David M. Vock’s research while affiliated with University of Minnesota and other places

Background Low blood absolute lymphocyte count (ALC) may predict severe COVID-19 outcomes. Knowledge gaps remain regarding the relationship of ALC trajectory with clinical outcomes and factors associated with lymphopenia. Methods Our post hoc analysis of the Therapeutics for Inpatients with COVID-19 platform trial utilized proportional hazards models to assess relationships between Day (D) 0 lymphopenia (ALC < 0.9 cells/uL), D0 severe lymphopenia (ALC < 0.5 cells/uL) or lymphopenia trajectory between D0 and D5 with mortality and secondary infections, and with sustained recovery using Fine-Gray models. Logistic regression was used to assess relationships between clinical variables and D0 lymphopenia or lymphopenia trajectory. Results D0 lymphopenia (1426/2579) and severe lymphopenia (636/2579) were associated with increased mortality (aHR 1.48; 1.08, 2.05, p = 0.016 and aHR 1.60; 1.20, 2.14, p = 0.001) and decreased recovery (aRRR 0.90; 0.82, 0.99, p = 0.033 and aRRR 0.78; 0.70, 0.87, p < 0.001 respectively). Trial participants with persistent D5 lymphopenia had increased mortality, and increased secondary infections, and participants with persistent or new lymphopenia had impaired recovery, as compared to participants with no lymphopenia. Persistent and new lymphopenia were associated with older age, male sex; prior immunosuppression, heart failure, aspirin use, and normal body mass index; biomarkers of organ damage (renal and lung), and ineffective immune response (elevated IL-6 and viral nucleocapsid antigen levels). Similar results were observed with severe lymphopenia. Conclusions Lymphopenia was predictive of severe COVID-19 outcomes, particularly when persistent or new during hospitalization. A better understanding of the underlying risk factors for lymphopenia will help illuminate disease pathogenesis and guide management strategies.

Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) was initiated by the US government to rapidly develop and test vaccines and therapeutics against COVID-19 in 2020. The ACTIV Therapeutics-Clinical Working Group selected ACTIV trial teams and clinical networks to expeditiously develop and launch master protocols based on therapeutic targets and patient populations. The suite of clinical trials was designed to collectively inform therapeutic care for COVID-19 outpatient, inpatient, and intensive care populations globally. In this report, we highlight challenges, strategies, and solutions around clinical protocol development and regulatory approval to document our experience and propose plans for future similar healthcare emergencies.

Randomized trials seek efficient treatment effect estimation within target populations, yet scientific interest often also centers on subpopulations. Although there are typically too few subjects within each subpopulation to efficiently estimate these subpopulation treatment effects, one can gain precision by borrowing strength across subpopulations, as is the case in a basket trial. While dynamic borrowing has been proposed as an efficient approach to estimating subpopulation treatment effects on primary endpoints, additional efficiency could be gained by leveraging the information found in secondary endpoints. We propose a multisource exchangeability model (MEM) that incorporates secondary endpoints to more efficiently assess subpopulation exchangeability. Across simulation studies, our proposed model almost uniformly reduces the mean squared error when compared to the standard MEM that only considers data from the primary endpoint by gaining efficiency when subpopulations respond similarly to the treatment and reducing the magnitude of bias when the subpopulations are heterogeneous. We illustrate our model’s feasibility using data from a recently completed trial of very low nicotine content cigarettes to estimate the effect on abstinence from smoking within three priority subpopulations. Our proposed model led to increases in the effective sample size two to four times greater than under the standard MEM.

Background Extrapulmonary complications (EPCs) are common in patients hospitalized for COVID-19, but data on their clinical consequences and association with viral replication and systemic viral dissemination is lacking. Methods Patients hospitalized for COVID-19 and enrolled in the TICO (Therapeutics for Inpatients with COVID-19) platform trial at 114 international sites between August 2020 and November 2021 were included in a prospective cohort study. We categorized EPCs into 39 event types within 9 categories and estimated their frequency through day 28 and their association with clinical outcomes through day 90. We analyzed the association between baseline viral burden (plasma nucleocapsid antigen [N-Ag] and upper airway viral load [VL]) and EPCs, adjusting for other baseline factors. Results 2,625 trial participants were included in the study. The median age was 57 years (IQR 46-68), 57.7% were male, and 537 (20.5%) had at least one EPC. EPCs were associated with higher day-90 all-cause mortality (HR 9.6, 95% CI 7.3, 12.7) after adjustment for other risk factors. The risk of EPCs increased with increasing baseline plasma N-Ag (HR 1.21 per log10 ng/L increase, 95% CI 1.09, 1.34), and upper airway VL (HR 1.12 per log10 copies/mL increase, 95% CI 1.04, 1.19), after adjusting for comorbidities, disease severity, inflammatory markers, and other baseline factors. Trial treatment allocation had no effect on EPC risk. Conclusions Systemic viral dissemination as evidenced by high plasma N-Ag and high respiratory viral burden are associated with development of EPCs in COVID-19, which in turn are associated with higher 90-day mortality.

Background Venous thromboembolism (VTE) is a preventable medical condition which has substantial impact on patient morbidity, mortality, and disability. Unfortunately, adherence to the published best practices for VTE prevention, based on patient centered outcomes research (PCOR), is highly variable across U.S. hospitals, which represents a gap between current evidence and clinical practice leading to adverse patient outcomes. This gap is especially large in the case of traumatic brain injury (TBI), where reluctance to initiate VTE prevention due to concerns for potentially increasing the rates of intracranial bleeding drives poor rates of VTE prophylaxis. This is despite research which has shown early initiation of VTE prophylaxis to be safe in TBI without increased risk of delayed neurosurgical intervention or death. Clinical decision support (CDS) is an indispensable solution to close this practice gap; however, design and implementation barriers hinder CDS adoption and successful scaling across health systems. Clinical practice guidelines (CPGs) informed by PCOR evidence can be deployed using CDS systems to improve the evidence to practice gap. In the Scaling AcceptabLE cDs (SCALED) study, we will implement a VTE prevention CPG within an interoperable CDS system and evaluate both CPG effectiveness (improved clinical outcomes) and CDS implementation. Methods The SCALED trial is a hybrid type 2 randomized stepped wedge effectiveness-implementation trial to scale the CDS across 4 heterogeneous healthcare systems. Trial outcomes will be assessed using the RE²-AIM planning and evaluation framework. Efforts will be made to ensure implementation consistency. Nonetheless, it is expected that CDS adoption will vary across each site. To assess these differences, we will evaluate implementation processes across trial sites using the Exploration, Preparation, Implementation, and Sustainment (EPIS) implementation framework (a determinant framework) using mixed-methods. Finally, it is critical that PCOR CPGs are maintained as evidence evolves. To date, an accepted process for evidence maintenance does not exist. We will pilot a “Living Guideline” process model for the VTE prevention CDS system. Discussion The stepped wedge hybrid type 2 trial will provide evidence regarding the effectiveness of CDS based on the Berne-Norwood criteria for VTE prevention in patients with TBI. Additionally, it will provide evidence regarding a successful strategy to scale interoperable CDS systems across U.S. healthcare systems, advancing both the fields of implementation science and health informatics. Trial registration Clinicaltrials.gov – NCT05628207. Prospectively registered 11/28/2022, https://classic.clinicaltrials.gov/ct2/show/NCT05628207.