Research Spotlight

Fann, J.R., Hart, T., Ciol, M.A., Moore, M., Bogner, J., Corrigan, J.D., Dams-O’Connor, K., Driver, S., Dubiel, R., Hammond, F.M., Kajankova, M., Watanabe, T.K. and Hoffman, J.M. (2021). “Improving transition from inpatient rehabilitation following traumatic brain injury:Protocol for the BRITE pragmatic comparative effectiveness trial.” Contemp Clin Trials Feb 27;106332. [Epub ahead of print]. 106332.

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Moderate to severe traumatic brain injury (TBI) is a common cause of long-term disability. Due to challenges that include inconsistent access to follow-up care, persons with TBI being discharged from inpatient rehabilitation facilities (IRFs) are at risk for rehospitalization, poor reintegration into the community, family stress, and other unfavorable outcomes resulting from unmet needs. In a six-center randomized pragmatic comparative effectiveness study, the BRITE trial (Brain Injury Rehabilitation: Improving the Transition Experience, ClinicalTrials.govNCT03422276), we compare the effectiveness of two existing methods for transition from IRF to community living or long-term nursing care. The Rehabilitation Discharge Plan (RDP) includes patient/family education and referrals for continued care. The Rehabilitation Transition Plan (RTP) provides RDP plus individualized, manualized care management via phone or videoconference, for 6 months. Nine hundred patients will be randomized (1:1) to RDP or RTP, with caregivers also invited to participate and contribute caregiver-reported outcomes. Extensive stakeholder input, including active participation of persons with TBI and their families, has informed all aspects of trial design and implementation planning. We hypothesize that RTP will result in better patient- and caregiver-reported outcomes (societal participation, quality of life, caregiver well-being) and more efficient use of healthcare resources at 6-months (primary outcome) and 12-months post-discharge, compared to RDP alone. Planned analyses will explore which participants benefit most from each transition model. With few exclusion criteria and other pragmatic features, the findings of this trial are expected to have a broad impact on improving transitions from inpatient TBI rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03422276.

Domecq, J.P., Lal, A., Sheldrick, C.R., Kumar, V.K., Boman, K., Bolesta, S., Bansal, V., Harhay, M.O., Garcia, M.A., Kaufman, M., Danesh, V., Cheruku, S., Banner-Goodspeed, V.M., Anderson, H.L., 3rd, Milligan, P.S., Denson, J.L., St Hill, C.A., Dodd, K.W., Martin, G.S., Gajic, O., Walkey, A.J. and Kashyap, R. (2021). “Outcomes of Patients With Coronavirus Disease 2019 Receiving Organ Support Therapies: The International Viral Infection and Respiratory Illness Universal Study Registry.” Crit Care Med 49(3): 437-448.

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OBJECTIVES: To describe the outcomes of hospitalized patients in a multicenter, international coronavirus disease 2019 registry. DESIGN: Cross-sectional observational study including coronavirus disease 2019 patients hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between February 15, 2020, and November 30, 2020, according to age and type of organ support therapies. SETTING: About 168 hospitals in 16 countries within the Society of Critical Care Medicine’s Discovery Viral Infection and Respiratory Illness University Study coronavirus disease 2019 registry. PATIENTS: Adult hospitalized coronavirus disease 2019 patients who did and did not require various types and combinations of organ support (mechanical ventilation, renal replacement therapy, vasopressors, and extracorporeal membrane oxygenation). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was hospital mortality. Secondary outcomes were discharge home with or without assistance and hospital length of stay. Risk-adjusted variation in hospital mortality for patients receiving invasive mechanical ventilation was assessed by using multilevel models with hospitals as a random effect, adjusted for age, race/ethnicity, sex, and comorbidities. Among 20,608 patients with coronavirus disease 2019, the mean (± sd) age was 60.5 (±17), 11,1887 (54.3%) were men, 8,745 (42.4%) were admitted to the ICU, and 3,906 (19%) died in the hospital. Hospital mortality was 8.2% for patients receiving no organ support (n = 15,001). The most common organ support therapy was invasive mechanical ventilation (n = 5,005; 24.3%), with a hospital mortality of 49.8%. Mortality ranged from 40.8% among patients receiving only invasive mechanical ventilation (n =1,749) to 71.6% for patients receiving invasive mechanical ventilation, vasoactive drugs, and new renal replacement therapy (n = 655). Mortality was 39% for patients receiving extracorporeal membrane oxygenation (n = 389). Rates of discharge home ranged from 73.5% for patients who did not require organ support therapies to 29.8% for patients who only received invasive mechanical ventilation, and 8.8% for invasive mechanical ventilation, vasoactive drugs, and renal replacement; 10.8% of patients older than 74 years who received invasive mechanical ventilation were discharged home. Median hospital length of stay for patients on mechanical ventilation was 17.1 days (9.7-28 d). Adjusted interhospital variation in mortality among patients receiving invasive mechanical ventilation was large (median odds ratio 1.69). CONCLUSIONS: Coronavirus disease 2019 prognosis varies by age and level of organ support. Interhospital variation in mortality of mechanically ventilated patients was not explained by patient characteristics and requires further evaluation.

Vemmou, E., Alaswad, K., Patel, M., Mahmud, E., Choi, J.W., Jaffer, F.A., Doing, A.H., Dattilo, P., Karmpaliotis, D., Krestyaninov, O., Khelimskii, D., Nikolakopoulos, I., Karacsonyi, J., Xenogiannis, I., Garcia, S., Burke, M.N., Abi Rafeh, N., ElGuindy, A., Goktekin, O., Abdo, A., Rangan, B.V., Abdullah, S. and Brilakis, E.S. (2021). “Chronic total occlusion percutaneous coronary intervention in octogenarians and nonagenarians.” J Am Geriatr Soc Feb 16. [Epub ahead of print].

