The Emergence of Population Health in US Academic Medicine

Importance In response to rapidly growing interest in population health, academic medical centers are launching department-level initiatives that focus on this evolving discipline. This trend, with its potential to extend the scope of academic medicine, has not been well characterized. Objective To describe the emergence of departments of population health at academic medical centers in the United States, including shared areas of focus, opportunities, and challenges. Design, Setting, and Participants This qualitative study was based on a structured in-person convening of a working group of chairs of population health–oriented departments on November 13 and 14, 2017, complemented by a survey of core characteristics of these and additional departments identified through web-based review of US academic medical centers. United States medical school departments with the word population in their name were included. Centers, institutes, and schools were not included. Main Outcomes and Measures Departments were characterized by year of origin, areas of focus, organizational structure, faculty size, teaching programs, and service engagement. Opportunities and challenges faced by these emerging departments were grouped thematically and described. Results Eight of 9 population health–oriented departments in the working group were launched in the last 6 years. The 9 departments had 5 to 97 full-time faculty. Despite varied organizational structures, all addressed essential areas of focus spanning the missions of research, education, and service. Departments varied significantly in their relationships with the delivery of clinical care, but all engaged in practice-based and/or community collaboration. Common attributes include core attention to population health–oriented research methods across disciplines, emphasis on applied research in frontline settings, strong commitment to partnership, interest in engaging other sectors, and focus on improving health equity. Tensions included defining boundaries with other academic units with overlapping areas of focus, identifying sources of sustainable extramural funding, and facilitating the interface between research and health system operations. Conclusions and Relevance Departments addressing population health are emerging rapidly in academic medical centers. In supporting this new framing, academic medicine affirms and strengthens its commitment to advancing population health and health equity, to improving the quality and effectiveness of care, and to upholding the social mission of medicine

Posttransplant survival is not diminished in heart transplant recipients bridged with implantable left ventricular assist devices

BackgroundThe purpose of this study was to compare posttransplantation morbidity and mortality in orthotopic heart transplant recipients bridged to transplant with a left ventricular assist device with nonbridged recipients. To account for potential differences across device types, we stratified bridge-to-transplant recipients by type of ventricular assist device: extracorporeal (EXTRA), paracorporeal (PARA), and intracorporeal (INTRA).MethodsThe United Network for Organ Sharing provided de-identified patient-level data. The study population included 10,668 orthotopic heart transplant recipients aged 18 years old or older and undergoing transplantation between January 1, 2001, and December 31, 2006. Follow-up data were provided through August 3, 2008, with a mean follow-up time of 3.17 ± 2.15 years (range, 0–8.11 years). The primary outcome was actuarial posttransplant graft survival. Other outcomes of interest included infection, stroke, and dialysis during the transplant hospitalization; primary graft failure at 30 days; transplant hospitalization length of stay; and long-term complications including diabetes mellitus, transplant coronary artery disease, and chronic dialysis. Multivariable Cox proportional hazards regression (backward, P < .15) was used to determine the relationship between groups and overall graft survival, and multivariable logistic regression analysis (backward, P < .15) was used to determine the relationship between groups and secondary outcome measures.ResultsIn multivariable Cox regression analysis, when compared with the nonbridged group, risk-adjusted greater than 90-day graft survival was diminished among the EXTRA group (hazard ratio = 3.54, 2.28–5.51, P < .001), but not the INTRA group (1.04, 0.719–1.51, P = .834) or the PARA group (1.06, 0.642–1.76, P = .809). There were no significant differences in risk-adjusted graft survival across the 4 groups during the 90-days to 1-year or 1- to 5-year intervals. However, at more than 5 years, risk-adjusted graft survival in the INTRA group (0.389, 0.205–0.738, P = .004) was better than in the nonbridged group. The EXTRA, PARA, and INTRA groups all experienced increased risks of infection. The EXTRA group had increased risks of dialysis, stroke, and primary graft failure at 30 days, whereas neither the PARA nor the INTRA group differed from the nonbridged group. Long-term complications did not differ by group.ConclusionThe use of implantable left ventricular assist devices as bridges to transplantation, including both intracorporeal and paracorporeal devices, is not associated with diminished posttransplant survival. However, 90-day survival was diminished in recipients bridged with extracorporeal devices

Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3)

BACKGROUND/AIMS: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. METHODS: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19. RESULTS: As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites. CONCLUSION: Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak

A triple helix model of medical innovation: supply, demand, and technological capabilities in terms of medical subject headings

We develop a model of innovation that enables us to trace the interplay among three key dimensions of the innovation process: (i) demand of and (ii) supply for innovation, and (iii) technological capabilities available to generate innovation in the forms of products, processes, and services. Building on triple helix research, we use entropy statistics to elaborate an indicator of mutual information among these dimensions that can provide indication of reduction of uncertainty. To do so, we focus on the medical context, where uncertainty poses significant challenges to the governance of innovation. We use the Medical Subject Headings (MeSH) of MEDLINE/PubMed to identify publications classified within the categories “Diseases" (C), "Drugs and Chemicals" (D), "Analytic, Diagnostic, and Therapeutic Techniques and Equipment" (E) and use these as knowledge representations of demand, supply, and technological capabilities, respectively. Three case-studies of medical research areas are used as representative 'entry perspectives' of the medical innovation process. These are: (i) human papilloma virus, (ii) RNA interference, and (iii) magnetic resonance imaging. We find statistically significant periods of synergy among demand, supply, and technological capabilities (C-D-E) that point to three-dimensional interactions as a fundamental perspective for the understanding and governance of the uncertainty associated with medical innovation. Among the pairwise configurations in these contexts, the demand-technological capabilities (C-E) provided the strongest link, followed by the supply-demand (D-C) and the supply-technological capabilities (D-E) channels

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. FUNDING: US National Institutes of Health and Operation Warp Speed

Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

Background: Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care. Methods: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg–cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab–cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing. Findings: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab–cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab–cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97–1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97–1·34]; p=0·13). Mortality was lower in the tixagevimab–cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50–0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab–cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68–1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab–cilgavimab group and 38 (5%) in the placebo group. Interpretation: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower. Funding: US National Institutes of Health (NIH) and Operation Warp Speed