Acute COVID-19 Management in Heart Failure Patients: A Specific Setting Requiring Detailed Inpatient and Outpatient Hospital Care.

The relationship existing between heart failure (HF) and COVID-19 remains questioned and poorly elucidated. Many reports suggest that HF events are reduced during pandemics, although other studies have demonstrated higher mortality and sudden death in patients affected by HF. Several vascular, thrombotic, and respiratory features may deteriorate stable HF patients; therefore, the infection may directly cause direct myocardial damage, leading to cardiac function deterioration. Another concern is related to the possibility that antiviral, anti-inflammatory, and corticosteroid agents commonly employed during acute COVID-19 infection may have potentially deleterious effects on the cardiovascular (CV) system. For these reasons, HF patients deserve specific management with a tailored approach in order to avoid arrhythmic complications and fluid retention events. In this review, we describe the complex interplay between COVID-19 and HF, the evolving trend of infection with related CV events, and the specific management strategy to adopt in this setting.

A Potential Role of the Spike Protein in Neurodegenerative Diseases: A Narrative Review.

Human prion protein and prion-like protein misfolding are widely recognized as playing a causal role in many neurodegenerative diseases. Based on in vitro and in vivo experimental evidence relating to prion and prion-like disease, we extrapolate from the compelling evidence that the spike glycoprotein of SARS-CoV-2 contains extended amino acid sequences characteristic of a prion-like protein to infer its potential to cause neurodegenerative disease. We propose that vaccine-induced spike protein synthesis can facilitate the accumulation of toxic prion-like fibrils in neurons. We outline various pathways through which these proteins could be expected to distribute throughout the body. We review both cellular pathologies and the expression of disease that could become more frequent in those who have undergone mRNA vaccination. Specifically, we describe the spike protein's contributions, via its prion-like properties, to neuroinflammation and neurodegenerative diseases; to clotting disorders within the vasculature; to further disease risk due to suppressed prion protein regulation in the context of widely prevalent insulin resistance; and to other health complications. We explain why these prion-like characteristics are more relevant to vaccine-related mRNA-induced spike proteins than natural infection with SARS-CoV-2. We note with an optimism an apparent loss of prion-like properties among the current Omicron variants. We acknowledge that the chain of pathological events described throughout this paper is only hypothetical and not yet verified. We also acknowledge that the evidence we usher in, while grounded in the research literature, is currently largely circumstantial, not direct. Finally, we describe the implications of our findings for the general public, and we briefly discuss public health recommendations we feel need urgent consideration. An earlier version of this article was previously posted to the Authorea preprint server on August 16, 2022.

Mitogen Activated Protein Kinase (MAPK) Activation, p53, and Autophagy Inhibition Characterize the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein Induced Neurotoxicity.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and prions use common pathogenic pathways to induce toxicity in neurons. Infectious prions rapidly activate the p38 mitogen activated protein kinase (MAPK) pathway, and SARS-CoV-2 spike proteins rapidly activate both the p38 MAPK and c-Jun NH2-terminal kinase (JNK) pathways through toll-like receptor signaling, indicating the potential for similar neurotoxicity, causing prion and prion-like disease. In this review, we analyze the roles of autophagy inhibition, molecular mimicry, elevated intracellular p53 levels and reduced Wild-type p53-induced phosphatase 1 (Wip1) and dual-specificity phosphatase (DUSP) expression in neurons in the disease process. The pathways induced by the spike protein via toll-like receptor activation induce both the upregulation of PrPC (the normal isoform of the prion protein, PrP) and the expression of ß amyloid. Through the spike-protein-dependent elevation of p53 levels via ß amyloid metabolism, increased PrPC expression can lead to PrP misfolding and impaired autophagy, generating prion disease. We conclude that, according to the age of the spike protein-exposed patient and the state of their cellular autophagy activity, excess sustained activity of p53 in neurons may be a catalytic factor in neurodegeneration. An autoimmune reaction via molecular mimicry likely also contributes to neurological symptoms. Overall results suggest that neurodegeneration is in part due to the intensity and duration of spike protein exposure, patient advanced age, cellular autophagy activity, and activation, function and regulation of p53. Finally, the neurologically damaging effects can be cumulatively spike-protein dependent, whether exposure is by natural infection or, more substantially, by repeated mRNA vaccination.

