Browsing by Author "Kadakia, Kushal"

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Open Access
Lost (and Found) in Translation: Applying the Accountable Care Framework to Support the Diffusion of Health Innovations
(2018-12) Kadakia, Kushal
Rising health expenditures and growing disease burden have generated new impetus for value-based health reforms across the world. However, fragmented evidence for implementation science in health policy limits the design and diffusion of health innovations to fill common gaps in care delivery. This paper explores how the accountable care framework can be used as a model for adapting international health innovations to improve outcomes and reduce costs for high-need, high-cost populations in the United States. A national advisory board of health policy experts and leaders was convened to identify the primary challenges faced by systems today. These criteria were used to develop a standardized survey for reviewing the global landscape of health innovations that increase access, improve outcomes, and reduce cost, resulting in a curated database of 175 international delivery and payment innovations. Innovations were analyzed using the accountable care framework for trends in performance, methodology, and diffusion experience. These insights were then synthesized into a model for translating innovations across health systems. To validate the model, three partner institutions – CareSouth Carolina, the University of Arkansas for Medical Sciences, and the Henry Ford Health System – were selected as use cases in the United States. Value-based readiness assessments were administered to the senior leadership teams of each health system, who then participated in an iterative six-month process to co-design an integrated solution set using the adaptation model, with feedback from health systems confirming the model’s applicability to support the diffusion of innovations to the health policy context of the United States. The results of this work offer a new paradigm for health innovation and identify practical opportunities for policymakers and practitioners to support care transformation in America.
Open Access
Metabolic Modulators of Soft Tissue Sarcomas
(2019-04-22) Kadakia, Kushal
This investigation characterizes the metabolic dependencies of soft tissue sarcomas and evaluates potential therapeutic implications for radiation therapy. Mice were genetically engineered to utilize the Cre/LoxP system, with Cre fused to the estrogen receptor and expressed from the Pax7 promoter in muscle satellite cells. Intramuscular delivery of 4-hydroxytamoxifen to the gastrocnemius muscle enabled Cre to translocate to the nucleus to delete the Trp53 tumor suppressor and activate oncogenic Nras to generate sarcomas. Infusions with 13C-labeled nutrients in tumor-bearing mice revealed glutamine and glucose to be the primary substrates for the Tricarboxylic Acid Cycle in sarcomas. However, metabolomic analysis post-radiation treatment indicated that radiation response in sarcomas was characterized by a shift away from glucose consumption and towards glutamine metabolism. Inhibition of glutamine catabolism in sarcoma cell lines via nutrient restriction, pharmacological blockade, and genetic deletion impaired tumor proliferation. Clonogenic assays demonstrated that glutamine restriction also reduced in vitro survival following radiation exposure. To validate these phenotypes in vivo, the Cre/LoxP system was used to generate mice with sarcomas deficient in glutaminase (Gls), the enzyme governing the rate-limiting reaction for glutamine catabolism. Cohorts of tumor-bearing irradiated and untreated mice were then followed to evaluate the effect of Gls deletion on survival. Collectively, the results from this study demonstrate that (1) glutamine is critical for sarcoma cell growth in vitro and in vivo and (2) inhibition of Gls has the potential to enhance the radiosensitivity of sarcomas.