or artificial perspirant as the vehicle. PFBA was found to have greater permeability than PFHxA, likely due to having a smaller molecular weight. The dosing vehicle did not appear to impact permeability rates but impacted the disposition through the skin model. While these PFAS compounds showed a low permeability rate through the skin membranes, they can stay in the skin, acting as a reservoir. [ABSTRACT FROM AUTHOR]

Firefighter occupational exposures were categorized as a class 1 (known) carcinogen by the International Agency for Research on Cancer in 2022. As a result, firefighters have become heavily focused on identifying effective and easy to implement decontamination strategies to reduce their chemical exposures. Skin decontamination using wipes post-exposure is one decontamination strategy that every firefighter has available to them. However, firefighters have expressed concerns over the ingredients in the wipe solution increasing dermal absorption. The goal of this study was to determine if the ingredients in skin decontamination wipe solution had any enhancement effect on the dermal absorption of phenanthrene. To determine any enhancement effects, the additive solution of four skin decontamination wipe products was applied to porcine skin 15 min after chemical dosing. The absorption of phenanthrene was tested in vitro using a flow-through diffusion cell system over eight hours. The wipe solution effects on dermal absorption were determined by measuring multiple absorption characteristics including cumulative absorption (µg/cm2), absorption efficiency (% dose absorbed), lag time (minutes), flux (µg/cm2/h), diffusivity (cm2/h), and permeability (cm/h). No penetration enhancement effects were observed in any of the skin decontamination wipe solutions tested; rather, all wipe solutions decreased the absorption of phenanthrene. Slight differences in cumulative absorption among two pairings of skin decontamination wipe solutions, wipes 1 and 3 vs. wipes 2 and 4, were observed, indicating that some ingredients may impact dermal absorption. These findings show that firefighters should continue using skin decontamination wipes to reduce their dermal exposures to fireground contaminants with little concern of increasing the absorption of phenanthrene. [ABSTRACT FROM AUTHOR]

ABSTRACT: Flunixin is a nonsteroidal anti-inflammatory drug approved for use in cattle to manage pyrexia associated with bovine respiratory disease, mastitis, and endotoxemia. In the United States, no nonsteroidal anti-inflammatory drugs are approved for use in goats, but analgesics are needed for management of painful conditions to improve animal welfare. The objective of this study was to evaluate the pharmacokinetics of transdermal flunixin in dairy goats to determine a milk withdrawal interval (WDI) to avoid violative residue contamination in the food supply. Six adult lactating dairy goats received 3.3 mg/kg of transdermal flunixin before milk, interstitial fluid (ISF), and blood samples were collected at various time points for 360 h. The samples were analyzed using tandem mass spectrometry to detect flunixin as well as the flunixin marker metabolite, 5-hydroxyflunixin followed by a pharmacokinetic WDI calculation using the US Food and Drug Administration tolerance limit method to propose safe residue levels in goat milk. The mean flunixin apparent plasma half-life was 21.63 h. The apparent milk half-life for 5-hydroxyflunixin was 17.52 h. Our findings provide a milk WDI of 60 h using the US Food and Drug Administration tolerance of 0.002 µg/mL (established for bovine milk) and a more conservative WDI of 96 h using a limit of quantification of 0.001 µg/mL following the extralabel use of transdermal flunixin in dairy goats.

Objective Overweight and obesity are important contributors to the non-communicable disease burden. The consumption of sugar-sweetened beverages (SSBs) has been associated with an increased risk of type 2 diabetes mellitus (T2DM), cardiovascular disease, cancer and other conditions. The objective of this study was to estimate the burden of disease attributable to the consumption of SSBs and the costs to the healthcare systems in Argentina, Brazil, El Salvador, and Trinidad and Tobago.Design Following a systematic review of models, a comparative risk assessment framework was developed to estimate the health and economic impact associated with the consumption of SSBs.Setting Argentina, Brazil, El Salvador, and Trinidad and Tobago.Participants Overall population.Primary and secondary outcome measures The model estimated the effects of SSB consumption on health through two causal pathways: one mediated by body mass index (BMI) and health conditions associated with BMI and another that reflected the independent effects of SSB consumption on T2DM and cardiovascular diseases.Results The model results indicated that for all four countries, in 1 year, SSB consumption was associated with 18 000 deaths (3.2% of the total disease-related deaths), seven million disease events (3.3% of the total disease-related events), a half-million DALYs and US$2 billion in direct medical costs. This included 1.5 million cases of overweight and obesity in children/adolescents (12% of the excess weight cases) and 2.8 million cases in adults (2.8%); 2.2 million cases of type 2 diabetes (19%); 200 000 cases of heart disease (3.8%); 124 000 strokes (3.9%); 116 000 cases of musculoskeletal disease (0.2%); 102 000 cases of kidney disease (0.9%); and 45 000 episodes of asthma (0.4%). The Trinidad and Tobago population were the most affected by disease events.Conclusions The study results indicate that the consumption of SSBs is associated with a significant burden of disease and death in Latin America and the Caribbean.

