Comparison of the Onset and End of Specific and Major Side Effects in Iranian Teenage Participants Vaccinated With COVID-19 Vaccine: Sinopharm and Soberana

Background Clinical trials were conducted on children on side effects after vaccination. We tried to assess the frequency and onset of the main symptoms in children who were vaccinated. We aimed to evaluate early and delayed adverse effects after coronavirus disease 2019 (COVID-19) vaccine among Iranian pediatrics and adolescents in a national survey. Methods This cross-sectional study included people <18 years who received the Soberana (PastoCoVac) and Sinopharm vaccines since 2021. The basic information was gender, age, type of vaccine, and reaction after vaccination besides the main events that occurred for them. The required data were collected via a predetermined checklist by trained interviewers through phone calls by their parents or legal guardians. The independent t test and Fisher exact test were used. P values less than 0.05 were considered significant. Results A total of 11,042 participants (age range, 10-18 years) consisting of 5374 boys (47.8%) and 5768 girls (52.2%) were studied and 88.1% of the children (n = 9727) were vaccinated by Sinopharm and 11.9% (n = 1315) by Soberana. The data of kidney-related side effects had delayed improvement of side effects after the Sinopharm compared with the Soberana vaccines (P = 0.012). Cardiovascular and hematological side effects showed early-onset (P = 0.006) and delayed improvement of side effects (P = 0.002) after the Soberana vaccine compared with the Sinopharm vaccine. Neurological side effects showed delayed improvement of side effects after the Soberana vaccine compared with the Sinopharm vaccine (P = 0.027). Joint-related side effects showed early-onset (P = 0.004) and delayed improvement of side effects (P = 0.023) after the Soberana vaccine compared with the Sinopharm vaccine. Respiratory side effects showed delayed improvement of side effects after the Soberana vaccine compared with the Sinopharm vaccine (P = 0.013), and dermatological side effects showed early-onset (P = 0.050) and delayed improvement of side effects (P = 0.035) after the Soberana vaccine compared with the Sinopharm vaccine. There was not any statistically significant difference regarding gastrointestinal side effects between the 2 vaccines (P > 0.05). Conclusion The cardiovascular and hematological, joint-related (non-neurologic musculoskeletal) and dermatological side effects after the Soberana vaccine appear earlier and end later compared with the Sinopharm vaccine. Improvement of renal side effects in the Sinopharm vaccine group and improvement of neurological and respiratory side effects in the Soberana vaccine group occurred with delay compared with other vaccines.

Comparison of the Onset and End of Specific and Major Side Effects in Iranian Teenage Participants Vaccinated With COVID-19 Vaccine: Sinopharm and Soberana.

Background: Clinical trials were conducted on children on side effects after vaccination. We tried to assess the frequency and onset of the main symptoms in children who were vaccinated. We aimed to evaluate early and delayed adverse effects after coronavirus disease 2019 (COVID-19) vaccine among Iranian pediatrics and adolescents in a national survey. Methods: This cross-sectional study included people <18 years who received the Soberana (PastoCoVac) and Sinopharm vaccines since 2021. The basic information was gender, age, type of vaccine, and reaction after vaccination besides the main events that occurred for them. The required data were collected via a predetermined checklist by trained interviewers through phone calls by their parents or legal guardians. The independent t test and Fisher exact test were used. P values less than 0.05 were considered significant. Results: A total of 11,042 participants (age range, 10-18 years) consisting of 5374 boys (47.8%) and 5768 girls (52.2%) were studied and 88.1% of the children (n = 9727) were vaccinated by Sinopharm and 11.9% (n = 1315) by Soberana. The data of kidney-related side effects had delayed improvement of side effects after the Sinopharm compared with the Soberana vaccines (P = 0.012). Cardiovascular and hematological side effects showed early-onset (P = 0.006) and delayed improvement of side effects (P = 0.002) after the Soberana vaccine compared with the Sinopharm vaccine. Neurological side effects showed delayed improvement of side effects after the Soberana vaccine compared with the Sinopharm vaccine (P = 0.027). Joint-related side effects showed early-onset (P = 0.004) and delayed improvement of side effects (P = 0.023) after the Soberana vaccine compared with the Sinopharm vaccine. Respiratory side effects showed delayed improvement of side effects after the Soberana vaccine compared with the Sinopharm vaccine (P = 0.013), and dermatological side effects showed early-onset (P = 0.050) and delayed improvement of side effects (P = 0.035) after the Soberana vaccine compared with the Sinopharm vaccine. There was not any statistically significant difference regarding gastrointestinal side effects between the 2 vaccines (P > 0.05). Conclusion: The cardiovascular and hematological, joint-related (non-neurologic musculoskeletal) and dermatological side effects after the Soberana vaccine appear earlier and end later compared with the Sinopharm vaccine. Improvement of renal side effects in the Sinopharm vaccine group and improvement of neurological and respiratory side effects in the Soberana vaccine group occurred with delay compared with other vaccines.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

