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SUPPORT SERVICES FOR THE PREVENTION AND TREATMENT THROUGH A COMPREHENSIVE CARE CONTINUUM FOR HIV-AFFECTED ADOLESCENTS IN RESOURCE CONSTRAINED SETTINGS IMPLEMENTATION SCIENCE NETWORK
Support Services for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) requires support for logistical and operational coordination, website and communication management, analytic and data management, infrastructure for emerging research, regulatory, and monitoring of research activities for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program. The NICHD and partner NIH Institutes anticipate funding 8 PATC3H-IN UG1 awards in Asia and throughout sub-Saharan Africa in 2023 through a cooperative agreement mechanism for interventions of high public health significance: The prevention of new HIV infections among adolescents at risk, and the identification of, linkage to and retention in care of, and long-term viral suppression among youth living with HIV in low-to-middle income countries with high HIV burden. The PATC3H-IN network will expand and/or improve on successes achieved by its predecessor, PATC3H, to new geographic settings and/or risk populations and stimulate much needed implementation science (IS) research in the prevention of new HIV infections among adolescents at risk and the identification of, and linkage and retention to care of and long-term viral suppression among youth living with HIV in low-to-middle income countries (LMICs). PATC3H-IN will establish a network of investigators with multidisciplinary expertise on the youth-specific PHCC and in IS research, whose mission will be to evaluate promising prevention innovations contextually and developmentally tailored for HIV uninfected at-risk youth, and treatment and care interventions for youth living with HIV which have demonstrated efficacy and/or effectiveness in adolescent or adult populations and to translate them into public health practices. The structure of PATC3H-IN will consist of multiple interdependent functional components: (1) Five Clinical Research Centers (CRC) awarded through the UG1 grant mechanism; (2) one Implementation Science Coordinating Center (ISCC) to be awarded through a UM2 grant mechanism in 2024; and (3) a Scientific Leadership Committee (SLC). The CRCs will conduct clinical research and clinical trials, including implementation, effectiveness, and hybrid implementation-effectiveness studies at their 8-or more participating Clinical Research Performance Sites (CRPS). The ISCC will establish infrastructure to support research education and capacity building across PATC3H-IN, as well as infrastructure for stakeholder engagement in and dissemination of findings from PATC3H-IN and advanced statistical modeling support across PATC3H-IN. The ISCC will also provide infrastructure for conducting foundational research to support the work of clinical sites, including possible modeling studies and translation projects, as well as national surveys, and/or systematic collection and analysis of relevant policies and laws. Lastly, the SLC will be responsible for PATC3H-IN governance, oversight, and coordination, and will develop and implement the network research agenda, convening working groups as needed, prioritizing emerging research projects, efficiently managing the development of clinical protocols, implementing and completing clinical trials, and ensuring timely publication and communication of results.
Uncovering genetic determinants of carbapenem resistance in Klebsiella pneumoniae
Carbapenem-resistant Klebsiella pneumoniae represents an urgent global health threat due to its increasing prevalence and high mortality rates, necessitating a comprehensive understanding of its resistance mechanisms. While key resistance mechanisms and their genetic determinants are known, such as beta- lactamases and porin mutations, the cause of resistance in many strains remains elusive. Moreover, other strains that carry known genetic carbapenem-resistance factors have been found to still be susceptible to carbapenems for unclear reasons. Further, strains can carry genetic elements which, while not conferring resistance directly, can promote resistance indirectly by accelerating its acquisition, such as through mutations in DNA repair systems or mobile genetic elements. To address these knowledge gaps, we propose a genome-wide association study (GWAS), with the aim of maximizing the discovery of gene variants associated with meropenem resistance, with experimental validation of candidates to identify true causal variants. We will overcome limitations of prior studies in the following ways: 1) We have compiled an expanded data set of publicly available K. pneumoniae genomes from strains isolated across a wide distribution of countries, with in hand access to >100 isolates upon which experimental validation studies will be performed. 2) We will perform comprehensive capture of genetic variants by employing a reference-free GWAS, utilizing unitigs, stretches of DNA sequence that represent the entire spectrum of genetic variation. 3) We will enhance statistical power to detect genetic variants with even subtle effects on resistance by using a quantitative, continuous minimum inhibitory concentration (MIC) phenotype to meropenem rather than a binary designation of resistant or susceptible. 4) We will reduce the number of false positives arising from correlation, or linkage disequilibrium (LD), with known carbapenemase and other known resistance factors by performing a conditional GWAS, where known factors are included as covariates. 5) We will further mitigate confounding effects due to population structure and LD, which cause non-random relationships between variants, by utilizing a pangenome-wide regression with an elastic net penalty. 6) Crucially, we will functionally validate our findings, which will include genetic variants associated with increased resistance, whether through direct or indirect mechanisms, as well as those that may restore susceptibility in strains already possessing known resistance factors. We will bridge the gap between GWAS findings and functional validation by leveraging our high-throughput experimental capabilities. This integrated approach promises to uncover novel mechanisms of carbapenem resistance, its acquisition, and susceptibility in K. pneumoniae, with the potential to inform the development of future diagnostics or therapeutic strategies.
Epilepsy Genetics – From Family Studies to Polygenic Risk Scores
Whilst epilepsy may be a consequence of an acquired insult including trauma, stroke, and brain tumours, the genetic component to epilepsies has been greatly under-estimated. Considerable progress has recently occurred in the understanding of epilepsy genetics, both at a clinical genetic level and in the basic science of epilepsies. The clinical evidence for genetic components will be first briefly discussed including data from population studies, twin analyses and multiplex family studies. Initial molecular discoveries occurred via classical methods of linkage and gene identification. Recent large-scale hypothesis-free whole exome studies searching for rare variants and genome-wide association studies detecting common variants have been very rewarding. These discoveries have now impacted on clinical practice, especially in severe childhood epilepsies but increasingly so in adult patients. The “genetic background” of patients has long been posited as part of the reason that some patients have epilepsy, or perhaps why some have more severe epilepsy. This has been unmeasurable but now, with the development of polygenic risk scores, the “background” is now in the research foreground. The current and future impact of polygenic risk scores will be explored.
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