Faculty Bibliography

SARS-CoV-2 poses a public health threat for which therapeutic agents are urgently needed. Herein, we report that high-throughput microfluidic screening of antigen-specific B-cells led to the identification of LY-CoV555, a potent anti-spike neutralizing antibody from a convalescent COVID-19 patient. Biochemical, structural, and functional characterization revealed high-affinity binding to the receptor-binding domain, ACE2 binding inhibition, and potent neutralizing activity. In a rhesus macaque challenge model, prophylaxis doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract. These data demonstrate that high-throughput screening can lead to the identification of a potent antiviral antibody that protects against SARS-CoV-2 infection.

Changing physician behaviors is difficult. Electronic health record (EHR) clinical decision support (CDS) offers an opportunity to promote guideline adherence. Behavioral economics (BE) has shown success as an approach to supporting evidence-based decision-making with little additional cognitive burden. We applied a user-centered approach to incorporate BE "nudges" into a CDS module in two "vanguard" sites utilizing: (1) semi-structured interviews with key informants (n = 8); (2) a design thinking workshop; and (3) semi-structured group interviews with clinicians. In the 133 day development phase at two clinics, the navigator section fired 299 times for 27 unique clinicians. The inbasket refill alert fired 124 times for 22 clinicians. Fifteen prescriptions for metformin were written by 11 clinicians. Our user-centered approach yielded a BE-driven CDS module with relatively high utilization by clinicians. Next steps include the addition of two modules and continued tracking of utilization, and assessment of clinical impact of the module.

BACKGROUND:In theory, efficient design of randomized controlled trials (RCTs) involves randomization algorithms that control baseline variable imbalance efficiently, and corresponding analysis involves pre-specified adjustment for baseline covariates. This review sought to explore techniques for handling potentially influential baseline variables in both the design and analysis phase of RCTs. METHODS:We searched PubMed for articles indexed "randomized controlled trial", published in the NEJM, JAMA, BMJ, or Lancet for two time periods: 2009 and 2014 (before and after updated CONSORT guidelines). Upon screening (343), 298 articles underwent full review and data abstraction. RESULTS:Typical articles reported on superiority (86%), multicenter (92%), two-armed (79%) trials; 81% of trials involved covariates in the allocation and 84% presented adjusted analysis results. The majority reported a stratified block method (69%) of allocation, and of the trials reporting adjusted analyses, 91% were pre-specified. Trials published in 2014 were more likely to report adjusted analyses (87% vs. 79%, p = 0.0100) and more likely to pre-specify adjustment in analyses (95% vs. 85%, p = 0.0045). Studies initiated in later years (2010 or later) were less likely to use an adaptive method of randomization (p = 0.0066; 7% of those beginning in 2010 or later vs. 31% of those starting before 2000) but more likely to report a pre-specified adjusted analysis (p = 0.0029; 97% for those initiated in 2010 or later vs. 69% of those started before 2000). CONCLUSION/CONCLUSIONS:While optimal reporting procedures and pre-specification of adjusted analyses for RCTs tend to be progressively more prevalent over time, we see the opposite effect on reported use of covariate-adaptive randomization methods.

To disseminate lessons learned from the implementation experience of a public-private sector partnership, we describe a comprehensive HIV/AIDS program including 5-year survival outcomes for individuals who initiated antiretroviral therapy (ART) treatment in Togo from 2010 to 2015. A retrospective case study analysis was conducted from a cohort of patients receiving ART at an HIV/AIDS care clinic in Kara Region, Togo. Kaplan-Meier curves with Log rank tests were used to compare estimated survival curves by demographic and clinical characteristics. Associations were described between survival probability and age, gender, World Health Organization (WHO) disease stage, and timing of ART initiation. Cox proportional hazard model was used to determine predictors of mortality. After approximately five-years since ART initiation (1780 days), there were 114 deaths, with a survival probability of 75.3% (95% CI: 70.3-80.6%). Participants with advanced WHO disease stage were more likely at risk of death relative to patients categorized as WHO Stage 1, with Stage 4 approximately 9 times more likely (aHR 9.22, 95% CI 4.29-19.84). Our study suggests that delivering comprehensive HIV care through a private-public partnership may serve as a model to expand and improve HIV/AIDS care as well as high quality primary care.

Recent work has quantified the geometric parameters of individual rat vibrissae (whiskers) and developed equations that describe how these parameters vary as a function of row and column position across the array. This characterization included a detailed quantification of whisker base diameter and arc length as well as the geometry of the whisker medulla. The present study now uses these equations for whisker geometry to quantify several properties of the whisker that govern its mechanical behavior. We first show that the average density of a whisker is lower in its proximal region than in its distal region. This density variation appears to be largely attributable to the presence of the whisker cuticle rather than the medulla. The density variation has very little effect on the center of mass of the whisker. We next show that the presence of the medulla decreases the deflection of the whisker under its own weight and also decreases its mass moment of inertia while sacrificing <1% stiffness at the whisker base compared with a solid whisker. Finally, we quantify two dimensionless parameters across the array. First, the deflection-to-length ratio decreases from caudal to rostral: caudal whiskers are longer but deflect more under their own weight. Second, the nondimensionalized radius of gyration is approximately constant across the array, which may simplify control of whisking by the intrinsic muscles. We anticipate that future work will exploit the mechanical properties computed in the present study to improve simulations of the mechanosensory signals associated with vibrissotactile exploratory behavior. NEW & NOTEWORTHY The mechanical signals transmitted by a whisker depend critically on its geometry. We used measurements of whisker geometry and mass to quantify the center of mass, mass moment of inertia, radius of gyration, and deflection under gravity of the whisker. We describe how variations in these quantities across the array could enhance sensing behaviors while reducing energy costs and simplifying whisking control. Most importantly, we provide derivations for these quantities for use in future simulation work.

