Patients with COVID-19 Infection and Stroke have Higher than Expected Mortality, Regardless of the Primary Presentation (preprint)

BackgroundCOVID-19 infection is associated with thrombotic events; however, this phenomenon is poorly understood. Few studies have reported the association between COVID-19 and stroke in the hospital setting. MethodsWe retrospectively reviewed and characterized all patients who presented to a single, quaternary medical center between March and December 2020 (N=603). COVID-19 positive patients who developed ischemic or hemorrhagic stroke were included in the analysis (N=66). This cohort was compared with patients who were COVID-19 negative at the time of stroke presentation in the same period (N=537). Statistical significance was evaluated using Pearsons Chi squared test with Yates continuity correction and linear model ANOVA. ResultsSixty-six patients had COVID-19 and Stroke. Of these patients, 22 (33.4%) patients initially presented with stroke and 44 (66.7%) initially presented with COVID-19. Patients who presented with COVID-19 and had a stroke during their hospitalization (COVID-first) had worse outcomes than patients presenting to the hospital with stroke whose COVID test became positive later in the hospitalization (stroke-first). Patients who presented with COVID-19 and had a stroke during their hospitalization had an increased rate of acute renal failure (48.9% vs 19.0%, p=0.021) and need for ventilation (60.0% vs 28.6%, p=0.017). Further, in the COVID-first cohort, the use of heparin prior to the stroke event was not associated with mortality or type of stroke (ischemic or hemorrhagic). ConclusionIn the early pandemic, patients with COVID-19 infection and stroke had a higher mortality rate compared to COVID-19 negative patients with stroke. Among patients with both COVID-19 and stroke, patients presenting with COVID-19 first had worse outcomes than patients presenting with stroke first. The use of heparin prior to the stroke event was not associated with mortality or type of stroke.

Impacts of the COVID-19 pandemic on pediatric and adult patients with haemophilia (preprint)

Background:The COVID-19-associated mortality rate of haemophilia patients is similar to that of the general population, but the risk of hospitalization and bleeding is higher. However, the specific impact of this infection on haemophilia patients has not been reported yet. In this study, we aimed to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the infection susceptibility, symptoms, drug use, and social intercourse of patients with haemophilia. Methods: A survey was distributed to a total of 265 patients with haemophilia [adult (n = 185) and pediatric patients (n = 80)] in the Fujian haemophilia therapeutic center (Fuzhou City, China) during the COVID-19 pandemic, and data were collected between January 2022 and January 2023. The impacts of SARS-CoV-2 infection on haemophilia symptoms, drug use, and social intercourse of these patients were investigated, and the association between the recovery time and disease conditions was explored in infected patients. Results: During the COVID-19 pandemic, compared with adult patients, pediatric patients had reduced social intercourse and outdoor activities because of the fear of contracting COVID-19 (85.0% vs. 66.5%; P = 0.002). Bleeding events were also significantly fewer in children than in adults (61.2% vs. 81.1%; P = 0.001). The SARS-CoV-2 infection rate was significantly higher in patients living in urban areas than in those living in rural areas (74.3% vs. 53.6%; P < 0.001). The duration of achieving symptomatic recovery from COVID-19 was not significantly associated with hemorrhage, type and classification of haemophilia, presence of inhibitors, complications, and vaccination status. Conclusion: Having COVID-19 infection did not significantly influence the symptoms and treatments in patients with haemophilia. Compared with adults, pediatric patients had significantly fewer bleeding events.