Antecedent Administration of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists and Survival After Hospitalization for COVID-19 Syndrome.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes the angiotensin-converting enzyme-2 (ACE-2) receptor to enter human cells. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB) are associated with ACE-2 upregulation. We hypothesized that antecedent use of ACEI/ARB may be associated with mortality in coronavirus disease 2019 (COVID-19). Methods and Results We used the Coracle registry, which contains data of patients hospitalized with COVID-19 in 4 regions of Italy, and restricted analyses to those ≥50 years of age. The primary outcome was in-hospital mortality. Among these 781 patients, 133 (17.0%) used an ARB and 171 (21.9%) used an ACEI. While neither sex nor smoking status differed by user groups, patients on ACEI/ARB were older and more likely to have hypertension, diabetes mellitus, and congestive heart failure. The overall mortality rate was 15.1% (118/781) and increased with age (PTrend<0.0001). The crude odds ratios (ORs) for death for ACEI users and ARB users were 0.98, 95% CI, 0.60-1.60, P=0.9333, and 1.13, 95% CI, 0.67-1.91, P=0.6385, respectively. After adjusting for age, hypertension, diabetes mellitus, and congestive heart failure, antecedent ACEI administration was associated with reduced mortality (OR, 0.55; 95% CI, 0.31-0.98, P=0.0436); a similar, but weaker trend was observed for ARB administration (OR, 0.58; 95% CI, 0.32-1.07, P=0.0796). Conclusions In those aged ≥50 years hospitalized with COVID-19, antecedent use of ACEI was independently associated with reduced risk of inpatient death. Our findings suggest a protective role of renin-angiotensin-aldosterone system inhibition in patients with high cardiovascular risk affected by COVID-19.

Statistical Analysis Methods Applied to Early Outpatient COVID-19 Treatment Case Series Data

When confronted with a public health emergency, significant innovative treatment protocols can sometimes be discovered by medical doctors at the front lines based on repurposed medications. We propose a statistical framework for analyzing the case series of patients treated with such new protocols, that enables a comparison with our prior knowledge of expected outcomes, in the absence of treatment. The goal of the proposed methodology is not to provide a precise measurement of treatment efficacy, but to establish the existence of treatment efficacy, in order to facilitate the binary decision of whether the treatment protocol should be adopted on an emergency basis. The methodology consists of a frequentist component that compares a treatment group against the probability of an adverse outcome in the absence of treatment, and calculates an efficacy threshold that has to be exceeded by this probability, in order to control the corresponding p-value and reject the null hypothesis. The efficacy threshold is further adjusted with a Bayesian technique, in order to also control the false positive rate. A random selection bias threshold is then calculated from the efficacy threshold to control for random selection bias. Exceeding the efficacy threshold establishes the existence of treatment efficacy by the preponderance of evidence, and exceeding the more demanding random selection bias threshold establishes the existence of treatment efficacy by the clear and convincing evidentiary standard. The combined techniques are applied to case series of high-risk COVID-19 outpatients that were treated using the early Zelenko protocol and the more enhanced McCullough protocol.

Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs.

The mRNA SARS-CoV-2 vaccines were brought to market in response to the public health crises of Covid-19. The utilization of mRNA vaccines in the context of infectious disease has no precedent. The many alterations in the vaccine mRNA hide the mRNA from cellular defenses and promote a longer biological half-life and high production of spike protein. However, the immune response to the vaccine is very different from that to a SARS-CoV-2 infection. In this paper, we present evidence that vaccination induces a profound impairment in type I interferon signaling, which has diverse adverse consequences to human health. Immune cells that have taken up the vaccine nanoparticles release into circulation large numbers of exosomes containing spike protein along with critical microRNAs that induce a signaling response in recipient cells at distant sites. We also identify potential profound disturbances in regulatory control of protein synthesis and cancer surveillance. These disturbances potentially have a causal link to neurodegenerative disease, myocarditis, immune thrombocytopenia, Bell's palsy, liver disease, impaired adaptive immunity, impaired DNA damage response and tumorigenesis. We show evidence from the VAERS database supporting our hypothesis. We believe a comprehensive risk/benefit assessment of the mRNA vaccines questions them as positive contributors to public health.

