Research Spotlight

Posted January 15th 2021

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).

Peter McCullough, M.D.

Peter McCullough, M.D.

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.


Posted January 15th 2021

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.

Robert L. Gottlieb, M.D., Ph.D.

Robert L. Gottlieb, M.D., Ph.D.

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.).


Posted January 15th 2021

Clinical and Radiographic Outcomes of Cementless Reverse Total Shoulder Arthroplasty for Proximal Humeral Fractures.

Eddie Y. Lo M.D.

Eddie Y. Lo M.D.

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.


Posted January 15th 2021

Association of Frailty and Sex With Wait List Mortality in Liver Transplant Candidates in the Multicenter Functional Assessment in Liver Transplantation (FrAILT) Study.

Robert Rahimi, M.D.

Robert Rahimi, M.D.

Lai, J.C., Ganger, D.R., Volk, M.L., Dodge, J.L., Dunn, M.A., Duarte-Rojo, A., Kappus, M.R., Rahimi, R.S., Ladner, D.P., Boyarsky, B., McAdams-DeMarco, M., Segev, D.L., McCulloch, C.E. and Verna, E.C. (2020). “Association of Frailty and Sex With Wait List Mortality in Liver Transplant Candidates in the Multicenter Functional Assessment in Liver Transplantation (FrAILT) Study.” JAMA Surg DEc 30. [Epub ahead of print].

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IMPORTANCE: Female liver transplant candidates experience higher rates of wait list mortality than male candidates. Frailty is a critical determinant of mortality in patients with cirrhosis, but how frailty differs between women and men is unknown. OBJECTIVE: To determine whether frailty is associated with the gap between women and men in mortality among patients with cirrhosis awaiting liver transplantation. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study enrolled 1405 adults with cirrhosis awaiting liver transplant without hepatocellular carcinoma seen during 3436 ambulatory clinic visits at 9 US liver transplant centers. Data were collected from January 1, 2012, to October 1, 2019, and analyzed from August 30, 2019, to October 30, 2020. EXPOSURES: At outpatient evaluation, the Liver Frailty Index (LFI) score was calculated (grip strength, chair stands, and balance). MAIN OUTCOMES AND MEASURES: The risk of wait list mortality was quantified using Cox proportional hazards regression by frailty. Mediation analysis was used to quantify the contribution of frailty to the gap in wait list mortality between women and men. RESULTS: Of 1405 participants, 578 (41%) were women and 827 (59%) were men (median age, 58 [interquartile range (IQR), 50-63] years). Women and men had similar median scores on the laboratory-based Model for End-stage Liver Disease incorporating sodium levels (MELDNa) (women, 18 [IQR, 14-23]; men, 18 [IQR, 15-22]), but baseline LFI was higher in women (mean [SD], 4.12 [0.85] vs 4.00 [0.82]; P = .005). Women displayed worse balance of less than 30 seconds (145 [25%] vs 149 [18%]; P = .003), worse sex-adjusted grip (mean [SD], -0.31 [1.08] vs -0.16 [1.08] kg; P = .01), and fewer chair stands per second (median, 0.35 [IQR, 0.23-0.46] vs 0.37 [IQR, 0.25-0.49]; P = .04). In unadjusted mixed-effects models, LFI was 0.15 (95% CI, 0.06-0.23) units higher in women than men (P = .001). After adjustment for other variables associated with frailty, LFI was 0.16 (95% CI, 0.08-0.23) units higher in women than men (P < .001). In unadjusted regression, women experienced a 34% (95% CI, 3%-74%) increased risk of wait list mortality than men (P = .03). Sequential covariable adjustment did not alter the association between sex and wait list mortality; however, adjustment for LFI attenuated the mortality gap between women and men. In mediation analysis, an estimated 13.0% (IQR, 0.5%-132.0%) of the gender gap in wait list mortality was mediated by frailty. CONCLUSIONS AND RELEVANCE: These findings demonstrate that women with cirrhosis display worse frailty scores than men despite similar MELDNa scores. The higher risk of wait list mortality that women experienced appeared to be explained in part by frailty.


Posted January 15th 2021

Uterine Transplantation; Review of Livebirths and Reproductive Implications.

Liza Johannesson, M.D.

Liza Johannesson, M.D.

Jones, B.P., Kasaven, L., Vali, S., Saso, S., Jalmbrant, M., Bracewell-Milnes, T., Thum, M.Y., Quiroga, I., Friend, P., Diaz-Garcia, C., Ghaem-Maghami, S., Yazbek, J., Lees, C., Testa, G., Johannesson, L., Jones, B. and Smith, J.R. (2020). “Uterine Transplantation; Review of Livebirths and Reproductive Implications.” Transplantation Dec 10. [Epub ahead of print].

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Uterine transplantation (UTx) is a fertility restoring treatment for women with absolute uterine factor infertility. At a time when there is no question of the procedure’s feasibility, and as the number of livebirths begins to increase exponentially, various important reproductive, fetal and maternal medicine implications have emerged. Detailed outcomes from 17 livebirths following UTx are now available, which are reviewed herein, along with contextualized extrapolation from pregnancy outcomes in other solid organ transplants. Differences in recipient demographics and reproductive aspirations between UTx and other transplant recipients make extrapolating management strategies and outcomes in other solid organ transplants inappropriate. Whereas preterm delivery remains prominent, small for gestational age or hypertensive disorders do not appear to be as prevalent following UTx when compared to other solid organ transplants. Given the primary objective of undertaking UTx is to achieve a livebirth, publication of reproductive outcomes is essential at this early stage, to reflect upon and optimize the management of future cases.