Ryanodine Receptor Staining Identifies Viable Cardiomyocytes in Human and Rabbit Cardiac Tissue Slices.

In terms of preserving multicellularity and myocardial function in vitro, the cultivation of beating myocardial slices is an emerging technique in basic and translational cardiac research. It can be used, for example, for drug screening or to study pathomechanisms. Here, we describe staining for viable cardiomyocytes based on the immunofluorescence of ryanodine receptors (RyRs) in human and rabbit myocardial slices. Biomimetic chambers were used for culture and measurements of contractile force. Fixable fluorophore-conjugated dextran, entering cells with a permeable membrane, was used for death staining. RyRs, nuclei and the extracellular matrix, including the t-system, were additionally stained and analyzed by confocal microscopy and image processing. We found the mutual exclusion of the RyR and dextran signals in cultivated slices. T-System density and nucleus size were reduced in RyR-negative/dextran-positive myocytes. The fraction of RyR-positive myocytes and pixels correlated with the contractile force. In RyR-positive/dextran-positive myocytes, we found irregular RyR clusters and SERCA distribution patterns, confirmed by an altered power spectrum. We conclude that RyR immunofluorescence indicates viable cardiomyocytes in vibratome-cut myocardial slices, facilitating the detection and differential structural analysis of living vs. dead or dying myocytes. We suggest the loss of sarcoplasmic reticulum integrity as an early event during cardiomyocyte death.

Reversing the trend: a scoping review of health innovation transfer or exchange from low- and middle-income countries to high-income countries.

The transfer of innovations from low and middle-income countries (LMICs) to high-income countries (HICs) has received little attention, leaving gaps in the understanding of the process, its benefits and the factors influencing it. This scoping review, part of a National Institutes of Health (NIH) project and the focus for a 2022 NIH-sponsored workshop on Global Health Reciprocal Innovation, sought to identify publications describing health innovations that were researched, developed and implemented in LMICs and adapted to address similar health challenges in HICs. A protocol was written a priori and registered on Open Science Framework. Four databases were searched for articles published in English from 2000 to 2022 and described health innovations developed in LMICs and were transferred to HICs. Using Covidence, two reviewers initially screened the title and abstract and then the full text; discrepancies were resolved through discussion. Two reviewers collected the data from each article using Covidence and Microsoft Excel; discrepancies were resolved by a separate third reviewer. 7191 records were retrieved and screened of which 12 studies were included. Various frameworks and methodologies were employed in these studies, with a particular emphasis on adaptation and adoption of innovations. The review uncovered different paradigms of LMIC to HIC innovation transfer and exchange, including unidirectional transfers from LMICs to HICs as well as bidirectional or multidirectional mutually beneficial exchanges. The use of both qualitative and quantitative data collection methods was common across all the included articles. Facilitators for innovation transfers included stakeholder engagement, relevance of local context, simplicity, and sufficient funding, promotion and branding. Barriers to transfers were mostly the opposite of the facilitators. Our results highlighted the underexplored field of LMIC to HIC innovation transfer and exchange and lay the foundation for future research studies.

Contractility measurements for cardiotoxicity screening with ventricular myocardial slices of pigs.

AIMS: Cardiotoxicity is one major reason why drugs do not enter or are withdrawn from the market. Thus, approaches are required to predict cardiotoxicity with high specificity and sensitivity. Ideally, such methods should be performed within intact cardiac tissue with high relevance for humans and detect acute and chronic side effects on electrophysiological behaviour, contractility, and tissue structure in an unbiased manner. Herein, we evaluate healthy pig myocardial slices and biomimetic cultivation setups (BMCS) as a new cardiotoxicity screening approach. METHODS AND RESULTS: Pig left ventricular samples were cut into slices and spanned into BMCS with continuous electrical pacing and online force recording. Automated stimulation protocols were established to determine the force-frequency relationship (FFR), frequency dependence of contraction duration, effective refractory period (ERP), and pacing threshold. Slices generated 1.3 ± 0.14 mN/mm2 force at 0.5 Hz electrical pacing and showed a positive FFR and a shortening of contraction duration with increasing pacing rates. Approximately 62% of slices were able to contract for at least 6 days while showing stable ERP, contraction duration-frequency relationship, and preserved cardiac structure confirmed by confocal imaging and X-ray diffraction analysis. We used specific blockers of the most important cardiac ion channels to determine which analysis parameters are influenced. To validate our approach, we tested five drug candidates selected from the Comprehensive in vitro Proarrhythmia Assay list as well as acetylsalicylic acid and DMSO as controls in a blinded manner in three independent laboratories. We were able to detect all arrhythmic drugs and their respective mode of action on cardiac tissue including inhibition of Na+, Ca2+, and hERG channels as well as Na+/Ca2+ exchanger. CONCLUSION: We systematically evaluate this approach for cardiotoxicity screening, which is of high relevance for humans and can be upscaled to medium-throughput screening. Thus, our approach will improve the predictive value and efficiency of preclinical cardiotoxicity screening.

