Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19.

BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [<6·99] C19-RS; hazard ratio [HR] 3·31 [95% CI 1·49-7·33], p=0·0033; and 2·58 [1·10-6·05], p=0·028), adjusted for clinical factors, biochemical biomarkers of inflammation and myocardial injury, and technical parameters. The adjusted HR for in-hospital mortality was 8·24 (95% CI 2·16-31·36, p=0·0019) in patients who received no dexamethasone treatment, but 2·27 (0·69-7·55, p=0·18) in those who received dexamethasone after the scan, suggesting that vascular inflammation might have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0·61, p=0·00031) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. INTERPRETATION: Radiotranscriptomic analysis of CT angiography scans introduces a potentially powerful new platform for the development of non-invasive imaging biomarkers. Application of this platform in routine CT pulmonary angiography scans done in patients with COVID-19 produced the radiotranscriptomic signature C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation and responsible for adverse clinical outcomes, which predicts in-hospital mortality and might allow targeted therapy. FUNDING: Engineering and Physical Sciences Research Council, British Heart Foundation, Oxford BHF Centre of Research Excellence, Innovate UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, Onassis Foundation.

Early experience with modified dose nirmatrelvir/ritonavir in dialysis patients with coronavirus disease-2019 (preprint)

Introduction: Nirmatrelvir/Ritonavir was approved for use in high risk outpatients with coronavirus disease (COVID-19). However, patients with severe chronic kidney disease, including patients on dialysis, were excluded from the phase 3 trial, and currently the drug is not recommended below a glomerular filtration rate of 30 ml/min/1.73m2 . Based on available pharmacological data and principles, we developed a modified dose which was lower, and administered at longer intervals.We administered nirmatrelvir/ritonavir as 300/100 mg on day one, followed by 150/100 mg daily from day two to day five. In this case series, we report the initial experience with this modified dose regimen. Methods: This is a retrospective chart review, conducted after obtaining institutional board approval. Demographic and outcome data was abstracted from the electronic medical record for dialysis patients who developed COVID-19 during the period of study and received nirmatrelvir/ritonavir. The principal outcomes we describe are symptom resolution, and safety data with the modified dose regimen in the dialysis patients. Results: 19 patients developed COVID-19 during the period of study of whom 15 received nirmatrelvir/ritonavir. 47% of them were female and 67% had diabetes. Most patients had received three doses of the vaccine (80%) while 13% were unvaccinated. Potential drug interactions concerns were common (median 2 drugs per patient) with amlodipine and atorvastatin being the commonest drugs requiring dose modification. Nirmatrelvir/ritonavir use was associated with symptom resolution in all patients, and was well tolerated. One patient had a rebound of symptoms, which improved in 2 more days. There were no COVID-19 related hospitalizations or deaths in any of the patients. Conclusion: In this case series of 15 hemodialysis patients with COVID-19, a modified dose of nirmatrelvir/ritonavir use, with pharmacist support for drug interaction management, was associated with symptom resolution, and was well tolerated with no serious adverse effects.

Immunogenicity of SARS-CoV-2 Vaccine in Dialysis.

BACKGROUND: Patients receiving maintenance dialysis represent a high-risk, immune-compromised population with 15%-25% COVID-19 mortality rate who were unrepresented in clinical trials of mRNA vaccines. METHODS: All patients receiving maintenance dialysis who received two doses of SARS-CoV-2 mRNA vaccines with antibody test results drawn ≥14 days after the second dose, as documented in the electronic health record through March 18, 2021, were included. Response was on the basis of levels of Ig-G against the receptor binding domain of the S1 subunit of SARS-CoV-2 spike-antigen (seropositive ≥2 U/L) using an FDA-approved semiquantitative chemiluminescent assay (ADVIA Centaur XP/XPT COV2G). RESULTS: Among 186 patients on dialysis from 30 clinics in eight states tested 23±8 days after receiving two vaccine doses, there were 165 (88.7%) responders with 70% at maximum titer. There was no significant difference between BNT162b2/Pfizer (148 out of 168, 88.1%) and mRNA-1273/Moderna (17 out of 18, 94.4%), P=0.42. All 38 patients with COVID-19 history were responders, with 97% at maximum titer. Among patients without COVID-19, 127 out of 148 (85.8%) were responders, comparable between BNT162b2/Pfizer (113 out of 133) and mRNA-1273/Moderna (14 out of 15) vaccines (85.0% versus 93.3%, P=0.38). CONCLUSIONS: Most patients receiving maintenance dialysis responded after two doses of BNT162b2/Pfizer or mRNA-1273/Moderna vaccine, suggesting the short-term development of antispike antibody is good, giving hope that most of these patients who are vulnerable, once immunized, will be protected from COVID-19. Longer-term evaluation is needed to determine antibody titer durability and if booster dose(s) are warranted. Further research to evaluate the approach to patients without a serologic response is needed, including benefits of additional dose(s) or administration of alternate options.