Inpatient Mortality According to Level of Respiratory Support Received for Severe Acute Respiratory Syndrome Coronavirus 2 (Coronavirus Disease 2019) Infection: A Prospective Multicenter Study.

OBJECTIVES: To describe patients according to the maximum degree of respiratory support received and report their inpatient mortality due to coronavirus disease 2019. DESIGN: Analysis of patients in the Coracle registry from February 22, 2020, to April 1, 2020. SETTING: Hospitals in the Piedmont, Lombardy, Tuscany, and Lazio regions of Italy. PATIENTS: Nine-hundred forty-eight patients hospitalized for coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 948 patients, 122 (12.87%) received invasive ventilation, 637 (67.19%) received supplemental oxygen only, and 189 (19.94%) received no respiratory support. The median (quartile 1-quartile 3) age was 65 years (54-76.59 yr), and there was evidence of differential respiratory treatment by decade of life (p = 0.0046); patients greater than 80 years old were generally not intubated. There were 606 men (63.9%) in this study, and they were more likely to receive respiratory support than women (p < 0.0001). The rate of in-hospital death for invasive ventilation recipients was 22.95%, 12.87% for supplemental oxygen recipients, and 7.41% for those who received neither (p = 0.0004). A sensitivity analysis of the 770 patients less than 80 years old revealed a lower, but similar mortality trend (18.02%, 8.10%, 5.23%; p = 0.0008) among the 14.42%, 65.71%, and 19.87% of patients treated with mechanical ventilation, supplemental oxygen only, or neither. Overall, invasive ventilation recipients who died were significantly older than those who survived (median age: 68.5 yr [60-81.36 yr] vs 62.5 yr [55.52-71 yr]; p = 0.0145). CONCLUSIONS: Among patients hospitalized for coronavirus disease 2019, 13% received mechanical ventilation, which was associated with a mortality rate of 23%.

Usefulness of Combined Renin-Angiotensin System Inhibitors and Diuretic Treatment In Patients Hospitalized with COVID-19.

Antecedent use of renin-angiotensin system inhibitors (RASi) prevents clinical deterioration and protects against cardiovascular/thrombotic complications of COVID-19, for indicated patients. Uncertainty exists regarding treatment continuation throughout infection and doing so with concomitant medications. Hence, the purpose of this study is to evaluate the differential effect of RASi continuation in patients hospitalized with COVID-19 according to diuretic use. We used the Coracle registry, which contains data of hospitalized patients with COVID-19 from 4 regions of Italy. We used Firth logistic regression for adult (>50 years) cases with admission on/after February 22, 2020, with a known discharge status as of April 1, 2020. There were 286 patients in this analysis; 100 patients (35.0%) continued RASi and 186 (65%) discontinued. There were 98 patients treated with a diuretic; 51 (52%) of those continued RASi. The in-hospital mortality rates in patients treated with a diuretic and continued versus discontinued RASi were 8% versus 26% (p = 0.0179). There were 188 patients not treated with a diuretic; 49 (26%) of those continued RASi. The in-hospital mortality rates in patients not treated with a diuretic and continued versus discontinued RASi were 16% versus 9% (p = 0.1827). After accounting for age, cardiovascular disease, and laboratory values, continuing RASi decreased the risk of mortality by approximately 77% (odds ratio 0.23, 95% confidence interval 0.06 to 0.95, p = 0.0419) for patients treated with diuretics, but did not alter the risk in patients treated with RASi alone. Continuing RASi in patients concomitantly treated with diuretics was associated with reduced in-hospital mortality.

Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients.

Aims: Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ random, controlled trials. Having developed combination therapies for Helicobacter pylori, the authors present a highly effective COVID-19 therapeutic combination, stemming from clinical observations. Patients & methods: In 24 COVID-19 subjects refusing hospitalization with high-risk features, hypoxia and untreated moderate to severe symptoms averaging 9 days, the authors administered this novel combination of ivermectin, doxycycline, zinc and vitamins D and C. Results & conclusions: All subjects resolved symptoms (in 11 days on average), and oxygen saturation improved in 24 h (87.4% to 93.1%; p = 0.001). There were no hospitalizations or deaths, less than (p < 0.002 or 0.05, respectively) background-matched CDC database controls. Triple combination therapy is safe and effective even when used in outpatients with moderate to severe symptoms. Clinical Trial Registration: NCT04482686 (ClinicalTrial.gov).

