Research Spotlight

Posted September 16th 2021

Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial.

Idrees Mogri, M.D.

Idrees Mogri, M.D.

Ehrmann, S., J. Li, M. Ibarra-Estrada, Y. Perez, I. Pavlov, B. McNicholas, O. Roca, S. Mirza, D. Vines, R. Garcia-Salcido, G. Aguirre-Avalos, M. W. Trump, M. A. Nay, J. Dellamonica, S. Nseir, I. Mogri, D. Cosgrave, D. Jayaraman, J. R. Masclans, J. G. Laffey and E. Tavernier (2021). “Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial.” Lancet Respir Med Aug 20;S2213-2600(21)00356-8. [Epub ahead of print].

Full text of this article.

BACKGROUND: Awake prone positioning has been reported to improve oxygenation for patients with COVID-19 in retrospective and observational studies, but whether it improves patient-centred outcomes is unknown. We aimed to evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19 in a large-scale randomised trial. METHODS: In this prospective, a priori set up and defined, collaborative meta-trial of six randomised controlled open-label superiority trials, adults who required respiratory support with high-flow nasal cannula for acute hypoxaemic respiratory failure due to COVID-19 were randomly assigned to awake prone positioning or standard care. Hospitals from six countries were involved: Canada, France, Ireland, Mexico, USA, Spain. Patients or their care providers were not masked to allocated treatment. The primary composite outcome was treatment failure, defined as the proportion of patients intubated or dying within 28 days of enrolment. The six trials are registered with ClinicalTrials.gov, NCT04325906, NCT04347941, NCT04358939, NCT04395144, NCT04391140, and NCT04477655. FINDINGS: Between April 2, 2020 and Jan 26, 2021, 1126 patients were enrolled and randomly assigned to awake prone positioning (n=567) or standard care (n=559). 1121 patients (excluding five who withdrew from the study) were included in the intention-to-treat analysis. Treatment failure occurred in 223 (40%) of 564 patients assigned to awake prone positioning and in 257 (46%) of 557 patients assigned to standard care (relative risk 0·86 [95% CI 0·75-0·98]). The hazard ratio (HR) for intubation was 0·75 (0·62-0·91), and the HR for mortality was 0·87 (0·68-1·11) with awake prone positioning compared with standard care within 28 days of enrolment. The incidence of prespecified adverse events was low and similar in both groups. INTERPRETATION: Awake prone positioning of patients with hypoxaemic respiratory failure due to COVID-19 reduces the incidence of treatment failure and the need for intubation without any signal of harm. These results support routine awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula.


Posted September 16th 2021

The Dark Side of Chasing the Perfect Donor. Is it Time for Us to Change Cardiac Transplant Program Performance Metrics?

Dan M. Meyer, M.D.

Dan M. Meyer, M.D.

Afzal, A. M. and D. M. Meyer (2021). “The Dark Side of Chasing the Perfect Donor. Is it Time for Us to Change Cardiac Transplant Program Performance Metrics?” Transplantation 105(9): 1919-1920.

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The authors used the database from Organ Procurement and Transplantation Network (OPTN) to retrospectively evaluate pediatric heart transplant data from 2007 to 2017. The authors evaluated the association between center refusal rate (RR) and waitlist time, waitlist removal for death/clinical deterioration, posttransplant survival, and survival after listing. A total of 5552 patients were listed at 59 centers. The centers with higher RR had a shorter time to first offer, had longer waitlist time, were more likely to remove patients from the waitlist due to death or deterioration, less likely to transplant listed patients, and had a lower likelihood of survival 1 year after listing. Based on these findings, the authors concluded that patients listed at high RR centers had worse survival rates despite having shorter times for the first offer and having similar 1-year posttransplant outcomes. The authors do highlight the limitations that are inherent to doing a retrospective analysis from a national database including the concern that the accuracy of refusal codes in the database is unknown or poor in most cases. [No abstract; excerpt from article].


Posted September 16th 2021

Synthetic mRNAs; Their Analogue Caps and Contribution to Disease.

Peter McCullough, M.D.

Peter McCullough, M.D.

Kyriakopoulos, A. M. and P. A. McCullough (2021). “Synthetic mRNAs; Their Analogue Caps and Contribution to Disease.” Diseases 9(3).

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The structure of synthetic mRNAs as used in vaccination against cancer and infectious diseases contain specifically designed caps followed by sequences of the 5′ untranslated repeats of β-globin gene. The strategy for successful design of synthetic mRNAs by chemically modifying their caps aims to increase resistance to the enzymatic deccapping complex, offer a higher affinity for binding to the eukaryotic translation initiation factor 4E (elF4E) protein and enforce increased translation of their encoded proteins. However, the cellular homeostasis is finely balanced and obeys to specific laws of thermodynamics conferring balance between complexity and growth rate in evolution. An overwhelming and forced translation even under alarming conditions of the cell during a concurrent viral infection, or when molecular pathways are trying to circumvent precursor events that lead to autoimmunity and cancer, may cause the recipient cells to ignore their differential sensitivities which are essential for keeping normal conditions. The elF4E which is a powerful RNA regulon and a potent oncogene governing cell cycle progression and proliferation at a post-transcriptional level, may then be a great contributor to disease development. The mechanistic target of rapamycin (mTOR) axis manly inhibits the elF4E to proceed with mRNA translation but disturbance in fine balances between mTOR and elF4E action may provide a premature step towards oncogenesis, ignite pre-causal mechanisms of immune deregulation and cause maturation (aging) defects.