COVID-19 vaccination hesitancy is not all a conspiracy theory: A qualitative study from Iran.

BACKGROUND: The COVID-19 pandemic has burdened disastrous mortality and morbidity rates in society all over the world. While vaccination is one of the most effective immunization methods to control infectious diseases globally, some have avoided receiving the vaccine. We have aimed to investigate the reasons behind the hesitancy of vaccination among healthcare workers. METHOD: We performed ten semi-structured interviews with volunteered healthcare workers of Rasoul Akram hospital. Then each interview was anonymized, and Braun and Clarke's thematic analysis method was used to analyze the interviews. RESULTS: Our data analysis revealed thirty-eight different codes as reasons for vaccination hesitancy among our interviewees. All these thirty-eight codes were grouped into ten sub-themes, and these sub-themes were further grouped into our four main themes: 1. Fear of side effects, 2. Distrust, 3. Inefficiency, and 4. Non-necessity. Fear of side effects was the most frequent reason that interviewees mentioned. Also, Half of the interviewees mentioned distrust as a reason for COVID-19 vaccine hesitancy. At least once, all interviewees mentioned that they believed vaccination is inefficient. Some interviewees had beliefs and reasons that made them assume vaccination is simply not necessary. CONCLUSION: Fear of side effects, distrust, inefficiency, and non-necessity were the reasons that our participants refused to get vaccinated. Fear of side effects and distrust were the most common reasons that led to non-vaccination.

Expression Pattern of Inflammatory and Anti-Inflammatory Cytokines and Key Differential Transcription Factors in Peripheral Blood Mononuclear Cells of Iranian Coronavirus Disease 2019 Patients with Different Disease Severity.

The purpose of this research was to investigate the gene expression levels of inflammatory cytokines interferon (IFN)γ, tumor necrosis factor (TNF)α, interleukin (IL)1ß, IL2, IL6, IL8, and IL17, and anti-inflammatory cytokines IL4, IL10, IFNα, and IFNß, as well as relevant key transcription factors (TFs), including GATA3, PU1, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), IRF3 (interferon regulatory factor 3), BCL6 (B cell lymphoma 6 protein), FOXP3 (forkhead box P3), RORγt, and T-bet (T-box expressed in T cell) in Iranian patients with moderate and severe coronavirus disease 2019 (COVID-19). Fifty-six patients with COVID-19, and 25 healthy controls (HCs) age and sex matched were investigated. Based on the interim guidance of COVID-19 from the World Health Organization, the patients were classified into 33 moderate and 23 severe patients with COVID-19. The gene expression levels of cytokines and relevant TFs were quantified in peripheral blood mononuclear cells by quantitative real-time polymerase chain reaction (qRT-PCR). The gene expression levels of TFs RoRγ (RAR-related orphan nuclear receptor γ), NF-κB, and T-bet were significantly higher in patients with COVID-19 compared with HCs. Furthermore, the gene expression levels of cytokines, including IL2, IFNγ, IL6, TNFα, IL1ß, IL8, and IL17, were significantly higher in patients with COVID-19 than HCs. However, there was a significant increase for IL6, TNFα, and IL17 in severe compared with moderate patients with COVID-19. Finally, The Spearman correlation analysis revealed a significantly positive correlation for IL6 and TNFα, IL6 and IL2, IL6, IFNγ, and IL2 and IFNγ. These data suggest that expression of IL6, TNFα, and IL17 as well as the synergic effect of elevated values of IL2 and IFNγ should be considered in the treatment and management of patients with severe COVID-19.

