Project description:The advent of recombinant DNA technology, development of infectious cDNA clones of RNA viruses, and reverse genetic technologies have revolutionized how viruses are studied. Genetic manipulation of full-length cDNA clones has become an especially important and widely used tool to study the biology, pathogenesis, and virulence determinants of both positive and negative stranded RNA viruses. The first full-length infectious cDNA clone of equine arteritis virus (EAV) was developed in 1996 and was also the first full-length infectious cDNA clone constructed from a member of the order Nidovirales. This clone was extensively used to characterize the molecular biology of EAV and other Nidoviruses. The objective of this review is to summarize the characterization of the virulence (or attenuation) phenotype of the recombinant viruses derived from several infectious cDNA clones of EAV in horses, as well as their application for characterization of the molecular basis of viral neutralization, persistence, and cellular tropism.
Project description:Insulin bolus calculators have proven effective in improving glycemia and patient safety. Insulin calculators are increasingly being implemented for inpatient hospital care. Multidisciplinary teams are often involved in the design and review of the efficacy and utilization for these calculators. At times, unintended consequences and benefits of utilization are found on review. Integration of our insulin calculator into our electronic health record system was a multidisciplinary effort. During implementation, several obstacles to effective care were identified and are discussed in the following manuscript. We describe the barriers to utilization and potential pitfalls in clinical integration. We further describe benefits in patient education, time of insulin administration versus meal delivery, variations in insulin bolus for ketone correction, variation in care, and maximum bolus administration. Sharing lessons learned from experiences using electronic insulin calculator order sets will further our goals of improved patient care in the hospital setting.
Project description:CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1 and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard of care agent, axitinib. RNAseq analysis was utilized to evaluate the expression profile produced by the targeted loss of Vhl, Pbrm1, Keap1 and Tsc1 in these mouse tumors. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2-independent.
Project description:Objective Evaluate the process and outcomes associated with pivoting Cooking Matters curriculum to online nutrition education during the COVID-19 pandemic. Use of Theory or Research Cooking Matters uses evidence-based curricula built upon the Social Cognitive Theory, with a focus on increasing self-efficacy through participatory food skills education to enable positive behavior change. Target Audience Low-income adults, parents and caregivers, and families receiving services or programming from schools and community-based organizations across the United States from June 2020 until June 2021. Program Description Cooking Matters curriculum was pivoted to an online nutrition education setting at the onset of the COVID-19 pandemic to teach participants how to shop for and prepare healthy meals on a limited budget. Evaluation Methods With support from IMPAQ International, LLC (a third-party evaluator), Cooking Matters online delivered programming was evaluated through 9,187 participant surveys completed post-participation and through virtual/Zoom in-depth interviews with 24 individuals from 13 partner organizations implementing the curricula. Results Participants reported high confidence to apply food skills such as making mealtimes positive and high intention to use food skills in the future such as money-saving tips. Over 90% of participants were satisfied with the instructor and class environment. Partners described that online programming accommodated more participants due to lack of physical space limitations, was convenient for participants because it decreased travel time, allowed for food preparation in participants' kitchens, was more burdensome for staff, decreased curriculum engagement at times, and did not foster the same communal ties as in-person. Conclusions Online delivery allowed Cooking Matters to continue offering programming during the pandemic. To ensure responsiveness to participant and partner needs, we centered the voice of our end users, developed nutrition education reflective of these unique needs and desires, and released our new online approach focusing on digital delivery. Based on this evaluation, Cooking Matters will continue supporting partners in delivering virtual programming as an additional means of reaching busy parents and caregivers. Funding None
Project description:Given the severity and suicide risk of patients typically treated by Dialectical Behavior Therapy (DBT) and the absence of guidelines regarding delivery of DBT via telehealth, it is crucial that the DBT treatment community gather and rapidly disseminate information about effective strategies for delivering DBT via telehealth. The current study surveyed DBT providers (N = 200) to understand challenges and lessons learned as they transitioned to conducting DBT via telehealth during the COVID-19 pandemic. Open-ended responses to challenges and lessons-learned were coded. Most frequently noted challenges were Therapy-Interfering Behaviors and elements related to the provision of Individual Therapy and Skills Training Group. The majority of providers offered advice for implementing group skills training, avoiding or overcoming therapist burnout, and emphasized continued adherence to treatment principles, even in the context of this new treatment modality. Overall, this qualitative study marks a starting point on identifying best practices delivering DBT via telehealth for which it is anticipated that clinical recommendations in this area will evolve, informed by clinician, researcher, and consumer input.
Project description:PurposeTo increase access of underserved/health disparities communities to National Cancer Institute (NCI) clinical trials, the Radiation Research Program piloted a unique model - the Cancer Disparities Research Partnership (CDRP) program. CDRP targeted community hospitals with a limited past NCI funding history and provided funding to establish the infrastructure for their clinical research program.MethodsInitially, 5-year planning phase funding was awarded to six CDRP institutions through a cooperative agreement (U56). Five were subsequently eligible to compete for 5-year implementation phase (U54) funding and three received a second award. Additionally, the NCI Center to Reduce Cancer Health Disparities supported their U56 patient navigation programs.ResultsCommunity-based hospitals with little or no clinical trials experience required at least a year to develop the infrastructure and establish community outreach/education and patient navigation programs before accrual to clinical trials could begin. Once established, CDRP sites increased their yearly patient accrual mainly to NCI-sponsored cooperative group trials (~60%) and Principal Investigator/mentor-initiated trials (~30%). The total number of patients accrued on all types of trials was 2,371, while 5,147 patients received navigation services.ConclusionDespite a historical gap in participation in clinical cancer research, underserved communities are willing/eager to participate. Since a limited number of cooperative group trials address locally advanced diseases seen in health disparities populations; this shortcoming needs to be rectified. Sustainability for these programs remains a challenge. Addressing these gaps through research and public health mechanisms may have an important impact on their health, scientific progress, and efforts to increase diversity in NCI clinical trials.