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OBJECTIVE: The outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in octogenarians and nonagenarians have received limited study. METHODS: We compared in-hospital outcomes of CTO PCI between patients ≥80 vs. <80-years-old in 6233 CTO PCIs performed between 2012 and 2020 at 33 U.S. and international centers. RESULTS: There were 415 octogenarians and nonagenarians in our study (7% of the total population). Compared with younger patients, octo- and nonagenarians were less likely to be men (73% vs. 83.2%, p < 0.0001) and more likely to have atrial fibrillation (27% vs. 12%, p < 0.0001) and prior coronary artery bypass graft surgery (CABG) (43% vs. 29%, p < 0.0001). They were more likely to have CTOs with moderate/severe calcification (71% vs. 46%, p < 0.0001), but had similar mean J-CTO scores (2.5 ± 1.3 vs. 2.4 ± 1.3, p = 0.08). They had lower technical and procedural success (82.2% vs. 86.3%, p = 0.0201; 80.3% vs. 84.8%, p = 0.016, respectively) and higher incidence of in-hospital major adverse cardiovascular events (3.4% vs. 1.8%, p = 0.021). On multivariable analysis PCI in octo- and nonagenarians was not independently associated with technical and procedural success or with in-hospital MACE. CONCLUSION: CTO PCI is feasible in octo- and nonagenarians, although success rates are lower, and the risk of complications is higher compared with younger patients, likely related to more comorbidities and higher coronary lesion complexity.

Markus, H., Zhao, J., Contente-Cuomo, T., Stephens, M.D., Raupach, E., Odenheimer-Bergman, A., Connor, S., McDonald, B.R., Moore, B., Hutchins, E., McGilvrey, M., de la Maza, M.C., Van Keuren-Jensen, K., Pirrotte, P., Goel, A., Becerra, C., Von Hoff, D.D., Celinski, S.A., Hingorani, P. and Murtaza, M. (2021). “Analysis of recurrently protected genomic regions in cell-free DNA found in urine.” Sci Transl Med 13(581).

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Cell-free DNA (cfDNA) in urine is a promising analyte for noninvasive diagnostics. However, urine cfDNA is highly fragmented. Whether characteristics of these fragments reflect underlying genomic architecture is unknown. Here, we characterized fragmentation patterns in urine cfDNA using whole-genome sequencing. Size distribution of urine cfDNA fragments showed multiple strong peaks between 40 and 120 base pairs (bp) with a modal size of 81- and sharp 10-bp periodicity, suggesting transient protection from complete degradation. These properties were robust to preanalytical perturbations, such as at-home collection and delay in processing. Genome-wide sequencing coverage of urine cfDNA fragments revealed recurrently protected regions (RPRs) conserved across individuals, with partial overlap with nucleosome positioning maps inferred from plasma cfDNA. The ends of cfDNA fragments clustered upstream and downstream of RPRs, and nucleotide frequencies of fragment ends indicated enzymatic digestion of urine cfDNA. Compared to plasma, fragmentation patterns in urine cfDNA showed greater correlation with gene expression and chromatin accessibility in epithelial cells of the urinary tract. We determined that tumor-derived urine cfDNA exhibits a higher frequency of aberrant fragments that end within RPRs. By comparing the fraction of aberrant fragments and nucleotide frequencies of fragment ends, we identified urine samples from cancer patients with an area under the curve of 0.89. Our results revealed nonrandom genomic positioning of urine cfDNA fragments and suggested that analysis of fragmentation patterns across recurrently protected genomic loci may serve as a cancer diagnostic.

Brodsky, J.W., Jaffe, D., Pao, A., Vier, D., Taniguchi, A., Daoud, Y., Coleman, S. and Scott, D.J. (2021). “Long-term Functional Results of Total Ankle Arthroplasty in Stiff Ankles.” Foot Ankle Int Feb 8;1071100720977847. [Epub ahead of print].

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BACKGROUND: Total ankle arthroplasty (TAA) is advocated over ankle arthrodesis to preserve ankle motion (ROM). Clinical and gait analysis studies have shown significant improvement after TAA. The role and outcomes of TAA in stiff ankles, which have little motion to be preserved, has been the subject of limited investigation. This investigation evaluated the mid- to long-term functional outcomes of TAA in stiff ankles. METHODS: A retrospective study of prospectively collected functional gait data in 33 TAA patients at a mean of 7.6 (5-13) years postoperatively used 1-way analysis of variance and multivariate regression analysis to compare among preoperative and postoperative demographic data (age, gender, body mass index, years postsurgery, and diagnosis) and gait parameters according to quartiles of preoperative sagittal ROM. RESULTS: The stiffest ankles had a mean ROM of 7.8 degrees, compared to 14.3 degrees for the middle 2 quartiles, and 21.0 degrees for the most flexible ankles. Patients in the lowest quartile (Q1) also had statistically significantly lower step length, speed, max plantarflexion, and power preoperatively. Postoperatively, they increased step length, speed, max plantarflexion, and ankle power to levels comparable to patients with more flexible ankles preoperatively (Q2, Q3, and Q4). They had the greatest absolute and relative increases in these parameters of any group, but the final total ROM was still statistically significantly the lowest. CONCLUSION: Preoperative ROM was predictive of overall postoperative gait function at an average of 7.6 (range 5-13) years. Although greater preoperative sagittal ROM predicted greater postoperative ROM, the stiffest ankles showed the greatest percentage increase in ROM. Patients with the stiffest ankles had the greatest absolute and relative improvements in objective function after TAA, as measured by multiple gait parameters. At intermediate- to long-term follow-up, patients with stiff ankles maintained significant functional improvements after TAA. LEVEL OF EVIDENCE: Level III, comparative study.