Background/UNASSIGNED:Current guidelines recommend less aggressive target hemoglobin A1c (HbA1c) levels based on older age and lower life expectancy for older adults with diabetes. The effectiveness of electronic health record (EHR) clinical decision support (CDS) in promoting guideline adherence is undermined by alert fatigue and poor workflow integration. Integrating behavioral economics (BE) and CDS tools is a novel approach to improving adherence to guidelines while minimizing clinician burden. Methods/UNASSIGNED: = 8), (2) a 2-h, design-thinking workshop to derive and refine initial module ideas, and (3) semi-structured group interviews at each site with clinic leaders and clinicians to elicit feedback on three proposed nudge module components (navigator section, inbasket refill protocol, medication preference list). Detailed field notes will be summarized by module idea and usability theme for rapid iteration. Frequency of firing and user action taken will be assessed in the first month of implementation via EHR reporting to confirm that module components and related reporting are working as expected as well as assess utilization. To assess the utilization and feasibility of the new tools and generate estimates of clinician compliance with the Choosing Wisely guideline for diabetes management in older adults, a 6-month, single-arm pilot study of the BE-EHR module will be conducted in six outpatient primary care clinics. Discussion/UNASSIGNED:We hypothesize that a low burden, user-centered approach to design will yield a BE-driven, CDS module with relatively high utilization by clinicians. The resulting module will establish a platform for exploring the ability of BE concepts embedded within the EHR to affect guideline adherence for other use cases.

The morphology of an animal's face will have large effects on the sensory information it can acquire. Here we quantify the arrangement of cranial sensory structures of the rat, with special emphasis on the mystacial vibrissae (whiskers). Nearly all mammals have vibrissae, which are generally arranged in rows and columns across the face. The vibrissae serve a wide variety of important behavioral functions, including navigation, climbing, wake following, anemotaxis, and social interactions. To date, however, there are few studies that compare the morphology of vibrissal arrays across species, or that describe the arrangement of the vibrissae relative to other facial sensory structures. The few studies that do exist have exploited the whiskers' grid-like arrangement to quantify array morphology in terms of row and column identity. However, relying on whisker identity poses a challenge for comparative research because different species have different numbers and arrangements of whiskers. The present work introduces an approach to quantify vibrissal array morphology regardless of the number of rows and columns, and to quantify the array's location relative to other sensory structures. We use the three-dimensional locations of the whisker basepoints as fundamental parameters to generate equations describing the length, curvature, and orientation of each whisker. Results show that in the rat, whisker length varies exponentially across the array, and that a hard limit on intrinsic curvature constrains the whisker height-to-length ratio. Whiskers are oriented to "fan out" approximately equally in dorsal-ventral and rostral-caudal directions. Quantifying positions of the other sensory structures relative to the whisker basepoints shows remarkable alignment to the somatosensory cortical homunculus, an alignment that would not occur for other choices of coordinate systems (e.g., centered on the midpoint of the eyes). We anticipate that the quantification of facial sensory structures, including the vibrissae, will ultimately enable cross-species comparisons of multi-modal sensing volumes.

Many rodents tactually sense the world through active motions of their vibrissae (whiskers), which are regularly arranged in rows and columns (arcs) on the face. The present study quantifies several geometric parameters of rat whiskers that determine the tactile information acquired. Findings include the following. 1) A meta-analysis of seven studies shows that whisker base diameter varies with arc length with a surprisingly strong dependence on the whisker's row position within the array. 2) The length of the whisker medulla varies linearly with whisker length, and the medulla's base diameter varies linearly with whisker base diameter. 3) Two parameters are required to characterize whisker "taper": radius ratio (base radius divided by tip radius) and radius slope (the difference between base and tip radius, divided by arc length). A meta-analysis of five studies shows that radius ratio exhibits large variability due to variations in tip radius, while radius slope varies systematically across the array. 4) Within the resolution of the present study, radius slope does not differ between the proximal and distal segments of the whisker, where "proximal" is defined by the presence of the medulla. 5) Radius slope of the medulla is offset by a constant value from radius slope of the proximal portion of the whisker. We conclude with equations for all geometric parameters as functions of row and column position.NEW & NOTEWORTHY Rats tactually explore their world by brushing and tapping their whiskers against objects. Each whisker's geometry will have a large influence on its mechanics and thus on the tactile signals the rat obtains. We performed a meta-analysis of seven studies to generate equations that describe systematic variations in whisker geometry across the rat's face. We also quantified the geometry of the whisker medulla. A database provides access to geometric parameters of over 500 rat whiskers.