Patient Trajectories Among Persons Hospitalized for COVID-19 : A Cohort Study.

BACKGROUND: Risk factors for progression of coronavirus disease 2019 (COVID-19) to severe disease or death are underexplored in U.S. cohorts. OBJECTIVE: To determine the factors on hospital admission that are predictive of severe disease or death from COVID-19. DESIGN: Retrospective cohort analysis. SETTING: Five hospitals in the Maryland and Washington, DC, area. PATIENTS: 832 consecutive COVID-19 admissions from 4 March to 24 April 2020, with follow-up through 27 June 2020. MEASUREMENTS: Patient trajectories and outcomes, categorized by using the World Health Organization COVID-19 disease severity scale. Primary outcomes were death and a composite of severe disease or death. RESULTS: Median patient age was 64 years (range, 1 to 108 years); 47% were women, 40% were Black, 16% were Latinx, and 21% were nursing home residents. Among all patients, 131 (16%) died and 694 (83%) were discharged (523 [63%] had mild to moderate disease and 171 [20%] had severe disease). Of deaths, 66 (50%) were nursing home residents. Of 787 patients admitted with mild to moderate disease, 302 (38%) progressed to severe disease or death: 181 (60%) by day 2 and 238 (79%) by day 4. Patients had markedly different probabilities of disease progression on the basis of age, nursing home residence, comorbid conditions, obesity, respiratory symptoms, respiratory rate, fever, absolute lymphocyte count, hypoalbuminemia, troponin level, and C-reactive protein level and the interactions among these factors. Using only factors present on admission, a model to predict in-hospital disease progression had an area under the curve of 0.85, 0.79, and 0.79 at days 2, 4, and 7, respectively. LIMITATION: The study was done in a single health care system. CONCLUSION: A combination of demographic and clinical variables is strongly associated with severe COVID-19 disease or death and their early onset. The COVID-19 Inpatient Risk Calculator (CIRC), using factors present on admission, can inform clinical and resource allocation decisions. PRIMARY FUNDING SOURCE: Hopkins inHealth and COVID-19 Administrative Supplement for the HHS Region 3 Treatment Center from the Office of the Assistant Secretary for Preparedness and Response.

The axon degeneration gene SARM1 is evolutionarily distinct from other TIR domain-containing proteins.

Many forms of neurodegenerative disease are characterized by Wallerian degeneration, an active program of axonal destruction. Recently, the important player which enacts Wallerian degeneration was discovered, the multidomain protein SARM1. Since the SARM1 protein has classically been thought of as an innate immune molecule, its role in Wallerian degeneration has raised questions on the evolutionary forces acting on it. Here, we synthesize a picture of SARM1's evolution through various organisms by examining the molecular and genetic changes of SARM1 and the genes around it. Using proteins that possess domains homologous to SARM1, we established distances and Ka/Ks values through 5671 pairwise species-species comparisons. We demonstrate that SARM1 diverged across species in a pattern similar to other SAM domain-containing proteins. This is surprising, because it was expected that SARM1 would behave more like its TIR domain relatives. Going along with this divorce from TIR, we also noted that SARM1's TIR is under stronger purifying selection than the rest of the TIR domain-containing proteins (remaining highly conserved). In addition, SARM1's synteny analysis reveals that the surrounding gene cluster is highly conserved, functioning as a potential nexus of gene functionality across species. Taken together, SARM1 demonstrates a unique evolutionary pattern, separate from the TIR domain protein family.

Socioeconomic Status Diversity of Trainees and Faculty in Residency Programs: A Pilot Study in Plastic Surgery.