Delayed Fatal Pulmonary Hemorrhage Following COVID-19 Vaccination: Case Report, Batch Analysis, And Proposed Autopsy Checklist (preprint)

We present a case of a 47-year-old male who died unexpectedly from acute pulmonary hemorrhage 555 days after completing the BNT162b2 (Pfizer) COVID-19 vaccination primary series. Before death, he exhibited symptoms of a mild respiratory infection. Despite a healthy medical history and no medication use, the patient’s condition rapidly deteriorated and he experienced severe respiratory distress, followed by cardiopulmonary arrest with evidence of profuse pulmonary bleeding. Autopsy findings revealed massive lung congestion without embolism, normal heart size, moderate coronary atherosclerosis without myocardial infarction, and no evidence of other hemorrhagic events. The patient tested negative for COVID-19 and other respiratory pathogens at autopsy. Despite these findings, the medical examiner determined the cause of death was attributed to atherosclerotic and hypertensive cardiovascular disease, without considering the recent pulmonary hemorrhage and unremarkable medical history. Investigation into the vaccine batch indicated a higher-than-average number of serious adverse events, including fatalities. The patient's BNT162b2 batch was among the top 2.8% for reported deaths. Moreover, the autopsy failed to investigate potential contributions from the vaccine, such as the presence of the Spike protein or related antibodies. The evidence suggests that the pulmonary hemorrhage, exacerbated by a viral infection, was the immediate cause of death, with the COVID-19 vaccine potentially playing a role in the development of cardiopulmonary pathology and hemorrhage. We propose autopsy protocols for COVID-19 vaccine recipients to better investigate vaccine-related pathologies among those with one or more prior injections.

Abnormal uterine bleeding during the COVID-19 pandemic: a national survey (preprint)

Objective: To evaluate and characterize menstrual changes among COVID-19 vaccinated and infected women. Design A national survey. Setting An online nationwide questionnaire survey, querying about menstrual changes after COVID-19 vaccination or infection. Population Reproductive-age non-pregnant women. Methods The questionnaire was distributed via an online link through social media and directed the participants to an online anonymous Google questionnaire. Results In total, 10,319 women responded, of which 7,904 met the inclusion criteria. Changes in menstrual patterns following the BNT162b2 vaccine were reported by 3,689 (46.7%). Of these, 2,974 women, (80.6%) described excessive bleeding (heavy, prolonged, or intermenstrual) compared with 715 (19.4%) who reported scant bleeding (light, short, or prolonged intervals). Among women who experienced abnormal uterine bleeding (AUB), in most cases (61.1%) it occurred between the vaccination and the ensuing menstrual period. Menstrual disturbances were more common among accurately vaccinated women compared with inaccurately vaccinated by having received a single shot or having undergone a prolonged interval between shots (51% vs 36.6%, P < .001). Menstrual disturbances were similar in type and distribution among the vaccinated and infected women. Conclusions AUB emerged as a side effect of the BNT162b2 vaccine and a symptom of the COVID-19 infection. It was characterized mainly by excessive bleeding. Although the precise incidence could not be determined in this study, the type of bleeding disturbance, as well as the characterization of women at risk, were well defined. The incidence and the long-term consequences of the BNT162b2 vaccine on uterine bleeding warrant further investigation.

The Diagnostic And Therapeutic Value Of Bronchoscopy In COVID-19 Patients On Veno-venous Extracorporeal Membrane Oxygenator (ECMO) Support: A Single Center Experience. (preprint)

Introduction: Mechanically ventilated patients COVID-19 patients on veno-venous extracorporeal membrane oxygenation (VV-ECMO) support often require bronchoscopy for pulmonary toilet. However, bronchoscopy in these patients may lead to tracheobronchial bleeding from instrumentation and vial aerosolization. The aim of this study was to assess the indications, benefits, and complications of bronchoscopy in critically ill patients with COVID-19 on VV-ECMO. Methods: This was a single center observational cohort study comprising of adults with COVID-19 infection that required mechanical ventilation and VV-ECMO from January 1, 2019 to November 1, 2021 and needed bronchoscopy. The primary outcome was improvement in patient outcome defined as either in improvement in PaO2 levels or VV-ECMO parameters 6 hours after the procedure. Secondary outcomes included microbiological data from the BAL samples. Mann-Whitney U and χ2 tests were used to compare continuous and categorical variables, respectively. Wilcoxon rank sum test for comparing correlated non-parametric continuous data. The median difference was calculated using the Hodges-Lehman estimator. Results: A total of 89 bronchoscopies were performed in 44 patients with COVID-19 on VV-ECMO. Median (IQR) PaO2 was 64 (57-75) mmHg prior to bronchoscopy, whereas it was mildly improved to 70 (58-89) mmHg, 6 hours after the procedure [Hodges-Lehman median difference (95% CI): 4.5 (2.0 – 8.0) mm Hg, p <0.01]. There was no significant difference in VV-ECMO parameters before and after the procedure. 10 patients had different microorganisms in broncheo-alveolar lavage that were not diagnosed with tracheal aspirate. No patient developed new bleeding post bronchoscopy requiring interruption of anticoagulation. No proceduralist reported testing positive for COVID-19 up to 2 weeks post bronchoscopy. Conclusions: Bronchoscopy is a feasible and relatively safe procedure in COVID-19 patients on VV-ECMO and might be beneficial in select patients to improve oxygenation and tailor antibiotic therapy. Larger studies are required to evaluate the overall impact on patient’s recovery with serial bronchoscopies.