Posted September 16th 2021

Measuring the Variation in the Prevention and Treatment of CI-AKI Among Interventional Cardiologists.

Peter McCullough, M.D.

Peter McCullough, M.D.

Valdenor, C., P. A. McCullough, D. Paculdo, M. C. Acelajado, J. R. Dahlen, E. Noiri, T. Sugaya and J. Peabody (2021). “Measuring the Variation in the Prevention and Treatment of CI-AKI Among Interventional Cardiologists.” Curr Probl Cardiol 46(9): 100851.

Full text of this article.

Contrast-induced acute kidney injury (CI-AKI) occurs in up to 10% of cardiac catheterizations and coronary interventions, resulting in increased morbidity, mortality, and cost. One main reason for these complications and costs is under-recognition of CI-AKI risk and under-treatment of patients with impaired renal status. 157 interventional cardiologists each cared for three simulated patients with common conditions requiring intravascular contrast media in three typical settings: pre-procedurally, during the procedure, and post-procedure. We evaluated their ability to assess the risk of developing CI-AKI, make the diagnosis, and treat CI-AKI, including proper volume expansion and withholding nephrotoxic medications. Overall, the quality-of-care scores averaged 46.0% ± 10.5, varying between 18% to 78%. The diagnostic scores for accurately assessing risk of CI-AKI were low at 57.1% ± 21.2% and the accuracy of diagnosis pre-existing chronic kidney disease was 50.2%. Poor diagnostic accuracy led to poor treatment: proper volume expansion done in only 30.7% of cases, in-hospital repeat creatinine evaluation performed in 32.1%, and avoiding nephrotoxic medications occurred in 14.2%. While volume expansion was relatively similar across the three settings (P = 0.287), the cardiologists were less likely to discontinue nephrotoxic medications in pre-procedurally (9.7%) compared to the other settings (27.0%), and to order in-hospital creatinine testing in peri-procedurally (18.8%) compared to post-procedure (57.8%) (P < 0.05 for both). The overall care of patients at risk for contrast-induced acute kidney injury varied widely and showed room for improvement. Improving care for this condition will require greater awareness by cardiologists and better diagnostic tools to guide them.


Posted September 16th 2021

Early multidrug treatment of SARS-CoV-2 infection (COVID-19) and reduced mortality among nursing home (or outpatient/ambulatory) residents.

Peter McCullough, M.D.

Peter McCullough, M.D.

Alexander, P. E., R. Armstrong, G. Fareed, J. Lotus, R. Oskoui, C. Prodromos, H. A. Risch, H. C. Tenenbaum, C. M. Wax, P. Dara, P. A. McCullough and K. K. Gill (2021). “Early multidrug treatment of SARS-CoV-2 infection (COVID-19) and reduced mortality among nursing home (or outpatient/ambulatory) residents.” Med Hypotheses 153: 110622.

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The outbreak of COVID-19 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world with tremendous morbidity and mortality in the elderly. In-hospital treatment addresses the multifaceted nature of the illness including initial viral replication, cytokine storm, and endothelial injury with thrombosis. We identified nine reports of early treatment outcomes in COVID-19 nursing home patients. Multi-drug therapy including hydroxychloroquine with one or more anti-infectives, corticosteroids, and antithrombotic anti-blood clotting agents can be extended to seniors in the nursing home setting without hospitalization. Data from nine studies found hydroxychloroquine-based multidrug regimens were associated with a statistically significant > 60% reduction in mortality. Going forward, we conclude that early empiric treatment for the elderly with COVID-19 in the nursing home setting (or similar congregated settings with elderly residents/patients e.g. LTF or ALF) has a reasonable probability of success and acceptable safety. This group remains our highest at-risk group and warrants acute treatment focus prior to symptoms worsening. Given the rapidity and severity of SARS-CoV-2 outbreaks in nursing homes, in-center treatment of acute COVID-19 patients is a reasonable strategy to reduce the risks of hospitalization and death. If elderly high-risk patients in such congregated nursing home type settings are allowed to worsen with no early treatment, they may be too sick and fragile to benefit from in-hospital therapeutics and are at risk for pulmonary failure, life-ending micro-thrombi of the lungs, kidneys etc. The issue is timing of therapeutics, and we argue that early treatment before hospitalization, is the right time and can potentially save lives, especially among our higher-risk elderly populations hit hardest by severe illness and death from COVID-19. We must reiterate, we are talking about ‘early’ treatment before the disease is far along in the disease sequelae where the patient then needs hospitalization and aggressive interventions. We are referring to the initial days e.g. day one, post infection when symptoms emerge or there is strong clinical suspicion. This early therapeutic option deserves serious and urgent consideration by the medical establishment and respective decision-makers. Doctors must be allowed their clinical discretion in how they optimally treat their patients. Doctors must be brave and trust their skilled judgements and do all to save the lives of their patients. We therefore hypothesize that early outpatient ambulatory treatment, once initiated as soon as symptoms begin in high-risk positive persons, would significantly reduce hospitalizations and prevent deaths. Specifically, the provision of early multi-drug sequenced therapy with repurposed drugs will reduce hospitalization and death in elderly patients being cared for in long-term-care facilities. The most important implications of our hypothesis are: 1) hospitalizations and deaths would be reduced 2) transmission would be reduced due to the mitigation of symptoms and 3) recovery following infection and treatment provides for natural exposure immunity that is broad based, durable, and robust (helping towards natural immunity within the population). The end result is reduced strain on hospitals and systems that would allow for other non-COVID illnesses to receive care.