Effectiveness of Plasmapheresis Treatment in the Treatment of Patients with COVID-19 Disease.

Background: According to the World Health Organization, COVID-19 management focuses primarily on infection prevention, case management, case monitoring, and supportive care. However, due to the lack of evidence, no specific anti-SARS-CoV-2 treatment is recommended. This study aimed to evaluate the effectiveness of plasmapheresis treatment in COVID-19 patients with symptoms of pulmonary involvement on the computed tomography (CT) of the lung. Methods: In 2021, an experimental study in critically ill patients admitted to the COVID-19 ward in the Hazrat-e Rasool hospital diagnosed with COVID-19 was conducted in the second phase (pilot study). The diagnosis was confirmed according to clinical signs, CT scan of the lung, and the Polymerase chain reaction (PCR) test. All patients received the usual treatments for COVID-19 disease and underwent plasmapheresis at a dose of 40 cc/kg daily up to 4 doses. All patients were observed for 24 hours for complications of plasmapheresis treatment and simultaneously for symptoms of COVID-19, after which only routine care measures were performed. The next day and 2 weeks after resumption of the treatment, patients experienced COVID-19 symptoms, including shortness of breath, cough, and fever. Blood oxygen saturation, and treatment results were evaluated. Qualitative and rank variables were described using absolute and relative frequencies and quantitative parametric variables were used using mean and confidence interval. Frequencies were compared in groups using the chi-square test. All tests were performed in 2 directions and P > 0.05 was considered statistically significant. Results: Of the 120 patients studied, 79 (65.8%) were men and 41 (34.2%) were women. The mean age was 60.30 ± 15.61 years (22-95 years). The mean hospital stay was 12.89 days ± 7.25 days (2-38 days). Increased blood oxygen saturation levels in patients had an increasing trend. Inflammatory indices had a downward trend in patients. The frequency of plasmapheresis had no significant effect on reducing the downward trend of inflammatory markers. The greatest reduction occurred in the first plasmapheresis. Conclusion: Finally, according to the findings, plasmapheresis is one of the appropriate treatments to improve patients' symptoms and reduce cytokine storm. Recovered patients had lower levels of inflammatory markers than those who died.

Pediatric and adolescent COVID-19 vaccination side effects: A retrospective cohort study of the Iranian teenage group in 2021.

To determine the safety and efficacy profile of teenager COVID-19 vaccination. In this retrospective cohort study, contact numbers of parents of teenagers under 18 years of age referred to a teenager vaccination centers in Tehran-Iran to receive the corona vaccine were collected, and the following information was obtained via the phones: demographic information, type of vaccine, and the number of doses received, as well as additional information like complications and required treatments. Eleven thousand forty-two subjects aged 10-18 years, mean age 14.55 ± 1.83 year including 5374 boys and 5768 girls were investigated. 88.1% received the Sinopharm and 11.9% the Soberana vaccine. General side effects, including fatigue, fever and chills, injection site pain and dizziness, and so forth happened in 2978 cases; 7421 children presented with at least one general or organ-specific side effect following vaccination, including potentially critical side effects, such as vascular injuries, respiratory complication, and so forth. 0.1% of the subject needed hospital admission. The breakthrough infection happened in 200 individuals. Our study shows that Sinopharm and Soberana (PastoCoVac) COVID-19 vaccines are generally safe with no serious side effects in less than 18 years old. COVID-19 infection and reinfection can occur after vaccination, but the incidence is actually tolerable and significantly lower than in the unvaccinated group.

The effect of opium on severity of COVID-19 infection:An original study from Iran.

