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Background and Purpose: With the spread of coronavirus disease 2019 (COVID-19) during the current worldwide pandemic, there is mounting evidence that patients affected by the illness may develop clinically significant coagulopathy with thromboembolic complications including ischemic stroke. However, there is limited data on the clinical characteristics, stroke mechanism, and outcomes of patients who have a stroke and COVID-19. Method(s): We conducted a retrospective cohort study of consecutive patients with ischemic stroke who were hospitalized between March 15, 2020, and April 19, 2020, within a major health system in New York, the current global epicenter of the pandemic. We compared the clinical characteristics of stroke patients with a concurrent diagnosis of COVID-19 to stroke patients without COVID-19 (contemporary controls). In addition, we compared patients to a historical cohort of patients with ischemic stroke discharged from our hospital system between March 15, 2019, and April 15, 2019 (historical controls). Result(s): During the study period in 2020, out of 3556 hospitalized patients with diagnosis of COVID-19 infection, 32 patients (0.9%) had imaging proven ischemic stroke. Cryptogenic stroke was more common in patients with COVID-19 (65.6%) as compared to contemporary controls (30.4%, P=0.003) and historical controls (25.0%, P<0.001). When compared with contemporary controls, COVID-19 positive patients had higher admission National Institutes of Health Stroke Scale score and higher peak D-dimer levels. When compared with historical controls, COVID-19 positive patients were more likely to be younger men with elevated troponin, higher admission National Institutes of Health Stroke Scale score, and higher erythrocyte sedimentation rate. Patients with COVID-19 and stroke had significantly higher mortality than historical and contemporary controls. Conclusion(s): We observed a low rate of imaging-confirmed ischemic stroke in hospitalized patients with COVID-19. Most strokes were cryptogenic, possibly related to an acquired hypercoagulability, and mortality was increased. Studies are needed to determine the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention in patients with COVID-19.Copyright © 2020 Lippincott Williams and Wilkins. All rights reserved.
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Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.
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Hypofractionation has shown to be beneficial in the management of a wide range of cancers1,2 including other advantages such as cost savings3. Trials over the last decade4,5,6 have demonstrated the advantages of hypofractionation compared with a standard radiotherapy regimen3. Covid-19 significantly impacted the way in which cancer patients7 are managed and even though the use of hypofractionation is well established in some cancer types;the application thereof during the pandemic has been widely expanded to minimise treatment time8. Even though the treatment outcomes have been well defined, there is limited evidence to suggest changes in patient care. Some oncology centres advocated for a reduced contact time between patient and staff9. Hypofractionation in an ageing population is particularly advantageous in allowing people to receive treatment in a shorter time demonstrating treatment outcomes similar to younger age groups10 however;greater consideration should be given to performance status and comorbidities associated with these treatment outcomes11. Fractionation schedules which allow delivery in less fractions, can be highly effective with limited treatment-related toxicity. Studies have shown that the late consequences of radiotherapy in these patient groups are seldom an issue even with larger fraction s12. However more recent studies suggest that a reduction in treatment time should not be the only reason for selecting this approach. Moderate hypofractionation should therefore be considered for those patient who are younger and who might experience long terms effects13. More studies are now investigating the tolerability of ultra-hypofractionated radiotherapy in an attempt to improve the therapeutic gain, suggesting that these approaches are well-tolerated and showed no statistical difference in toxicity14. Hypofractionation in radiotherapy may be a good alternative to conventional fractionation however patience care remains paramount in the management of all toxicities related the radiotherapy delivery. There is no evidence to suggest the patient care of these patients have changed, however the tolerability and outcomes of this method of delivery requires constant review. Patient care needs to consider the site of treatment, age of the patient, performance status, and tolerability. A model of shared decision making in managing care is advocated with greater emphasis on selfcare.