The COVID-19 pandemic and clinical characteristics of colorectal cancer: a multicenter retrospective study (preprint)

Purpose. The spread of COVID-19 has led to numerous hospitals prioritizing case management and to delays in diagnosis and treatment. Consequently, many cancer patients have developed life-threatening complications during the COVID-19 pandemic. The aim of this study was to investigate the impact of COVID-19 pandemic on colorectal cancer (CRC), including its clinical and pathologic characteristics.Methods. This multicenter cohort study was performed at six institutions in Korea and included a total of 3871 patients with CRC treated between March 2019 and February 2021. After exclusion of 211 patients who did not undergo surgery, the data of 3660 patients were compared 1 year before and after the COVID-19 pandemic. The patients’ baseline characteristics, CRC-related complications, perioperative outcomes including emergency surgery, R0 resection rates, stoma formations, postoperative complications, and pathologic outcomes were assessed.Results. The number of patients decreased during the pandemic (− 18.0%, from 2127 to 1744), but the baseline characteristics did not differ. The pandemic group had greater disease severity given the presence of bleeding, perforation, and obstruction as complications (9.8% vs. 12.7%, P = 0.033). The proportion of patients who had open surgery (15.9% vs. 17.6%, P = 0.049), stoma formation (11.9% vs. 15.4%, P < 0.001), early postoperative complications (13.5% vs. 17.5%, P = 0.001), and adjuvant chemotherapy increased in the pandemic group (45.5% vs. 50.1%, P = 0.003).Conclusion. The clinical and pathologic features of CRC partly worsened during the pandemic. Healthcare providers and governments should prepare to encounter patients with CRC having poor clinical features for years and encourage people to participate in cancer screening programs.Trial registration: The Clinical Research Information Service (No. KCT0008063), January 2, 2023, retrospectively registered.

Neuropsychiatric sequelae in an experimental model of post-COVID syndrome in mice (preprint)

The global impact of the COVID-19 pandemic has been unprecedented, and presently, the world is facing a new challenge known as Post-COVID syndrome (PCS). Current estimates suggest that more than 65 million people are grappling with PCS, encompassing several manifestations, including pulmonary, musculoskeletal, metabolic, and neuropsychiatric sequelae (cognitive and behavioral). The mechanisms underlying PCS remain unclear. The present study aimed to: (i) comprehensively characterize the acute effects of pulmonary inoculation of the betacoronavirus MHV-A59 in immunocompetent mice at clinical, cellular, and molecular levels; (ii) examine potential acute and long-term pulmonary, musculoskeletal, and neuropsychiatric sequelae induced by the betacoronavirus MHV-A59; and to (iii) assess sex-specific differences. Male and female C57Bl/6 mice were initially inoculated with varying viral titers (3x103 to 3x105 PFU/30 L) of the betacoronavirus MHV-A59 via the intranasal route to define the highest inoculum capable of inducing disease without causing mortality. Further experiments were conducted with the 3x104 PFU inoculum. Mice exhibited an altered neutrophil/lymphocyte ratio in the blood in the 2nd and 5th day post-infection (dpi). Marked lung lesions were characterized by hyperplasia of the alveolar walls, infiltration of polymorphonuclear leukocytes (PMN) and mononuclear leukocytes, hemorrhage, increased concentrations of CCL2, CCL3, CCL5, and CXCL1 chemokines, as well as high viral titers until the 5th dpi. While these lung inflammatory signs resolved, other manifestations were observed up to the 60 dpi, including mild brain lesions with gliosis and hyperemic blood vessels, neuromuscular dysfunctions, anhedonic-like behavior, deficits in spatial working memory, and short-term aversive memory. These musculoskeletal and neuropsychiatric complications were exclusive to female mice and were prevented after ovariectomy. In summary, our study describes for the first time a novel sex-dependent model of PCS focused on neuropsychiatric and musculoskeletal disorders. This model provides a unique platform for future investigations regarding the effects of acute therapeutic interventions on the long-term sequelae unleashed by betacoronavirus infection.