INTRODUCTION: The socioeconomic diversity of residents, fellows, and faculty members in any medical or surgical specialty is currently unknown making it difficult to understand socioeconomic status (SES) disparities and create programs to improve diversity. Additionally, the career trajectories of residents and faculty members who come from different SES backgrounds have not been explored. We have performed a survey-based research study to understand the SES composition and career trajectories of residents and faculty members within U.S. Plastic and Reconstructive Surgery (PRS) residency programs. METHODS: An anonymous online survey was administered to 754 recipients within plastic surgery residency programs in the United States. Self-reported SES information such as household income prior to age 18 and parental education level was collected. Data regarding career trajectories was obtained through questions about away rotations and research productivity. RESULTS: A total of 196 fellows, and faculty members participated in the study, with an estimated survey respondent rate of 25.9%. Only 9.9% (10 of 101) of residents and fellows reported a childhood (under age 18) family income less than $40,000. When analyzing parental education and occupation (EO-status), 42.6% (43 of 101) of residents and fellows had at least 1 parent in an executive, managerial, or professional position with a doctorate/professional degree. Low-income and low EO-status were associated with increased utilization of federal and state assistance programs (p = 0.0001) and approval for AAMC's Fee Assistance Program (FAP) (p = 0.0001). Residents and fellows who identified as White were not as likely to be from low EO-status households as those who identified as Asian (OR 0.3 and p = 0.015 vs. OR 2.9 and p = 0.038). Residents and fellows from low EO-status backgrounds were more likely to take a gap in education (87% vs. 65.4%, p = 0.047) compared to their high EO-status peers. Notably, more current residents and fellows performed away rotations and had first-author publications during or before medical school compared to full professors (p = 0.0001). CONCLUSION: Understanding the backgrounds and career trajectories of trainees and faculty in medicine is essential, yet it has not been performed at the resident or faculty level. This survey is the first to demonstrate the lack of socioeconomic diversity in a specialty (PRS) and identifies variation in career trajectories among those from different SES backgrounds. Large-scale research efforts are necessary to understand current SES diversity and barriers encountered by trainees and educators from low-SES backgrounds in all medical and surgical specialties.

Sustained IGF-1 delivery ameliorates effects of chronic denervation and improves functional recovery after peripheral nerve injury and repair.

Functional recovery following peripheral nerve injury is limited by progressive atrophy of denervated muscle and Schwann cells (SCs) that occurs during the long regenerative period prior to end-organ reinnervation. Insulin-like growth factor 1 (IGF-1) is a potent mitogen with well-described trophic and anti-apoptotic effects on neurons, myocytes, and SCs. Achieving sustained, targeted delivery of small protein therapeutics remains a challenge. We hypothesized that a novel nanoparticle (NP) delivery system can provide controlled release of bioactive IGF-1 targeted to denervated muscle and nerve tissue to achieve improved motor recovery through amelioration of denervation-induced muscle atrophy and SC senescence and enhanced axonal regeneration. Biodegradable NPs with encapsulated IGF-1/dextran sulfate polyelectrolyte complexes were formulated using a flash nanoprecipitation method to preserve IGF-1 bioactivity and maximize encapsulation efficiencies. Under optimized conditions, uniform PEG-b-PCL NPs were generated with an encapsulation efficiency of 88.4%, loading level of 14.2%, and a near-zero-order release of bioactive IGF-1 for more than 20 days in vitro. The effects of locally delivered IGF-1 NPs on denervated muscle and SCs were assessed in a rat median nerve transection-without- repair model. The effects of IGF-1 NPs on axonal regeneration, muscle atrophy, reinnervation, and recovery of motor function were assessed in a model in which chronic denervation is induced prior to nerve repair. IGF-1 NP treatment resulted in significantly greater recovery of forepaw grip strength, decreased denervation-induced muscle atrophy, decreased SC senescence, and improved neuromuscular reinnervation.

Utility of Viscoelastic Tests to Predict Flap Thrombosis: A Systematic Review.

BACKGROUND: Flap thrombosis is a rare but devastating complication in microsurgery. Preoperative identification of patients at increased risk for microvascular thrombosis remains challenging. Viscoelastic testing (VET) provides a comprehensive evaluation of the clotting process and can effectively identify hypercoagulability. However, the utility of VET in microvascular reconstruction remains unclear. METHODS: A systematic review of the association between VET and pedicle thrombosis and free flap loss was performed in accordance with Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. Identified studies were reviewed independently by two authors for pertinent data. RESULTS: Six studies met inclusion criteria. Heterogenous study design and outcome reporting complicated direct comparisons and precluded a formal meta-analysis. Four studies found a statistically significant relationship between VET results and flap thrombosis or flap loss. The maximum clot strength and the fibrinogen-to-platelet ratio (FPR) were key viscoelastic parameters in these studies, both representing a measure of maximal clot strength. Specifically, an elevated FPR (>42%) generated a sensitivity and specificity for flap loss ranging from 57% to 75% and 60% to 82%, respectively. Notably, the negative predictive value for flap failure with a normal preoperative FPR was greater than 90% in all studies reporting a correlation. The remaining two studies reported no predictive value for VET with respect to flap failure or pedicle thrombosis. CONCLUSION: The results of this review suggest that VET, particularly parameters relating to clot strength, may help clinicians identify patients at risk for flap thrombosis. However, uncontrolled and heterogenous reporting limit definitive conclusions, and high-quality diagnostic studies are needed to better determine the clinical utility of viscoelastic testing for free flap patients.