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Objective: To further characterize the relationship between markers of inflammation and outcome in patients undergoing mechanical thrombectomy for acute stroke. Background: Inflammation and infection after ischemic stroke are known to exacerbate tissue injury and worsen clinical outcome. Thrombectomy has become standard of care in stroke, but little data exist regarding how inflammation affects outcome after thrombectomy. Design/Methods: We performed retrospective chart review of stroke patients who underwent mechanical thrombectomy at 2 tertiary academic centers between December 2018 and November 2020. The relationship between discharge mortality, admission WBC count, admission neutrophil percentage, peak WBC count, and fever (peak temperature >38°C) were analyzed using the Wilcoxon rank sum test, Student's t-test, and Fisher's exact test. Multivariable analysis was performed to test for independent predictors of discharge mortality. Analyses were performed for the entire cohort, then repeated in a cohort excluding COVIDpositive patients. Results: Of 254 patients who had thrombectomy for acute stroke, 42 (16.5%) died prior to discharge. Mortality was associated with admission WBC count (10.7 [8.9-14] vs. 8.6 [7-12], p=0.0064), admission neutrophil percentage (78% ± 11 vs. 70% ± 14, p=0.0001), peak WBC count (17 [13-22] vs. 12 [8.9-15], p<0.0001), and fever (71% vs. 29%, p<0.0001). In multivariable analysis, admission WBC count (OR 14, CI 1.5-158, p=0.024), neutrophil percentage (OR 1.04, CI 1.0-1.1, p=0.039), peak WBC count (OR 343, CI 27-5702, p<0.0001) and fever (OR 8.6, CI 3.6-23, p<0.0001) were significantly predictive of discharge mortality after controlling for age, admission NIHSS and post-thrombectomy ASPECTS score. Fifteen patients tested positive for COVID-19. In analyses excluding these patients, peak WBC count and fever remained independent predictors of discharge mortality. Conclusions: Elevated markers of inflammation during hospitalization predict discharge mortality in patients who undergo mechanical thrombectomy for acute stroke. Further study is warranted to investigate causation and identify opportunities to improve quality of care in this patient population.
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These are complex, turbulent, and uncertain times to be sure. The Department of Defense (DOD) is at an important inflection point. COVID-19 has irrevocably altered the dynamics of international security and reshaped DODs decision-making landscape. As a result, DOD will have to adapt to significantly different strategic circumstances post-COVID than those assumed operative in the 2018 National Defense Strategy (NDS18). We recommend that DOD recognize this to be true, seize the initiative, create opportunity from crisis, and recraft defense strategy to re-emerge from COVID as a stronger, more hypercompetitive institution.
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Introduction: While the thrombotic complications of COVID-19 have been described, there are limited data on its implications in hemorrhagic stroke. The clinical characteristics, underlying stroke mechanism, and outcomes in this group of patients are especially salient as empiric therapeutic anticoagulation becomes increasingly common in the treatment and prevention of thrombotic complications of COVID-19. Methods: We conducted a retrospective cohort study of patients with hemorrhagic stroke (both nontraumatic intracerebral hemorrhage and spontaneous non-aneurysmal subarachnoid hemorrhage) who were hospitalized between 3/1/20-5/15/20 at a NYC hospital system, during the coronavirus pandemic. We compared the demographic and clinical characteristics of patients with hemorrhagic stroke and COVID-19 to those without COVID-19 admitted to our hospital between 3/1/20-5/15/20 (contemporary controls) and 3/1/19-5/15/19 (historical controls), using Fischer's exact test and nonparametric testing. We adjusted for multiple comparisons using the Bonferroni method. Results: During the study period, 19 out of 4071 (0.5%) patients who were hospitalized with COVID-19 had hemorrhagic stroke on imaging. Of all COVID-19 with hemorrhagic stroke, only 3 had non-aneurysmal SAH without intraparenchymal hemorrhage. Among hemorrhagic stroke and COVID-19 patients, coagulopathy was the most common etiology (73.7%);empiric anticoagulation was started in 89.5% vs 4.2% of contemporary and 10.0% of historical controls (both with p = <0.001). Compared to contemporary and historical controls, COVID-19 patients had higher initial NIHSS scores, INR, PTT and fibrinogen levels. These patients also had higher rates of in-hospital mortality [84.6% vs. 4.6%, p =<0.001]. Sensitivity analyses excluding patients with strictly subarachnoid hemorrhage yielded similar results. Conclusion: We observed an overall low rate of imaging-confirmed hemorrhagic stroke among patients hospitalized with COVID-19. Most hemorrhages in COVID-19 patients occurred in the setting of therapeutic anticoagulation and were associated with increased mortality. Further studies are needed to evaluate the safety and efficacy of therapeutic anticoagulation in COVID-19 patients.