HIGH FIDELITY SIMULATION TRAINING: DOES IT IMPROVE INTERNAL MEDICINE RESIDENT PHYSICIAN CONFIDENCE, KNOWLEDGE, AND SKILL PERFORMANCE REGARDING TRACHEOSTOMY?

TOPIC: Education, Research, and Quality Improvement TYPE: Original Investigations PURPOSE: Internal Medicine (IM) resident physicians lack confidence and knowledge on how to manage basic and emergent clinical situations involving tracheostomy. High fidelity simulation is an effective training medium to address such deficiencies but is under-researched and under-utilized. This prospective, quantitative pilot educational and quality improvement study sought to answer if high fidelity simulation training on tracheostomy improves IM resident knowledge, confidence, and team skill performance. METHODS: Over 4 months (January - April 2021), 31 post-graduate year (PGY) 2 and PGY3 IM residents at a large academic hospital participated in this study. Participants were scored on baseline skill performance as a team in a high fidelity simulation of desaturation in a tracheostomy patient using a validated checklist. Thereafter, participants underwent a 3 hour educational intervention comprised of lecture, skills stations, and several simulations of emergent tracheostomy clinical situations. Final team performance on the same simulation initially used to assess baseline performance was scored. Pre and post intervention confidence and knowledge were assessed and compared to PGY2 and PGY3 IM residents who did not take the course. RESULTS: 20 PGY2 IM residents underwent the course. Confidence (P<0.0001) and knowledge (P<0.0001) significantly improved from pre-intervention to post-intervention. Confidence for residents post-intervention was greater than for PGY2 and PGY3’s who did not take the course (P<0.0001). Knowledge for residents post-intervention was greater than for PGY2 and PGY3’s who did not take the course (P<0.0001). In general, team skill performance in simulation improved from pre-intervention to post-intervention, though findings are limited by power and are not statistically significant. CONCLUSIONS: Our study demonstrates PGY2 IM resident confidence and knowledge on basic and emergent tracheostomy clinical situations improves significantly following educational intervention with hands-on instruction and high fidelity simulation. Confidence and knowledge in PGY2 IM residents following the course was significantly greater than for PGY2 and PGY3 IM residents who did not take the course. Our study also suggests team skill performance may be improved by the intervention. CLINICAL IMPLICATIONS: This study demonstrates that high fidelity simulation is an effective method of teaching IM resident physicians the knowledge necessary to manage basic and emergent tracheostomy clinical situations and also improves confidence. Given that many patients with acute respiratory failure from COVID-19 and other causes are frequently treated with tracheostomy and cared for by IM residents, this intervention may improve clinical outcomes for patients with tracheostomies. DISCLOSURES: No relevant relationships by Paul Christos, source=Web Response No relevant relationships by Timothy Clapper, source=Web Response No relevant relationships by Kelly Crane, source=Web Response No relevant relationships by Kapil Rajwani, source=Web Response

Severe methanol poisoning treated with a novel hemodialysis system: a case report, analysis, and review.

In May and June 2020, an outbreak of methanol poisoning arose in the southwest United States linked to ingestion of contaminated hand sanitizer imported during the coronavirus disease 2019 pandemic, ultimately resulting in over a dozen hospitalizations and at least four deaths in New Mexico and Arizona. In this report, we describe one of these cases in which profound methanol intoxication was successfully treated with the Tablo® Hemodialysis System, the first reported case of toxic alcohol poisoning treated with this novel device. We carry out a formal regression analysis of the serial methanol levels obtained in this case to conservatively estimate that intermittent hemodialysis with Tablo achieved a clearance of methanol of 239 mL/min (95% confidence interval, 173-305 mL/min), a clearance that is well within the previously published standard of care. We conclude by reviewing both the treatment of toxic alcohol poisoning and the determinants of small molecule clearance with hemodialysis, emphasizing the importance of optimizing the dialytic treatment of intoxications with extended treatment times and the use of high-efficiency dialyzers.