Effect of Heparin and Tocilizumab in Patients with Severe COVID-19: The HEPMAB Randomized Clinical Trial (preprint)

BackgroundClinical presentation of severe Coronavirus disease 2019 (COVID-19) is associated to an intense inflammatory response and thrombogenesis. The benefits of the association of interleukin-6 receptor blockade (tocilizumab) and therapeutic-dose anticoagulation remains unclear. We aimed to assess whether heparin and tocilizumab could effectively reduce inflammation and thrombogenesis in severe COVID-19 patients. MethodsThis is an open-label, multicenter, randomized, clinical trial, involving patients with severe COVID-19 infection. Eligible patients were randomly assigned in a 1:1:1:1 ratio to receive either therapeutic or prophylactic anticoagulation with heparin, with or without an intravenous single dose of tocilizumab. The participants in the study were assigned to one of the four distinct arms: 1) therapeutic anticoagulation; 2) prophylactic anticoagulation; 3) therapeutic anticoagulation plus a single intravenous dose of tocilizumab; and 4) prophylactic anticoagulation plus a single intravenous dose of tocilizumab. The primary outcome was clinical improvement at day 30, defined as a composite of hospital discharge and/or a reduction of at least 2 points of the modified ordinal scale of 7 points recommended by the World Health Organization. ResultsWe enrolled 308 patients. Patients randomized to receive therapeutic anticoagulation more frequently had clinical improvement at day 30 when compared to the prophylactic anticoagulation patients [64/75 (85%) versus 51/80 (64%), odds ratio, 3.31; 95% confidence interval, 1.51; 7.26 P=0.003]. Major bleeding was more frequent in the therapeutic anticoagulation group (6.7%) and in the therapeutic anticoagulation plus tocilizumab group (5.0%), compared to the prophylactic anticoagulation group (P=0.02). All-cause mortality at day 30 was significantly lower in therapeutic anticoagulation group (9.3%), when compared to prophylactic anticoagulation group (28.7%), therapeutic anticoagulation plus tocilizumab group (21.5%) and prophylactic anticoagulation plus tocilizumab group (25.7%), P=0.02. ConclusionsIn this randomized clinical trial involving severe COVID-19 patients, therapeutic anticoagulation resulted in clinical improvement at 30 days. Even if therapeutic anticoagulation increased bleeding, it was associated with a reduced overall mortality. Tocilizumab did not provide additional benefits to heparin in COVID-19 patients. Trial registrationClinicaltrials.gov NCT04600141. Registered October 22, 2020. https://www.clinicaltrials.gov/study/NCT04600141?term=NCT04600141&rank=1

The impact of COVID-19 vaccines on patients with immune thrombocytopenic purpura:A protocol for a systematic review and meta-analysis (preprint)