BackgroundThe environmental prevalence of widely prescribed human pharmaceuticals that target key evolutionary conserved biomolecules present across phyla is concerning. Antidepressants, one of the most widely consumed pharmaceuticals globally, have been developed to target biomolecules modulating monoaminergic neurotransmission, thus interfering with the endogenous regulation of multiple key neurophysiological processes. Furthermore, rising prescription and consumption rates of antidepressants caused by the burgeoning incidence of depression is consistent with increasing reports of antidepressant detection in aquatic environments worldwide. Consequently, there are growing concerns that long-term exposure to environmental levels of antidepressants may cause adverse drug target-specific effects on non-target aquatic organisms. While these concerns have resulted in a considerable body of research addressing a range of toxicological endpoints, drug target-specific effects of environmental levels of different classes of antidepressants in non-target aquatic organisms remain to be understood. Interestingly, evidence suggests that molluscs may be more vulnerable to the effects of antidepressants than any other animal phylum, making them invaluable in understanding the effects of antidepressants on wildlife. Here, a protocol for the systematic review of literature to understand drug target-specific effects of environmental levels of different classes of antidepressants on aquatic molluscs is described. The study will provide critical insight needed to understand and characterize effects of antidepressants relevant to regulatory risk assessment decision-making, and/or direct future research efforts.MethodsThe systematic review will be conducted in line with the guidelines by the Collaboration for Environmental Evidence (CEE). A literature search on Scopus, Web of Science, PubMed, as well as grey literature databases, will be carried out. Using predefined criteria, study selection, critical appraisal and data extraction will be done by multiple reviewers with a web-based evidence synthesis platform. A narrative synthesis of outcomes of selected studies will be presented. The protocol has been registered in the Open Science Framework (OSF) registry with the registration DOI: 10.17605/OSF.IO/P4H8W.

Community health worker programs have proliferated worldwide based on evidence that they help prevent mortality, particularly among children. However, there is limited evidence from randomized studies on the processes and effectiveness of implementing community health worker programs through public health systems. This paper describes the results of a cluster-randomized pragmatic implementation trial (registration number ISRCTN96819844) and qualitative process evaluation of a community health worker program in Tanzania that was implemented from 2011-2015. Program effects on maternal, newborn and child health service utilization, childhood morbidity and sick childcare seeking were evaluated using difference-in-difference regression analysis with outcomes measured through pre- and post-intervention household surveys in intervention and comparison trial arms. A qualitative process evaluation was conducted between 2012 and 2014 and comprised of in-depth interviews and focus group discussions with community health workers, community members, facility-based health workers and staff of district health management teams. The community health worker program reduced incidence of illness and improved access to timely and appropriate curative care for children under five; however, there was no effect on facility-based maternal and newborn health service utilization. The positive outcomes occurred because of high levels of acceptability of community health workers within communities, as well as the durability of community health workers' motivation and confidence. Implementation factors that generated these effects were the engagement of communities in program startup; the training, remuneration and supervision of the community health workers from the local health system and community. The lack of program effects on maternal and newborn health service utilization at facilities were attributed to lapses in the availability of needed care at facilities. Strategies that strengthen and align communities' and health systems core capacities, and their ability to learn, adapt and integrate evidence-based interventions, are needed to maximize the health impact of community health workers.