Immunogenicity of SARS-CoV-2 Vaccine in Dialysis (preprint)

Abstract Importance: Patients receiving maintenance dialysis patients are at high risk for morbidity and mortality from COVID-19. The immunogenicity of SARS-CoV-2 mRNA vaccines is unknown in this vulnerable population where immune compromise is common. Objective: To determine seroresponse to vaccination against SARS-CoV-2 utilizing mRNA vaccines among patients receiving maintenance dialysis. Design: Retrospective observational study. Setting: Dialysis Clinic, Inc. (DCI) outpatient dialysis clinics in the United States. Participants: All patients receiving maintenance dialysis that received two doses of SARS-CoV-2 mRNA vaccines with SARS-CoV-2 spike-antibody test results drawn at least 14 days after the second dose, as documented in the electronic health record through March 18, 2021. Exposure: Two doses of BNT162b2/Pfizer or of mRNA-1273/Moderna vaccines administered per manufacturer recommendations. Main Outcomes and Measures: Levels of immunoglobulin-G against the receptor binding domain of the S1 subunit of SARS-CoV-2 spike antigen (seropositive: 2 or greater) using FDA-approved semi-quantitative chemiluminescent assay (ADVIA Centaur XP/XPT COV2G). The DCI clinical protocol for in-clinic administration included baseline and follow-up levels although initial administration of the vaccine occurred primarily elsewhere (e.g. long-term care facilities, hospitals, etc.) during the evaluation period. Hence, only post-vaccination antibody levels were reported. Results: Among 186 patients receiving maintenance dialysis from 32 clinics in 8 states tested an average of 23 days after receiving 2 vaccine doses, mean age was 68 years, with 47% women, 21% Black, 26% residents in long-term care facilities and 97% undergoing in-center hemodialysis. Overall seropositive rate was 165/186 (88.7%) with 70% at maximum titer and with no significant difference in seropositivity between BNT162b2/Pfizer (N=148) and mRNA-1273/Moderna (N=18) vaccines (88.1% vs. 94.4%, p=0.42). Among patients with COVID-19 history, seropositive rate was 38/38 (100%) with 97% at maximum titer. Conclusions and Relevance: Most patients receiving maintenance dialysis were seropositive after two doses of BNT162b2/Pfizer or mRNA-1273/Moderna vaccine. Early evidence suggests that vaccinated dialysis patients with prior COVID-19 develop robust antibody response. These results support an equitable and aggressive vaccination strategy for all eligible patients receiving maintenance dialysis, regardless of age, sex, race, ethnicity, or disability, to prevent the extremely high morbidity and mortality associated with COVID-19 in this high risk population.

Strategic management in the hotel industry: Proposed strategic practices to recover from COVID- 19 global crisis

Hotel companies operate in a highly competitive environment, targeting much clientele from the international market with many specialties. The management in these too demanding conditions is called upon to apply modern strategic management practices by analyzing global developments and supporting the decision-making process by limiting the uncertainty created by the external environment. In this context, it is imperative to analyze the financial and administrative impact of COVID- 19, which strongly threatens tourist traffic and largely overturning current budget estimations. Strategic management can make a decisive contribution to addressing this threat by adopting the established business strategy. This article is based on similar past crises, as they were faced with strategic tools. This work aims to discuss and present the most appropriate recovery management strategies, which can help the hotel industry respond to this unprecedented crisis. © 2020 Dimitrios et.al.

Global quieting of high-frequency seismic noise due to COVID-19 pandemic lockdown measures.

Human activity causes vibrations that propagate into the ground as high-frequency seismic waves. Measures to mitigate the coronavirus disease 2019 (COVID-19) pandemic caused widespread changes in human activity, leading to a months-long reduction in seismic noise of up to 50%. The 2020 seismic noise quiet period is the longest and most prominent global anthropogenic seismic noise reduction on record. Although the reduction is strongest at surface seismometers in populated areas, this seismic quiescence extends for many kilometers radially and hundreds of meters in depth. This quiet period provides an opportunity to detect subtle signals from subsurface seismic sources that would have been concealed in noisier times and to benchmark sources of anthropogenic noise. A strong correlation between seismic noise and independent measurements of human mobility suggests that seismology provides an absolute, real-time estimate of human activities.