Abstract Introduction Immune thrombocytopenic purpura (ITP) is characterized by a decrease in platelet counts and can be triggered by various factors, such as viral infections and vaccinations. Concerns have emerged regarding potential links between the vaccines for COVID-19 and the worsening of ITP. This systematic review aims to comprehensively assess the impact of COVID-19 vaccines on patients with ITP, including associated risks and outcomes. Methods and Analysis A thorough search will be conducted across multiple electronic databases, including PubMed, MEDLINE, EMBASE, Cochrane Library, CNKI, Wan Fang, VIP, and CBM, to identify pertinent studies. This study will encompass randomized controlled trials, cohort studies, case-control studies, and case series that assess the effects of COVID-19 vaccines on individuals with ITP. The primary outcome will center on alterations in platelet count, while secondary outcomes will encompass the occurrence of thromboembolic events, bleeding complications, recurrence rate of ITP, impact of ITP exacerbation, and adverse events. The data will be synthesized and subjected to meta-analysis using Review Manager Software (RevMan) V.5.3. Additionally, subgroup analyses will be conducted to investigate potential sources of heterogeneity.

SARS-CoV-2 infects neurons, astrocytes, choroid plexus epithelial cells and pericytes of the human central nervous system (preprint)

SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, is associated with a range of neurological manifestations including haemorrhage, thrombosis and ischaemic necrosis and encephalitits. However, the mechanism by which this occurs is unclear. Neurological disease associated with SARS-CoV-2 infection has been proposed to occur following direct infection of the central nervous system and/or indirect sequelae as a result of peripheral inflammation. We profiled ACE2 and TMPRSS2 in brain tissue from five healthy human donors, and observed expression of these proteins in astrocytes, neurons and choroid plexus epithelium within frontal cortex and medulla. Primary human astrocytes, neurons and choroid plexus epithelial cells supported productive SARS-CoV-2 infection in an ACE2- dependent manner. Infected cells supported the full viral lifecycle, releasing infectious virus particles. In contrast, primary brain microvascular endothelial cells, pericytes and microglia were refractory to SARS-CoV-2 infection. These data support a model whereby SARS-CoV-2 is neurotropic, and this may in part explain the neurological sequelae of infection. ImportanceA subset of patients with COVID-19 develop neurological symptoms, but the underlying cause is poorly understood. We observed that cells within normal human brain express the SARS-CoV-2 entry factors ACE-2 and TMPRRS2, with expression mainly observed within astrocytes, neurons and choroid plexus epithelium. Primary human astrocytes, neurons and choroid plexus epithelial cells cultured in vitro supported the full SARS-CoV-2 life cycle with a range of SARS-CoV-2 variants. This study demonstrates that cells of the human central nervous system express SARS-CoV-2 entry factors in vivo and support viral infection in vitro, thus supporting a model where neurological symptoms seen in some COVID-19 patients may be as a result of direct viral infection of the central nervous system. Furthermore, these data highlight the importance of investigating the ability of therapeutics to clear virus from this potential reservoir of infection.

Long-term outcomes of hospitalized SARS-CoV-2/COVID-19 patients with and without neurological involvement: 3-year follow-up assessment (preprint)