Increasing Effectiveness and Equity in Strengthening Health Research Capacity Using Data and Metrics: Recent Advances of the ESSENCE Mechanism.

Background: The ESSENCE on Health Research initiative established a Working Group on Review of Investments in 2018 to improve coordination and collaboration among funders of health research capacity strengthening. The Working Group comprises more than a dozen ESSENCE members, including diverse representation by geography, country income level, the public sector, and philanthropy. Objective: The overall goal of the Working Group is increased research on national health priorities as well as improved pandemic preparedness, and, ultimately, fewer countries with very limited research capacity. Methods: We developed a basic set of metrics for national health research capacity, assessed different models of coordination and collaboration, took a deeper dive into eight countries to characterize their national research capacity, and began to identify opportunities to better coordinate our investments. In this article, we summarize the presentations, discussions, and outcomes of our second annual (virtual) meeting, which had more than 100 participants representing funders, researchers, and other stakeholders from higher- and lower-income countries worldwide. Findings and conclusions: Presentations on the first day included the keynote speaker, Dr. Soumya Swaminathan, chief scientist of the World Health Organization (WHO), and updates on data and metrics for research capacity, which are critical to establish targets, road maps, and budgets. The second day focused on improving collaboration and coordination among funders and other stakeholders, the potential return on investment for health research, ongoing work to increase coordination at the country level, and examples of research capacity strengthening efforts in diverse health research areas from around the world. We concluded that an intentional data- and metric-driven approach to health research capacity strengthening, emphasizing coordination among funders, local leadership, and equitable partnerships and allocation of resources, will enhance the health systems of resource-poor countries as well as the world's pandemic preparedness.

Recommendations for the use of mathematical modelling to support decision-making on integration of non-communicable diseases into HIV care.

INTRODUCTION: Integrating services for non-communicable diseases (NCDs) into existing primary care platforms such as HIV programmes has been recommended as a way of strengthening health systems, reducing redundancies and leveraging existing systems to rapidly scale-up underdeveloped programmes. Mathematical modelling provides a powerful tool to address questions around priorities, optimization and implementation of such programmes. In this study, we examine the case for NCD-HIV integration, use Kenya as a case-study to highlight how modelling has supported wider policy formulation and decision-making in healthcare and to collate stakeholders' recommendations on use of models for NCD-HIV integration decision-making. DISCUSSION: Across Africa, NCDs are increasingly posing challenges for health systems, which historically focused on the care of acute and infectious conditions. Pilot programmes using integrated care services have generated advantages for both provider and user, been cost-effective, practical and achieve rapid coverage scale-up. The shared chronic nature of NCDs and HIV means that many operational approaches and infrastructure developed for HIV programmes apply to NCDs, suggesting this to be a cost-effective and sustainable policy option for countries with large HIV programmes and small, un-resourced NCD programmes. However, the vertical nature of current disease programmes, policy financing and operations operate as barriers to NCD-HIV integration. Modelling has successfully been used to inform health decision-making across a number of disease areas and in a number of ways. Examples from Kenya include (i) estimating current and future disease burden to set priorities for public health interventions, (ii) forecasting the requisite investments by government, (iii) comparing the impact of different integration approaches, (iv) performing cost-benefit analysis for integration and (v) evaluating health system capacity needs. CONCLUSIONS: Modelling can and should play an integral part in the decision-making processes for health in general and NCD-HIV integration specifically. It is especially useful where little data is available. The successful use of modelling to inform decision-making will depend on several factors including policy makers' comfort with and understanding of models and their uncertainties, modellers understanding of national priorities, funding opportunities and building local modelling capacity to ensure sustainability.