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Introduction: While coronavirus disease 2019 (COVID-19) has been associated with acute ischemic stroke (AIS), the causal relationship has yet to be elucidated. Factors that likely confer increased stroke risk are COVID-19-associated coagulopathy and hyperinflammatory response. Studying clinical features of patients with otherwise undetermined cause of AIS could help better define COVID-19-associated stroke. Methods: We performed a multicenter cross-sectional study of consecutive patients presenting with AIS and COVID-19 to one of two large healthcare systems in New York City during the local COVID- 19 surge from March 1, 2020 to May 31, 2020. In-hospital stroke cases were excluded. We compared demographic and clinical features of patients with COVID-19 and a cryptogenic AIS subtype to patients with COVID-19 and a determined subtype. Baseline characteristics and clinical variables were compared using chi-squared and Fisher exact tests. Results: A total of 62 patients with AIS and COVID-19 at the time of hospital arrival were identified. Of these, 30 were classified as having a cryptogenic subtype (80% after complete diagnotics evaluation), and 32 had an identifiable stroke mechanism. Patients with cryptogenic AIS were significantly younger (p=0.011) and less likely to have co-morbid hypertension (p=0.019), coronary artery disease (p=0.024), heart failure (p=0.039), atrial fibrillation (<0.0001), and prior stroke or TIA (p=0.033) compared to those with defined mechanisms. Further, d-dimer, but not C-reactive protein, was significantly higher in patients with cryptogenic stroke compared to those with defined causes (p=0.009). Conclusion: Patients with AIS in the setting of COVID-19 and no other determined stroke mechanism were younger, less likely to have classic risk factors, and had higher d-dimer levels when compared to those with a determined mechanism. Further study of COVID-19-associated hypercoagulability as a mechanism of stroke is warranted.
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OBJECTIVES: Hyponatremia occurs in up to 30% of patients with pneumonia and is associated with increased morbidity and mortality. The prevalence of hyponatremia associated with coronavirus disease 2019 and the impact on outcome is unknown. We aimed to identify the prevalence, predictors, and impact on outcome of mild, moderate, and severe admission hyponatremia compared with normonatremia among coronavirus disease 2019 patients. DESIGN: Retrospective, multicenter, observational cohort study. SETTING: Four New York City hospitals that are part of the same health network. PATIENTS: Hospitalized, laboratory-confirmed adult coronavirus disease 2019 patients admitted between March 1, 2020, and May 13, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hyponatremia was categorized as mild (sodium: 130-134 mmol/L), moderate (sodium: 121-129 mmol/L), or severe (sodium: <= 120 mmol/L) versus normonatremia (135-145 mmol/L). The primary outcome was the association of increasing severity of hyponatremia and in-hospital mortality assessed using multivariable logistic regression analysis. Secondary outcomes included encephalopathy, acute renal failure, mechanical ventilation, and discharge home compared across sodium levels using Kruskal-Wallis and chi-square tests. In exploratory analysis, the association of sodium levels and interleukin-6 levels (which has been linked to nonosmotic release of vasopressin) was assessed. Among 4,645 patient encounters, hyponatremia (sodium < 135 mmol/L) occurred in 1,373 (30%) and 374 of 1,373 (27%) required invasive mechanical ventilation. Mild, moderate, and severe hyponatremia occurred in 1,032 (22%), 305 (7%), and 36 (1%) patients, respectively. Each level of worsening hyponatremia conferred 43% increased odds of in-hospital death after adjusting for age, gender, race, body mass index, past medical history, admission laboratory abnormalities, admission Sequential Organ Failure Assessment score, renal failure, encephalopathy, and mechanical ventilation (adjusted odds ratio, 1.43;95% CI, 1.08-1.88;p = 0.012). Increasing severity of hyponatremia was associated with encephalopathy, mechanical ventilation, and decreased probability of discharge home (all p < 0.001). Higher interleukin-6 levels correlated with lower sodium levels (p = 0.017). CONCLUSIONS: Hyponatremia occurred in nearly a third of coronavirus disease 2019 patients, was an independent predictor of in-hospital mortality, and was associated with increased risk of encephalopathy and mechanical ventilation.