HCV-Positive Allograft Use in Heart Transplantation Is Associated With Increased Access to Overdose Donors and Reduced Waitlist Mortality Without Compromising Outcomes.

BACKGROUND: Because of ongoing shortages of donors for heart transplantation, the use of donor candidates whose availabilities are the result of drug overdoses (ODs) has become increasingly prevalent, even though these donors carry a high preponderance of the now curable hepatitis C virus (HCV). This study investigated temporal trends and regional variabilities in HVC-positive (HCV+) allograft use in heart transplantation and assessed the relationship between the use of HCV+ graft donors and the use of OD donors as well as assessing waitlist and post-transplant outcomes. METHODS AND RESULTS: A retrospective review of the United Network for Organ Sharing database assessed adults listed for heart transplantation. Patients were stratified both temporally into pre-HCV and HCV eras related to HCV+ graft use trends and regionally by degree of HCV+ allograft use. Regions of high HCV+ donor use were associated with an increase in OD donor access by 7.8% across eras compared to 0.4% in low HCV+ donor-use regions. One-year waitlist mortality decreased from 4.7% to 2.5% across eras in high HCV+ donor-use regions (P= 0.001) and remained roughly the same as before in low HCV+ donor-use regions (3.0% vs 2.4%; P= 0.244.). Post-transplant survival at 1 year remained similar across eras. CONCLUSIONS: HCV+ donor allograft use can help to optimize donor use, decreasing waitlist mortality without compromising early survival. Ongoing assessment is essential to ensure long-term safety and efficacy of using HCV+ donors.

Experiences, Lessons, and Challenges With Adapting REDCap for COVID-19 Laboratory Data Management in a Resource-Limited Country: Descriptive Study.

BACKGROUND: The COVID-19 pandemic brought challenges requiring timely health data sharing to inform accurate decision-making at national levels. In Botswana, we adapted and integrated the Research Electronic Data Capture (REDCap) and the District Health Information System version 2 (DHIS2) platforms to support timely collection and reporting of COVID-19 cases. We focused on establishing an effective COVID-19 data flow at the national public health laboratory, being guided by the needs of health care professionals at the National Health Laboratory (NHL). This integration contributed to automated centralized reporting of COVID-19 results at the Ministry of Health (MOH). OBJECTIVE: This paper reports the experiences, challenges, and lessons learned while designing, adapting, and implementing the REDCap and DHIS2 platforms to support COVID-19 data management at the NHL in Botswana. METHODS: A participatory design approach was adopted to guide the design, customization, and implementation of the REDCap platform in support of COVID-19 data management at the NHL. Study participants included 29 NHL and 4 MOH personnel, and the study was conducted from March 2, 2020, to June 30, 2020. Participants' requirements for an ideal COVID-19 data management system were established. NVivo 11 software supported thematic analysis of the challenges and resolutions identified during this study. These were categorized according to the 4 themes of infrastructure, capacity development, platform constraints, and interoperability. RESULTS: Overall, REDCap supported the majority of perceived technical and nontechnical requirements for an ideal COVID-19 data management system at the NHL. Although some implementation challenges were identified, each had mitigation strategies such as procurement of mobile Internet routers, engagement of senior management to resolve conflicting policies, continuous REDCap training, and the development of a third-party web application to enhance REDCap's capabilities. Lessons learned informed next steps and further refinement of the REDCap platform. CONCLUSIONS: Implementation of REDCap at the NHL to streamline COVID-19 data collection and integration with the DHIS2 platform was feasible despite the urgency of implementation during the pandemic. By implementing the REDCap platform at the NHL, we demonstrated the possibility of achieving a centralized reporting system of COVID-19 cases, hence enabling timely and informed decision-making at a national level. Challenges faced presented lessons learned to inform sustainable implementation of digital health innovations in Botswana and similar resource-limited countries.

Programmable siRNA pro-drugs that activate RNAi activity in response to specific cellular RNA biomarkers.

Since Paul Ehrlich's introduction of the "magic bullet" concept in 1908, drug developers have been seeking new ways to target drug activity to diseased cells while limiting effects on normal tissues. In recent years, it has been proposed that coupling riboswitches capable of detecting RNA biomarkers to small interfering RNAs (siRNAs) to create siRNA pro-drugs could selectively activate RNA interference (RNAi) activity in specific cells. However, this concept has not been achieved previously. We report here that we have accomplished this goal, validating a simple and programmable new design that functions reliably in mammalian cells. We show that these conditionally activated siRNAs (Cond-siRNAs) can switch RNAi activity against different targets between clearly distinguished OFF and ON states in response to different cellular RNA biomarkers. Notably, in a rat cardiomyocyte cell line (H9C2), one version of our construct demonstrated biologically meaningful inhibition of a heart-disease-related target gene protein phosphatase 3 catalytic subunit alpha (PPP3CA) in response to increased expression of the pathological marker atrial natriuretic peptide (NPPA) messenger RNA (mRNA). Our results demonstrate the ability of synthetic riboswitches to regulate gene expression in mammalian cells, opening a new path for development of programmable siRNA pro-drugs.

Superoxide Dismutase-Loaded Nanoparticles Attenuate Myocardial Ischemia-Reperfusion Injury and Protect Against Chronic Adverse Ventricular Remodeling.

Early revascularization is critical to reduce morbidity after myocardial infarction, although reperfusion incites additional oxidative injury. Superoxide dismutase (SOD) is an antioxidant that scavenges reactive oxygen species (ROS) but has low endogenous expression and rapid myocardial washout when administered exogenously. This study utilizes a novel nanoparticle carrier to improve exogeneous SOD retention while preserving enzyme function. Its role is assessed in preserving cardiac function after myocardial ischemia-reperfusion (I/R) injury. Here, nanoparticle-encapsulated SOD (NP-SOD) exhibits similar enzyme activity as free SOD, measured by ferricytochrome-c assay. In an in vitro I/R model, free and NP-SOD reduce active ROS, preserve mitochondrial integrity and improve cell viability compared to controls. In a rat in vivo I/R injury model, NP-encapsulation of fluorescent-tagged SOD improves intramyocardial retention after direct injection. Intramyocardial NP-SOD administration in vivo improves left ventricular contractility at 3-hours post-reperfusion by echocardiography and 4-weeks by echocardiography and invasive pressure-volume catheter analysis. These findings suggest that NP-SOD mitigates ROS damage in cardiac I/R injury in vitro and maximizes retention in vivo. NP-SOD further attenuates acute injury and protects against myocyte loss and chronic adverse ventricular remodeling, demonstrating potential for translating NP-SOD as a therapy to mitigate myocardial I/R injury.