Project description:Ten years after completion of the Human Genome Project, progress towards making "personalized medicine" a reality has been slower than expected. The reason is twofold. Firstly, the science is more difficult than expected. Secondly, limited progress has been made in aligning economic incentives to invest in diagnostics. This paper develops nine case studies of "success" where diagnostic tests are bringing personalized medicine into clinical practice with health and economic impact for patients, healthcare systems, and manufacturers. We focus on the availability of evidence for clinical utility, which is important not only for clinicians but also for payers and budget holders. We find that demonstrating diagnostic clinical utility and the development of economic evidence is currently feasible (i) through drug-diagnostic co-development, and (ii) when the research is sponsored by payers and public bodies. It is less clear whether the diagnostic industry can routinely undertake the work necessary to provide evidence as to the clinical utility and economic value of its products. It would be good public policy to increase the economic incentives to produce evidence of clinical utility: otherwise, opportunities to generate value from personalized medicine-in terms of both cost savings and health gains-may be lost.
Project description:BackgroundWhile liver transplantation (LT) with neoadjuvant chemoradiation is increasingly utilized for the management of unresectable cholangiocarcinoma (CCA), data on post-LT survival are limited.MethodsWe identified 844 patients who underwent LT (2002-2019) for nonincidental (CCA listing) or incidental (CCA on explant, not at listing) CCA in the Scientific Registry of Transplant Recipients. Kaplan-Meier and multivariable proportional hazards regression methods evaluated the effects of patient characteristics, donor type, transplant era (before/after 2010), and center volume (center-level CCALTs/active year) on the risk of graft failure and patient mortality.ResultsOne center performed >12 CCALTs/y, and the rest performed ≤4. Five-year graft survival was 50.6%. Multivariable models demonstrated laboratory model of end-stage liver disease ≥40 versus <15 and center volumes of 1, >1 to ≤2, and >2 to ≤4 CCALTs/y compared to >12 were associated with increased risk of graft failure and mortality (all P ≤ 0.002). Extra vessel use was associated with center volume. Among all recipients, extra vessel use occurred in 55.4% of CCALTs performed at the highest volume center and in 14.0% of cases at centers having ≤4 CCAs/y (P < 0.05).ConclusionsCenter volume-related differences in outcomes and extra vessel use highlight the importance of establishing a unified, effective treatment protocol and the potential utility of regionalization of LT for CCA.
Project description:BackgroundHealth economists have shown a growing interest in deliberation and multi-criteria decision analysis (MCDA) as possible pathways to transparently integrate value judgments in cost-utility analyses. In line with these developments, this study piloted a consensus process to derive a German value set for the Short-Form Six-Dimension (SF-6D). In a conference setting, a group was tasked to deliberate on scores and weights for the SF-6D from the perspective of a self-determined and independent life.MethodsThe one-day consensus conference was based on a deliberative process in combination with the MCDA method MACBETH (Measuring Attractiveness by a Categorical Based Evaluation Technique). According to MACBETH, participants were asked to qualitatively rate pairwise comparisons of SF-6D health states. The scoring within each dimension was conducted in parallel group sessions. Final agreement on the scores as well as weights for the SF-6D dimensions were derived in a subsequent plenary assembly. Results were analyzed using the software M-MACBETH and qualitative content analysis.ResultsA total of 34 participants were recruited. While each of the 6 small groups presented a consented score, the plenary assembly reached consensus on all dimensions apart from pain. Concerning dimension weights, some participants favored prioritizing pain and mental health. Others disputed that trade-offs between dimensions and thus assigning weights were not acceptable in a context where this may involve withholding care from someone. As a consequence, no consensus on a value set was reached. Participants identified the group size of the plenary session and the applied weighting procedure as main obstacles to the process.ConclusionsThis pilot study presents a consensus-based approach for valuing health-related quality of life. However, further research is needed on deliberative processes that yield quantifiable results. Future conferences should explore smaller group sizes, longer durations of the deliberative process and alternatives to the additive value function applied in MACBETH.
Project description:Aortic stenosis has traditionally been addressed with surgical aortic valve replacement (AVR). In recent years, several technologies have emerged as alternative treatment methods for aortic valve disease. Among them, the Perceval (LivaNova, London, UK) is a sutureless valve that has been used in clinical practice for over 10 years. It has been implanted in over 20,000 patients worldwide. With nearly 600 Perceval implants since 2011, the Montreal Heart Institute has developed a worldwide expertise with this technology. In this article, we provide an overview of the clinical data currently available in the literature and discuss the lessons we have learned from our experience with the Perceval prosthesis.