A Mechanism for Reviewing Investments in Health Research Capacity Strengthening in Low- and Middle-Income Countries.

More than 40 agencies that fund health research capacity strengthening in low- and middle-income countries (LMICs) participate in the ESSENCE Health Research initiative, which has established a mechanism for reviewing and coordinating their funding. Taken together, the expected outcomes of implementation of the review mechanism are increases in the efficiency and equity in health research capacity strengthening activities with decreased duplication of efforts. The overall goal is increased support of research on national health priorities as well as improved pandemic preparedness in LMICs, and, eventually, fewer countries with very limited research capacity.

Erratum to "Readiness of Sub-Saharan Africa Healthcare Systems for the New Pandemic, Diabetes: A Systematic Review".

[This corrects the article DOI: 10.1155/2018/9262395.].

Readiness of Sub-Saharan Africa Healthcare Systems for the New Pandemic, Diabetes: A Systematic Review.

Background: Effective health systems are needed to care for the coming surge of diabetics in sub-Saharan Africa (SSA). Objective: We conducted a systematic review of literature to determine the capacity of SSA health systems to manage diabetes. Methodology: We used three different databases (Embase, Scopus, and PubMed) to search for studies, published from 2004 to 2017, on diabetes care in SSA. Results: Fifty-five articles met the inclusion criteria, covering the different aspects related to diabetes care such as availability of drugs and diagnostic tools, the capacity of healthcare workers, and the integration of diabetes care into HIV and TB platforms. Conclusion: Although chronic care health systems in SSA have developed significantly in the last decade, the capacity for managing diabetes remains in its infancy. We identified pilot projects to enhance these capacities. The scale-up of these pilot interventions and the integration of diabetes care into existing robust chronic disease platforms may be a feasible approach to begin to tackle the upcoming pandemic in diabetes. Nonetheless, much more work needs to be done to address the health system-wide deficiencies in diabetes care. More research is also needed to determine how to integrate diabetes care into the healthcare system in SSA.

Global partnerships to support noncommunicable disease care in low and middle-income countries: lessons from HIV/AIDS.

OBJECTIVE: The aim of this study was to identify lessons learned from partnerships addressing the HIV/AIDS epidemic that can inform those needed to mitigate the noncommunicable diseases (NCDs) epidemic in low and middle-income countries (LMICs). DESIGN: We selected and analysed a convenience sample of organizational partnerships developed to address the HIV/AIDS epidemic in LMICs, focusing on their specific strategies and contributions. METHODS: A review of published literature and website information pertaining to a convenience sample of five global organizations and/or types of partnerships that provide support to fight the HIV/AIDS epidemic was qualitatively analysed to assess key areas of support provided to scale-up services in response to the HIV/AIDS epidemic. RESULTS: Six topical areas of support were identified: HIV/AIDS service delivery; enhancing comprehensive health systems capacity; operational and implementation science research to improve care delivery; introducing and improving the availability of new products; political advocacy; and early-stage planning for sustainability and transition to more independent implementing-country delivery programmes. These six areas of support were qualitatively assessed for identify a focus, contributory or minimal contribution on the part of each of the organizations and/or types of partnerships reviewed. CONCLUSION: No single global partnership addresses the range of support needed to respond to the HIV/AIDS epidemic, and this will likely be true for an effective response to the emerging NCD epidemic. A range of coordinated financial and/or technical support as well as lessons learned from global HIV/AIDS partnerships will be key to achieving an effective response to the global NCD epidemic.

Implementation science for integration of HIV and non-communicable disease services in sub-Saharan Africa: a systematic review.

