Research Spotlight

McCullough, P.A. and Oskoui, R. (2020). “Early multidrug regimens in new potentially fatal medical problems.” Rev Cardiovasc Med 21(4): 507-508.

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The SARS-CoV-2 (COVID-19) pandemic has been the greatest challenge to medical practice in decades. We have witnessed fear, panic, confusion, division, and a wide array of regulatory and public health responses to the crisis (National Institutes of Health, 2020). We believe it is important for all physicians to keep in mind this pandemic is an emergency crisis and is not a usual context for drug development, guidelines, and recommendations for patient practice. In cardiovascular medicine we have had many disruptive forces as the field has evolved and we have witnessed reasonable responses with respect to pharmacotherapy when there was an absence of randomized trials to first guide the approach. [No abstract; excerpt from article].

Mathai, S.K., Cardwell, J., Metzger, F., Powers, J., Walts, A.D., Kropski, J.A., Eickelberg, O., Hauck, S.M., Yang, I.V. and Schwartz, D.A. (2020). “Preclinical Pulmonary Fibrosis Circulating Protein Biomarkers.” Am J Respir Crit Care Med 202(12): 1720-1724.

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Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, irreversible scarring of the lung parenchyma that can require invasive diagnostic testing (1). Interstitial lung abnormalities (ILAs) have been described in the general population (2). Among asymptomatic first-degree relatives of patients with familial interstitial pneumonia (FIP), 14% have radiologic ILAs and 35% have interstitial abnormalities on biopsy (3). In the Framingham population, fibrotic ILAs were present in 1.8% of subjects ≥50 years of age (4) and associated with increased risk of death (5, 6), suggesting ILAs may be a harbinger of IPF. [No abstract; excerpt from article].

McCullough, P.A., Alexander, P.E., Armstrong, R., Arvinte, C., Bain, A.F., Bartlett, R.P., Berkowitz, R.L., Berry, A.C., Borody, T.J., Brewer, J.H., Brufsky, A.M., Clarke, T., Derwand, R., Eck, A., Eck, J., Eisner, R.A., Fareed, G.C., Farella, A., Fonseca, S.N.S., Geyer, C.E., Jr., Gonnering, R.S., Graves, K.E., Gross, K.B.V., Hazan, S., Held, K.S., Hight, H.T., Immanuel, S., Jacobs, M.M., Ladapo, J.A., Lee, L.H., Littell, J., Lozano, I., Mangat, H.S., Marble, B., McKinnon, J.E., Merritt, L.D., Orient, J.M., Oskoui, R., Pompan, D.C., Procter, B.C., Prodromos, C., Rajter, J.C., Rajter, J.J., Ram, C.V.S., Rios, S.S., Risch, H.A., Robb, M.J.A., Rutherford, M., Scholz, M., Singleton, M.M., Tumlin, J.A., Tyson, B.M., Urso, R.G., Victory, K., Vliet, E.L., Wax, C.M., Wolkoff, A.G., Wooll, V. and Zelenko, V. (2020). “Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).” Rev Cardiovasc Med 21(4): 517-530.

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The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.

Lundgren, J.D., Grund, B., Barkauskas, C.E., Holland, T.L., Gottlieb, R.L., Sandkovsky, U., Brown, S.M., Knowlton, K.U., Self, W.H., Files, D.C., Jain, M.K., Benfield, T., Bowdish, M.E., Leshnower, B.G., Baker, J.V., Jensen, J.U., Gardner, E.M., Ginde, A.A., Harris, E.S., Johansen, I.S., Markowitz, N., Matthay, M.A., Østergaard, L., Chang, C.C., Davey, V.J., Goodman, A., Higgs, E.S., Murray, D.D., Murray, T.A., Paredes, R., Parmar, M.K.B., Phillips, A.N., Reilly, C., Sharma, S., Dewar, R.L., Teitelbaum, M., Wentworth, D., Cao, H., Klekotka, P., Babiker, A.G., Gelijns, A.C., Kan, V.L., Polizzotto, M.N., Thompson, B.T., Lane, H.C. and Neaton, J.D. (2020). “A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.” N Engl J Med Dec 22;NEJMoa2033130. [Epub ahead of print].

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BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19. METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5. RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47). CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

Lo, E.Y., Rizkalla, J., Montemaggi, P., Majekodunmi, T. and Krishnan, S.G. (2020). “Clinical and Radiographic Outcomes of Cementless Reverse Total Shoulder Arthroplasty for Proximal Humeral Fractures.” J Shoulder Elbow Surg Dec 23;S1058-2746(20)30930-7. [Epub ahead of print].

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INTRODUCTION: Reverse total shoulder arthroplasty (RTSA) has demonstrated successful outcomes in the treatment of both the acute and chronic proximal humerus fractures (PHFx). Traditional RTSA surgical technique utilizes a methyl methacrylate cemented humeral component to restore and maintain both humeral height and retroversion. However, use of humeral bone cement has been associated intraoperatively with cardiopulmonary risk, increased operative cost, and postoperatively with difficulty if revision arthroplasty is required. Here we report clinical and radiographic outcomes of a completely cementless RTSA technique for PHFx surgery. METHODS: Between 2013 and 2018, 60 consecutive patients underwent surgical management of a PHFx with cementless RTSA. All surgeries were performed by a single senior shoulder surgeon using a modified deltopectoral approach and a completely uncemented RTSA technique. Fractures were defined as “acute” and “chronic” based on a 4-week injury-to surgery benchmark. Mean age was 67 years (range 47-85 years). There were 18 acute fractures and 42 chronic fractures. Mean time from injury to surgery for acute fractures was 2 weeks (range 0.4-4) and chronic fractures was 60 months (range 1-482). Seventeen cases were excluded from postoperative evaluation due to revision, lost to follow-up, or both. All remaining 43 underwent clinical and radiographic evaluation by two independent fellowship-trained shoulder surgeons at mean 21 months postoperatively (Range 10-46). Independent statistical analysis was performed using paired t-test and Wilcoxon signed-rank test. RESULTS: At final review, mean active anterior elevation was 157° (range 100-170°), active external rotation 52° (range 6-80°), and active internal rotation 66° (range 0-80°). Improvements were seen in visual analog pain score (6-0.2, p<0.001), Simple Shoulder Test (SST) (9-93, p<0.001), American Shoulder and Elbow Surgeons (ASES) (19- 91, p<0.001), and Single-Assessment Numeral Evaluation (SANE) scores (21% - 89%, p<0.001). Overall, 39 of 43 (91%) of greater tuberosities demonstrated osseous healing to the humeral shaft. There were no significant differences in clinical and radiographic outcomes in acute vs chronic cases, and cases with minimum 1-year vs 2-year follow-up. Overall, there were 4 major complications necessitating surgical revision (6.7%), and no case of aseptic humeral stem loosening. CONCLUSION: Cementless RTSA for acute and chronic PHFx demonstrates clinical and radiographic outcomes similar to traditional cemented RTSA. The successful greater tuberosity healing and absence of humeral stem loosening in this short-term cohort are encouraging for continued long-term success of this technique. By avoiding cemented humeral implants, surgeons may minimize intraoperative complications, operative cost, and postoperative revision difficulty.