Background and ObjectivesAcute neurological manifestations are a common complication of acute COVID-19 disease. This study investigated the 3-year outcomes of patients with and without significant neurological manifestations during initial COVID-19 hospitalization. MethodsPatients infected by SARS-CoV-2 between March 1 and April 16, 2020 and hospitalized in the Montefiore Health System in the Bronx, an epicenter of the early pandemic, were included. Follow-up data was captured up to January 23, 2023 (3 years post COVID-19). This cohort consisted of 414 COVID-19 patients with significant neurological manifestations and 1199 propensity-matched COVID- 19 patients without neurological manifestations. Primary outcomes were mortality, stroke, heart attack, major adverse cardiovascular events (MACE), reinfection, and hospital readmission post-discharge. Secondary outcomes were clinical neuroimaging findings (hemorrhage, active stroke, prior stroke, mass effect, and microhemorrhage, white-matter changes, microvascular disease, and volume loss). Predictive models were used to identify risk factors of mortality post-discharge. ResultsMore patients in the neurological cohort were discharged to acute rehabilitation (10.54% vs 3.68%, p<0.0001), skilled nursing facilities (30.67% vs 20.78%, p=0.0002) and fewer to home (55.27% vs 70.21%, p<0.0001) compared to the matched controls. Incidence of readmission for any medical reason (65.70% vs 60.72%, p=0.036), stroke (6.28% vs 2.34%, p<0.0001), and MACE (20.53% vs 16.51%, p=0.032) was higher in the neurological cohort post-discharge. Neurological patients were more likely to die post-discharge (58 (14.01%) vs 94 (7.84%), p=0.0001) compared to controls (HR=2.346, 95% CI=(1.586, 3.470), p<0.0001). The major causes of death post-discharge were heart disease (14.47%), sepsis (13.82%), influenza and pneumonia (11.18%), COVID-19 (8.55%) and acute respiratory distress syndrome (7.89%). Factors associated with mortality after leaving the hospital were belonging to the neurological cohort (OR=1.802 (1.237, 2.608), p=0.002), discharge disposition (OR=1.508, 95% CI=(1.276, 1.775), p<0.0001), congestive heart failure (OR=2.281 (1.429, 3.593), p=0.0004), higher COVID-19 severity score (OR=1.177 (1.062, 1.304), p=0.002), and older age (OR=1.027 (1.010, 1.044), p=0.002). There were no group differences in gross radiological findings, except the neurological cohort showed significantly more age-adjusted brain volume loss (p<0.05) compared to controls. DiscussionCOVID-19 patients with neurological manifestations have worse long-term outcomes compared to matched controls. These findings raise awareness and the need for closer monitoring and timely interventions for COVID-19 patients with neurological manifestations.

ST-Segment Elevation Myocardial Infarction on the Line: Inadvertent Arterial Infusion of Vasopressors Causing Acute Myocardial Infarction.

Central venous catheters (CVCs), regarded as lines of life, are helpful in hemodynamic monitoring and delivering medications to patients. However, there are several complications that can result from the placement of CVCs. This includes accidental arterial puncture, which has a temporal association with hemorrhage, hematoma, and stroke. Infusion of vasopressors through such a mispositioned arterial CVC further increases the risk of these complications with potential end-organ ischemia. Here, we discuss the case of a 76-year-old woman who developed a myocardial infarction, heart failure, and subarachnoid hemorrhage following the arterial infusion of vasopressors through a malpositioned CVC.

Nebulized recombinant tissue plasminogen activator (rt-PA) for acute COVID-19-induced severe respiratory failure: an exploratory proof of concept trial (preprint)

Nebulized thrombolysis offers locally targeted therapy with potentially lower bleeding risk than systemic administration for coronavirus disease 2019 (COVID-19) respiratory failure. In a proof-of-concept safety study, adult patients with COVID-19-induced respiratory failure and a <300mmHg PaO2/FiO2 (P/F) ratio, requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care during the first two UK COVID-19 waves. Matched historical controls (MHC; n=18) were used in C1. Safety co-primary endpoints were treatment-related bleeds and fibrinogen reduction to <1.0–1.5 g/L. A dose escalation strategy for improved efficacy with the least safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA per day for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeding events (one severe and three mild) in three patients were considered treatment-related. No significant fibrinogen reductions were reported. Greater improvement in mean P/F ratio from baseline to end of study was observed in C1 compared with MHC [C1; 154 to 299 vs MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in P/F ratio was observed in NIRS patients [NIRS; 126 to 240 vs IMV; 120 to 188) and they required fewer treatment days (NIRS; 7.86 vs IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, showing a trend of improved oxygenation and faster recovery in patients with acute COVID-19-induced respiratory failure requiring respiratory support; this effect was more pronounced in the NIRS group. Further investigation is required to study the potential of this novel treatment approach.

Edoxaban Versus Low-Molecular-Weight Heparin in Hospitalized COVID-19 Patients With Atrial Fibrillation.