A simple and robust method for automating analysis of naïve and regenerating peripheral nerves.

BACKGROUND: Manual axon histomorphometry (AH) is time- and resource-intensive, which has inspired many attempts at automation. However, there has been little investigation on implementation of automated programs for widespread use. Ideally such a program should be able to perform AH across imaging modalities and nerve states. AxonDeepSeg (ADS) is an open source deep learning program that has previously been validated in electron microscopy. We evaluated the robustness of ADS for peripheral nerve axonal histomorphometry in light micrographs prepared using two different methods. METHODS: Axon histomorphometry using ADS and manual analysis (gold-standard) was performed on light micrographs of naïve or regenerating rat median nerve cross-sections prepared with either toluidine-resin or osmium-paraffin embedding protocols. The parameters of interest included axon count, axon diameter, myelin thickness, and g-ratio. RESULTS: Manual and automatic ADS axon counts demonstrated good agreement in naïve nerves and moderate agreement on regenerating nerves. There were small but consistent differences in measured axon diameter, myelin thickness and g-ratio; however, absolute differences were small. Both methods appropriately identified differences between naïve and regenerating nerves. ADS was faster than manual axon analysis. CONCLUSIONS: Without any algorithm retraining, ADS was able to appropriately identify critical differences between naïve and regenerating nerves and work with different sample preparation methods of peripheral nerve light micrographs. While there were differences between absolute values between manual and ADS, ADS performed consistently and required much less time. ADS is an accessible and robust tool for AH that can provide consistent analysis across protocols and nerve states.

Defining the relative impact of muscle versus Schwann cell denervation on functional recovery after delayed nerve repair.

Functional recovery following peripheral nerve injury worsens with increasing durations of delay prior to repair. From the time of injury until re-innervation occurs, denervated muscle undergoes progressive atrophy that limits the extent to which motor function can be restored. Similarly, Schwann cells (SC) in the distal nerve lacking axonal interaction progressively lose their capacity to proliferate and support regenerating axons. The relative contributions of these processes to diminished functional recovery is unclear. We developed a novel rat model to isolate the effects of SC vs. muscle denervation on functional recovery. Four different groups underwent the following interventions for 12 weeks prior to nerve transfer: 1) muscle denervation; 2) SC denervation; 3) muscle + SC denervation (negative control); 4) no denervation (positive control). Functional recovery was measured weekly using the stimulated grip strength testing (SGST). Animals were sacrificed 13 weeks post nerve transfer. Retrograde labeling was used to assess the number of motor neurons that regenerated their axons. Immunofluorescence was performed to evaluate target muscle re-innervation and atrophy, and to assess the phenotype of the SC within the distal nerve segment. Functional recovery in the muscle denervation and SC denervation groups mirrored that of the negative and positive control groups, respectively. The SC denervation group achieved better functional recovery, with a greater number of reinnervated motor endplates and less muscle atrophy, than the muscle denervation group. Retrograde labeling suggested a higher number of neurons contributing to muscle reinnervation in the muscle denervation group as compared to SC denervation (p > 0.05). The distal nerve segment in the muscle denervation group had a greater proportion of SCs expressing the proliferation marker Ki67 as compared to the SC denervation group (p < 0.05). Conversely, the SC denervation group had a higher percentage of senescent SCs expressing p16 as compared to the muscle denervation group (p < 0.05). The deleterious effects of muscle denervation are more consequential than the effects of SC denervation on functional recovery. The effects of 12 weeks of SC denervation on functional outcome were negligible. Future studies are needed to determine whether longer periods of SC denervation negatively impact functional recovery.