Usefulness of Combined Renin-Angiotensin System Inhibitors and Diuretic Treatment In Patients Hospitalized with COVID-19

Antecedent use of renin-angiotensin system inhibitors (RASi) prevents clinical deterioration and protects against cardiovascular/thrombotic complications of COVID-19, for indicated patients. Uncertainty exists regarding treatment continuation throughout infection and doing so with concomitant medications. Hence, the purpose of this study is to evaluate the differential effect of RASi continuation in patients hospitalized with COVID-19 according to diuretic use. We used the Coracle registry, which contains data of hospitalized patients with COVID-19 from 4 regions of Italy. We used Firth logistic regression for adult (>50 years) cases with admission on/after February 22, 2020, with a known discharge status as of April 1, 2020. There were 286 patients in this analysis;100 patients (35.0%) continued RASi and 186 (65%) discontinued. There were 98 patients treated with a diuretic;51 (52%) of those continued RASi. The in-hospital mortality rates in patients treated with a diuretic and continued versus discontinued RASi were 8% versus 26% (p = 0.0179). There were 188 patients not treated with a diuretic;49 (26%) of those continued RASi. The in-hospital mortality rates in patients not treated with a diuretic and continued versus discontinued RASi were 16% versus 9% (p = 0.1827). After accounting for age, cardiovascular disease, and laboratory values, continuing RASi decreased the risk of mortality by approximately 77% (odds ratio 0.23, 95% confidence interval 0.06 to 0.95, p = 0.0419) for patients treated with diuretics, but did not alter the risk in patients treated with RASi alone. Continuing RASi in patients concomitantly treated with diuretics was associated with reduced in-hospital mortality.

Retrospective Study of Outcomes and Hospitalization Rates of Patients in Italy with a Confirmed Diagnosis of Early COVID-19 and Treated at Home Within 3 Days or After 3 Days of Symptom Onset with Prescribed and Non-Prescribed Treatments Between November 2020 and August 2021.

BACKGROUND This retrospective study aimed to investigate outcomes and hospitalization rates in patients with a confirmed diagnosis of early COVID-19 treated at home with prescribed and non-prescribed treatments. MATERIAL AND METHODS The medical records of a cohort of 158 Italian patients with early COVID-19 treated at home were analyzed. Treatments consisted of indomethacin, low-dose aspirin, omeprazole, and a flavonoid-based food supplement, plus azithromycin, low-molecular-weight heparin, and betamethasone as needed. The association of treatment timeliness and of clinical variables with the duration of symptoms and with the risk of hospitalization was evaluated by logistic regression. RESULTS Patients were divided into 2 groups: group 1 (n=85) was treated at the earliest possible time (<72 h from onset of symptoms), and group 2 (n=73) was treated >72 h after the onset of symptoms. Clinical severity at the beginning of treatment was similar in the 2 groups. In group 1, symptom duration was shorter than in group 2 (median 6.0 days vs 13.0 days, P<0.001) and no hospitalizations occurred, compared with 19.18% hospitalizations in group 2. One patient in group 1 developed chest X-ray alterations and 2 patients experienced an increase in D-dimer levels, compared with 30 and 22 patients, respectively, in group 2. The main factor determining the duration of symptoms and the risk of hospitalization was the delay in starting therapy (P<0.001). CONCLUSIONS This real-world study of patients in the community showed that early diagnosis and early supportive patient management reduced the severity of COVID-19 and reduced the rate of hospitalization.

WITHDRAWN: A Report on Myocarditis Adverse Events in the U.S. Vaccine Adverse Events Reporting System (VAERS) in Association with COVID-19 Injectable Biological Products.

The Publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated.

Role of hydroxychloroquine in multidrug treatment of COVID-19.

No abstract present.