OBJECTIVE: During the first wave of the SARS-CoV-2 pandemic, management of anticoagulation therapy in hospitalized patients with atrial fibrillation (AF) was simplified to low-molecular-weight heparin (LMWH) followed by oral anticoagulation, mainly owing to the risk of drug-drug interactions. However, not all oral anticoagulants carry the same risk. METHODS: Observational, retrospective, and multicenter study that consecutively included hospitalized patients with AF anticoagulated with LMWH followed by oral anticoagulation or edoxaban concomitantly with empirical COVID-19 therapy. Time-to-event (mortality, total bleeds, and admissions to ICU) curves, using an unadjusted Kaplan-Meier method and Cox regression model adjusted for potential confounders were constructed. RESULTS: A total of 232 patients were included (80.3 ± 7.7 years, 50.0% men, CHA2DS2-VASc 4.1 ± 1.4; HAS-BLED 2.6 ± 1.0). During hospitalization, patients were taking azithromycin (98.7%), hydroxychloroquine (89.7%), and ritonavir/lopinavir (81.5%). The mean length of hospital stay was 14.6 ± 7.2 days, and total follow-up was 31.6 ± 13.4 days; 12.9% of patients required admission to ICU, 18.5% died, and 9.9% had a bleeding complication (34.8% major bleeding). Length of hospital stay was longer in patients taking LMWH (16.0 ± 7.7 vs 13.3 ± 6.5 days; P = .005), but mortality and total bleeds were similar in patients treated with edoxaban and those treated with LMWH followed by oral anticoagulation. CONCLUSIONS: Mortality rates, arterial and venous thromboembolic complications, and bleeds did not significantly differ between AF patients receiving anticoagulation therapy with edoxaban or LMWH followed by oral anticoagulation. However, the duration of hospitalization was significantly lower with edoxaban. Edoxaban had a similar therapeutic profile to LMWH followed by oral anticoagulation and may provide additional benefits.

Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial.

Importance: Platelet activation is a potential therapeutic target in patients with COVID-19. Objective: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19. Design, Setting, and Participants: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients. Intervention: Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures: The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis. Results: At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77). Conclusions and Relevance: In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

COVID-19 Disease and Menstrual-Related Disturbances: A Spanish Retrospective Observational Study in Formerly Menstruating Women (preprint)

After three years of the onset of the pandemic, there is scarce evidence about how COVID-19 disease affect the female reproductive system, and consequently, the menstrual cycle. Since the common causes of secondary amenorrhea are considered as exclusion criteria in the studies about menstrual changes following SARS-CoV-2 infection, the prevalence of this event and the influencing factors in formerly menstruating women remains unknown. A retrospective observational cross-sectional study was conducted on Spanish adult women (N= 17,512), using an online survey; a subpopulation of SARS-CoV-2-infected-formerly menstruating women was included in the present analysis (n= 72). Collected data included general characteristics, medical history, and specific information about COVID-19 disease. 38.9% of the respondents experienced menstrual-related disturbances after suffering from the COVID-19 disease, unexpected vaginal bleeding being the most common (20.8%). Other alterations related with the length – “shorter” by 12.5% − and the flow − “heavier than usual” 30.3% − of the menstrual bleeding were reported. The binary logistic regression showed that being a perimenopausal woman (AOR 4.608, CI 95%, 1.018 – 20.856, p = 0.047) and having heavy menstrual bleeding (AOR 4.857, CI 95%, 1.239 – 19.031, p=0.023) are influential factors. This evidence could help health professionals to provide scientifically up-to-date information to their patients, empowering them to actively manage their reproductive health, especially in those societies where menstrual health is still a taboo.

Stroke Hospitalization Administration & Monitoring: Routine Or Covid-19 Care (SHAMROCC) (preprint)