OBJECTIVE: As the burden of chronic non-communicable diseases (NCDs) rises across sub-Saharan Africa (SSA), global donors and governments are exploring strategies to integrate HIV and NCD care. Implementation science is an emerging research paradigm that can help such programs achieve health impact at scale. We define implementation science as a systematic, scientific approach to ask and answer questions about how to deliver what works in populations who need it with greater speed, appropriate fidelity, efficiency, and relevant coverage. We identified achievements and gaps in the application of implementation science to HIV/NCD integration, developed an HIV/NCD implementation science research agenda, and detailed opportunities for capacity building and training. DESIGN: We conducted a systematic review of the application of implementation science methods to integrated HIV/NCD programs in SSA. METHODS: We searched PubMed, CINAHL, PsycINFO, and EMBASE for evaluations of integrated programs in SSA reporting at least one implementation outcome. RESULTS: We identified 31 eligible studies. We found that most studies used only qualitative, economic, or impact evaluation methods. Only one study used a theoretical framework for implementation science. Acceptability, feasibility, and penetration were the most frequently reported implementation outcomes. Adoption, appropriateness, cost, and fidelity were rare; sustainability was not evaluated. CONCLUSIONS: Implementation science has a promising role in supporting HIV/NCD integration, although its impact will be limited unless theoretical frameworks, rigorous study designs, and reliable measures are employed. To help support use of implementation science, we need to build sustainable implementation science capacity. Doing so in SSA and supporting implementation science investigators can help expedite HIV/NCD integration.

Building on the HIV chronic care platform to address noncommunicable diseases in sub-Saharan Africa: a research agenda.

OBJECTIVE: The remarkable progress made in confronting the global HIV epidemic offers a unique opportunity to address the increasing threat of noncommunicable diseases (NCDs). However, questions remain about how to enhance the HIV platforms to deliver integrated HIV and NCD care to people living with HIV (PLHIV) in sub-Saharan Africa (SSA). We aimed to develop a priority research agenda to advance this effort. METHODS: Researchers, policymakers, and implementers from the United States and SSA conducted three scoping reviews on HIV/NCD prevention and care focused on clinical, health system, and community levels. Based on the review findings and expert inputs, we conducted iterative consensus-development activities to generate a prioritized research agenda. RESULTS: Population-level data on NCD prevalence among PLHIV in SSA are sparse. The review identified NCD screening and management approaches that could be integrated into HIV programs in SSA. However, few studies focused on the effectiveness, cost, and best practices for integrated chronic care platforms, making it difficult to derive policy recommendations. To address these gaps, we propose a prioritized research agenda focused on developing evidence-based service delivery models, increasing human capacity through workforce education, generating data through informatics platforms and research, managing the medication supply chain, developing new financing and sustainability models, advancing research-informed policy, and addressing other crosscutting health system issues. CONCLUSION: Based on collaborative, interdisciplinary efforts, a research agenda was developed to provide guidance that advances efforts to adapt the current health system to deliver integrated chronic care for PLHIV and the population at large.

Global health: the Fogarty International Center, National Institutes of Health: vision and mission, programs, and accomplishments.

The Fogarty International Center (FIC) of the US National Institutes of Health has supported long-term training and research for more than 3600 future leaders in science and public health from low-income and middle-income countries; tens of thousands more persons have received short-term training. More than 23 extramural training and research programs plus an intramural program are now operating. Newer FIC training programs are addressing chronic, noncommunicable diseases and strengthening the quality of medical schools and health care provider training. Most FIC trainees return to their countries of origin, where they mentor and train thousands of individuals in their home countries.

Roundtable. Strategies to discourage brain drain.

Building health research expertise in developing countries often requires personnel to receive training beyond national borders. For research funding agencies that sponsor this type of training, a major goal is to ensure that trainees return to their country of origin: attaining this objective requires the use of proactive strategies. The strategies described were developed under the extramural acquired immunodeficiency syndrome (AIDS) International Training and Research Program (AITRP) funded by the Fogarty International Center (FIC) at the National Institutes of Health, United States. This programme supports universities in the United States that provide research training to scientists from developing countries to enable them to address the global epidemic of human immunodeficiency virus (HIV)/AIDS and the related tuberculosis (TB) epidemic. This paper describes the strategies employed to discourage brain drain by the principle investigators (PIs) of five of the longest-funded AITRPs (funded for 15 years). Long-term trainees in these programmes spent from 11 to 96 months (an average of 26 months) studying. Using scientific, political and economic strategies that address brain drain issues, PIs working in AITRPs have attained an average rate of return home for their trainees of 80%.