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P

Objectives: In response to the coronavirus 2019 (COVID-19) pandemic, a research project was developed with a cohort of 45 and Up Study participants to generate timely, relevant evidence to guide policy, practice and planning. This paper describes the research model, the cohort establishment and characteristics, and some findings. Methods: A subgroup of 45 and Up Study participants was invited to enrol in 45 and Up COVID Insights –a series of five online surveys conducted during 2020–22. The model involved a close collaborative partnership with the New South Wales Ministry of Health and a panel of scientific advisers, an agile data collection methodology and rapid dissemination of findings. Frequent, iterative engagement with stakeholders provided a framework for identifying survey themes and questions and ensured wide dissemination of findings. Themes included healthcare use, attitudes toward and uptake of COVID-19 prevention measures, and the impact of the pandemic on mental health, loneliness, and lifestyle behaviours. Results: 45 and Up COVID Insights achieved strong stakeholder engagement through extensive consultation and rapid reporting of results. The project recruited a diverse cohort of 32 115 participants: median age 68 years (range: 56–100+); 8% from outer regional/remote areas; 12% from the most socioeconomically disadvantaged communities; and 9% from culturally and linguistically diverse backgrounds. The first four surveys found that the impact of the pandemic varied across populations and stages of the pandemic. Between February–April (survey 2) 2021, 10% reported missed healthcare in the past month because of the pandemic, rising to 26% by September–November 2021 (survey 4). Quality of life remained high (>90% good–excellent across the surveys). As the pandemic progressed, the proportion reporting worsened mental health as a result increased from 29% (July–December 2020, survey 1) to 46% (survey 4). In survey 2 (February–April 2021), 89% intended to get the COVID-19 vaccine, with 8% unsure. By late 2021, vaccination uptake was high, with 98% of respondents having received at least one vaccination. Conclusion: There is great value in harnessing a large longitudinal, well-described, and diverse cohort study to generate evidence in a changing context with evolving information needs. The collaborative model enhanced the value and relevance of the data to inform decisions.

ObjectiveAs environmental and economic pressures converge with demands to achieve sustainability development goals, low- and middle-income countries (LMIC) increasingly require strategies to strengthen and scale-up evidence-based practices (EBP) related to family planning (FP). Implementation science (IS) can help these efforts. The purpose of this article is to elucidate patterns in the use of IS in FP research and identify ways to maximize the potential of IS to advance FP in LMIC.Design and methodsWe conducted a systematic review that describes how IS concepts and principles have been operationalized in LMIC FP research published from 2007–2021. We searched six databases for implementation studies of LMIC FP interventions. Our review synthesizes the characteristics of implementation strategies and research efforts used to enhance the performance of FP-related EBP in these settings, identifying gaps, strengths and lessons learned.ResultsFour-hundred and seventy-two studies were eligible for full-text review. Ninety-two percent of studies were carried out in one region only, whereas 8 percent were multi-country studies that took place across multiple regions. 37 percent of studies were conducted in East Africa, 21 percent in West and Central Africa, 19 percent in Southern Africa and South Asia, respectively, and fewer than 5 percent in other Asian countries, Latin America and Middle East and North Africa, respectively. Fifty-four percent were on strategies that promoted individuals' uptake of FP. Far fewer were on strategies to enhance the coverage, implementation, spread or sustainability of FP programs. Most studies used quantitative methods only and evaluated user-level outcomes over implementation outcomes. Thirty percent measured processes and outcomes of strategies, 15 percent measured changes in implementation outcomes, and 31 percent report on the effect of contextual factors. Eighteen percent reported that they were situated within decision-making processes to address locally identified implementation issues. Fourteen percent of studies described measures to involve stakeholders in the research process. Only 7 percent of studies reported that implementation was led by LMIC delivery systems or implementation partners.ConclusionsIS has potential to further advance LMIC FP programs, although its impact will be limited unless its concepts and principles are incorporated more systematically. To support this, stakeholders must focus on strategies that address a wider range of implementation outcomes; adapt research designs and blend methods to evaluate outcomes and processes; and establish collaborative research efforts across implementation, policy, and research domains. Doing so will expand opportunities for learning and applying new knowledge in pragmatic research paradigms where research is embedded in usual implementation conditions and addresses critical issues such as scale up and sustainability of evidence-informed FP interventions.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42020199353.