BACKGROUND Monitoring stroke patients in critical-care units for 24 hours after thrombolysis or endovascular thrombectomy is considered standard of care but is not evidence-based. Due to the Covid-19 pandemic, our center modified its protocol in April 2021 with 24-hour critical-care monitoring no longer being guaranteed for stroke patients. We aim to compare the incidence and timing of complications over the first 24 hours post-reperfusion therapies and their association to hospital unit in 2019, 2020 and 2021. METHODS We conducted a single-center retrospective cohort study. We analyzed data from stroke patients treated with thrombolysis and/or endovascular thrombectomy at our center in 2019 (pre-Covid-19, standard of care), 2020 (during Covid-19, standard of care) and 2021 (during Covid-19, new protocol). Data extracted included demographics, the nature and timing of complications within the first 24 hours, and the unit at the time of any complication. Major complications included neurologic deterioration, symptomatic intracranial hemorrhage, recurrent stroke, myocardial infarction, systemic bleeding, rapid assessment of critical events call, and death. RESULTS Three hundred forty-nine patients were included in our study: 78 patients in 2019, 115 patients in 2020, and 156 patients in 2021. In 2021, 32% of patients experienced at least one complication within the first 24 hours compared to 34% in 2020 and 27% in 2019. In 2021, 33% of patients admitted to critical-care units had a complication compared to 31% in 2020 and 26% in 2019. In 2021, 70% of complications had occurred by hour eight compared to 49% in 2020 and 29% in 2019. CONCLUSIONS Despite the change of protocol in April 2021, the incidence and timing of complications did not significantly worsen compared to prior years and were not associated with hospital location. Further research is required to evaluate the necessity of critical care monitoring for 24 hours in this population.

Vascular Spectrum of Imaging Findings in COVID-19: Ischemic, Hemorrhagic, and Thromboembolic Complications

Abstract Ischemic strokes secondary to occlusion of large vessels have been described in patients with COVID-19. Also, venous thrombosis and pulmonary thromboembolism have been related to the disease. Vascular occlusion may be associated with a prothrombotic state due to COVID-19-related coagulopathy and endotheliopathy. Intracranial hemorrhagic lesions can additionally be seen in these patients. The causative mechanism of hemorrhage could be associated with anticoagulant therapy or factors such as coagulopathy and endotheliopathy. We report on cases of ischemic, thrombotic, and hemorrhagic complications in six patients diagnosed with SARS-CoV-2 infection. Chest computed tomography (CT) showed typical SARS-CoV-2 pneumonia findings in all the cases, which were all confirmed by either serology or reverse transcription polymerase chain reaction (RT-PCR) tests.

Impact of atrial fibrillation and anticoagulation on the risk of death, thromboembolic disease and bleeding in patients with COVID-19: the ACO-VID Registry.

OBJECTIVE: To describe the clinical profile, risk of complications and impact of anticoagulation in COVID-19 hospitalized patients, according to the presence of atrial fibrillation (AF). METHODS: Multicenter, retrospective, and observational study that consecutively included patients >55 years admitted with COVID-19 from March to October 2020. In AF patients, anticoagulation was chosen based on clinicians' judgment. Patients were followed-up for 90 days. RESULTS: A total of 646 patients were included, of whom 75.2% had AF. Overall, mean age was 75 ± 9.1 years and 62.4% were male. Patients with AF were older and had more comorbidities. The most common anticoagulants used during hospitalization in patients with AF were edoxaban (47.9%), low molecular weight heparin (27.0%), and dabigatran (11.7%) and among patients without AF, these numbers were 0%, 93.8% and 0%. Overall, during the study period (68 ± 3 days), 15.2% of patients died, 8.2% of patients presented a major bleeding and 0.9% had a stroke/systemic embolism. During hospitalization, patients with AF had a higher risk of major bleeding (11.3% vs 0.7%; p < .01), COVID-19-related deaths (18.0% vs 4.5%; p = .02), and all-cause deaths (20.6% vs 5.6%; p = .02). Age (HR 1.5; 95% CI 1.0-2.3) and elevated transaminases (HR 3.5; 95% CI 2.0-6.1) were independently associated with all-cause mortality. AF was independently associated with major bleeding (HR 2.2; 95% CI 1.1-5.3). CONCLUSIONS: Among patients hospitalized with COVID-19, patients with AF were older, had more comorbidities and had a higher risk of major bleeding. Age and elevated transaminases during hospitalization, but not AF nor anticoagulant treatment increased the risk of all-cause death.