Background: The COVID-19 infection is a novel virus without any specific targeted therapies; thus, focusing on primary epidemiologic concerns, preventive strategies, risk factors, exacerbation factors, and mortality-related factors are of great importance to better control this disorder. There are some controversies about the factors associated with COVID-19 in different theories, and addiction is no exception. Methods: We conducted a large cross-sectional study of 513 hospitalized Iranian patients with COVID-19 infection to evaluate the severity of disease courses in patients with or without history of opium addiction. We recorded these data retrospectively after patients' discharge from the hospital. For the quantitative data, we used independent-samples t and Mann-Whitney tests. The qualitative data were calculated using Fisher exact and chi-square tests in IBM SPSS Statistics Version 22. Also, p<0.05 was considered statistically significant. Results: There was no significant difference regarding mean days of hospitalization in opium positive and negative groups (7.95±8.39 vs 8.35±5.11, respectively) (p=0.771); however, the need for intensive care unit (ICU) admission was significantly higher in the opium positive group (36% vs 11%) (p=0.005). The mean days of ICU stay was significantly higher in the opium positive group (2.36±3.81 vs 0.86±2.90) (p=0.026). The percentage of febrile patients, anosmia/hyposmia, and dysgeusia at the initiation of hospitalization was significantly lower in the opium positive group (39% vs 66%; 8% vs 23%; 8% vs; 20%, respectively) (p=0.002, 0.018, and.031, respectively). In the laboratory tests, only the white blood cell (WBC) count and the segmented cells were higher in the opium positive group (10.1±6.60 vs 7.38±4.14 and 73±20.47 vs 56.5±32.60, respectively) (p=0.018 and.001, respectively) and lymphocytes were lower in the opium positive (15.60±8.25 vs18.70±10.12) (p=0.048). Opium addicts had a significantly lower rate of azithromycin and lopinavir/ritonavir prescription in their initiation therapy (19% vs 34%, and 47% vs 70%, respectively) (p=0.038 and 0.012, respectively). Conclusion: Opium addict patients with COVID infection may be more febrile and experience more disease-specific symptoms and more severe disease course. These patients may show more evidence of laboratory inflammation and probable superinfections, so may manage with more caution and somehow different therapeutic regimen.

Histopathologic survey on lung necropsy specimens of 15 patients who died from COVID-19: A large study from Iran with a high rate of anthracosis.

Background: In the pandemic era of Coronavirus disease 19 (COVID-19), one of the most important issues is the nature of real pathological events that occur during disease course in different parts of the body. There are several ways to know more about COVID-related histopathological events,such as tissue sampling which means biopsy from the tissues of either livepeople or necropsy/autopsy of people who died from COVID-19. Methods: We conducted an original study for assessing histopathological findings of lung necropsy samples collected from 15 Iranian patients.The continuous variables were presented as mean and standard deviation, and for the qualitative data on histopathological findings, the percentage or qualitative scores (0 to +3) were used. Results: We found similar presentations of COVID-related histopathologic events regarding percentage and severity in pulmonary tissue, includinglymphocytic infiltrations, inflammatory infiltrations of septal and perivascular areas, desquamated type2 pneumocytes, hyaline membrane changes, fibrin material depositions, abnormal changes of alveolar capillaries, presence of megakaryocytes, PMN infiltrations, septal necrosis, microabscess formation and bacterial colony formation. Also, we found few interesting features which were not completely compatible with previous similar studies or newly reported by ours asa high percentage of anthracosis (86%: 13 patients) that was not clearly reported in other previous studies, also a lower percentage of microthrombotic vascular lung injuries (20%: 3 patients), and a higher percentage of viral cytopathic effects (27%: 4 patients). Conclusion: This article suggests a greater need for evaluatingthe autopsy samples of COVID-19 patients to provide better management strategies and propose the question of whether anthracosismay be a mortality risk factor in COVID-19 patients.

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Renal failure and lung hemorrhage as a presentation of COVID-19 infection, a case report.

The concurrent involvement of the lung and kidneys happens in COVID-19 infection. The patient's respiratory symptoms resolved after hemodialysis. This finding raises the question that if hemodialysis can have a role in the treatment of COVID-19.

Lung abscess as a complication of COVID-19 infection, a case report.

To our knowledge, no previous studies have reported lung abscess as a complication of COVID-19 infection. It is essential to follow-up with the patients after discharge for such complications, especially if they are symptomatic.

Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies.

BACKGROUND: Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown. METHODS: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts. CONCLUSIONS: INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.