Improved diagnosis of COVID-19 vaccine-associated myocarditis with cardiac scarring identified by cardiac magnetic resonance imaging. (preprint)

BackgroundMyocarditis is a rare but potentially serious complication of COVID-19 vaccination. Cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) imaging can identify cardiac scar, which may improve diagnostic accuracy and prognostication. ObjectivesTo define the incidence of long-term LGE post COVID-19 vaccine-associated myocarditis (C-VAM) and to establish the additive role of CMR in the diagnostic work-up. MethodsPatients with Brighton Collaboration Criteria Level 1 (definite) or Level 2 (probable) C-VAM were prospectively recruited from the Surveillance of Adverse Events Following Vaccination In the Community (SAEFVIC) database to undergo CMR at least 12 months after diagnosis. As there were limited patients with access to baseline CMR, prior CMR results were not included in the initial case definition. The presence of LGE on follow-up CMR was then integrated into the diagnostic algorithm and the reclassification rate (definite vs. probable) was calculated. ResultsSixty-seven patients with C-VAM (mean age 30 {+/-} 13 years, 72% male) underwent CMR evaluation. Median time from vaccination to CMR was 548 (range 398-603) days. Twenty patients (30%) had persistent LGE, most frequently found in the basal inferolateral segment (n = 11). At diagnosis, nine patients (13%) were classified as definite and 58 (87%) as probable myocarditis. With integration of CMR LGE data, 16 patients (28%) were reclassified from probable to definite myocarditis. ConclusionPersistent LGE on CMR occurs in one third of patients with C-VAM. Without CMR at diagnosis, almost one third of patients are misclassified as probable rather than definite myocarditis.

Renalase Identified by Machine Learning Methods As A Novel Independent Predictor Of Mortality In Hospitalized Patients With COVID-19 (preprint)

Low levels of renalase, a flavoprotein released by kidneys, has been linked with cytokine release syndrome and disease severity of viral infections. We sought to, 1) identify traditional and novel predictors of mortality for patients hospitalized with COVID-19; and 2) investigate whether renalase independently predicts mortality. In a retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 patients. Patients were excluded if < 18 years or opted out of research. Novel research markers – renalase, kidney injury molecule-1, interferon (α,δ,ι), interleukin (IL-1, IL6), and tumor necrosis factor were measured. The primary outcome was mortality within 180 days of index visit. Among 437 patients who provided 897 blood samples, mean age was 64 years (SD ± 17), 233 (53%) were males, and 48% were non-whites. Seventy-one patients (16%) died. Area under the curve (AUC) for mortality prediction was as follows: using logistic regression with a priori feature selection (AUC = 0.72; CI 0.62, 0.82), logistic regression with backward feature selection (0.70; CI 0.55, 0.77), and XGBoost (0.87; CI 0.77, 0.93)]. PR-AUC and calibration plots also showed best performance with XGBoost model. Elevated BNP, advanced age, oxygen saturation deviation, and low renalase were the leading predictors of mortality in XGBoost. Renalase emerged as an independent predictor of mortality for COVID-19 across all statistical models.

Finding space for nature in cities: the considerable potential of redundant car parking

Nature-based solutions (NBS) are recognised as a means to address challenges such as heatwaves, flooding and biodiversity loss. Delivering these benefits at scale will require large areas of scarce urban land to be converted into green space. Here we show an approach by which cities can make substantial progress towards their sustainability targets using NBS, by converting redundant street parking into biodiverse green space. We demonstrate that up to half of street parking in our case study municipality (The City of Melbourne) could be accommodated in garages within 200 m, freeing up large areas for greening. Our modelling projects significant benefits in terms of tree canopy over, stormwater and ecological connectivity. These would represent strong progress towards a number of the city’s ambitious NBS targets. As many cities allocate extensive areas to both street parking and off-street garages, this approach to freeing up space for nature in cities is widely applicable.

Discordance between clinical and post-surgical staging of patients with operable non-small cell lung cancer: a retrospective audit of lung cancer surgery with curative intent from a single pathology practice

Clinical staging of non-small cell lung cancer (NSCLC) by CT and PET, with or without endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes (EBUS-TBNA), is essential for prognostication and to direct treatment. Clinical understaging can lead to inappropriate radical excision of the primary tumour with no clinical benefit, whereas overstaging might deprive patients of beneficial or potentially curable treatments. Although not widely documented, several reports have indicated a suboptimal concordance between clinical and post-surgical staging. This study has investigated the incidence of discordance between clinical and post-surgical staging of operable NSCLC cases evaluated at PathWest Fiona Stanley Hospital (Perth, WA, Australia). The study formed part of an approved Quality Improvement Activity and included patients with NSCLC who underwent lobectomy between Jan 1, 2016, and Dec 31, 2021, at hospitals serviced by the PathWest anatomical pathology department at Fiona Stanley Hospital. Data from pathology, imaging, and EBUS-TBNA or biopsy reports were retrieved from digital medical records databases and multidisciplinary meeting notes. A project database designed and established in REDCap was used to collect and analyse data. 419 patients (216 [52%] women, 203 [48%] men) in the age range of 20·5–85·8 years (median 69·2 years [IQR 63·3–74·5]) were included. EBUS-TBNA was done for 121 (29%) patients and imaging results (from CT, PET, or both) were available for 406 (97%) patients. Discordant clinical and post-surgical T and N staging were evident;post-surgical T stage was higher in 96 (23%) cases and lower in 54 (13%) cases. Eight tumours staged post-surgically as N1 had been clinically staged as N0. For ten cases with unforeseen N2 involvement, clinical staging was N0 (n=4), N1 (n=3) or not available (n=3);surgery might not have been necessary for these patients. Median times between CT and lobectomy (105 days [IQR 77·0–143·0]), PET and lobectomy (79 days [56·0–109·0]), and EBUS-TBNA and surgery (59 days [42–94]) were outside of Australian guidelines, which recommend a time to start of treatment for lung cancer of less than 42 days from initial referral. Time intervals between final screening study (imaging or EBUS-TBNA) and lobectomy before and during the COVID-19 pandemic (2016–19 and 2020–21, respectively) were significantly different (p=0·019). It is noteworthy that Western Australia had not recorded high numbers of COVID-19 cases during that time. This study has identified substantial disagreement between clinical and post-surgical staging of NSCLC. Discordance between clinical and post-surgical T and N staging might have led to different treatment pathways for some patients. To improve the accuracy of clinical staging of NSCLC, the sensitivity, specificity, and interpretation of imaging and lymph node cytology, as well as the timeliness of treatment (clinical care pathway) would each need to be evaluated. Strengths of this study include the large number and lack of selection of cases, and the small number of medical service providers. Weaknesses include the absence of outcomes data for these patients. Overall results are consistent with previous and historical investigations of hospital and clinical trial cohorts. OT is the recipient of a student scholarship from the Royal College of Pathologists of Australasia that funded this work. [ FROM AUTHOR] Copyright of Lancet Oncology is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

SOFA score performs worse than age for predicting mortality in patients with COVID-19 (preprint)

The use of the Sequential Organ Failure Assessment (SOFA) score, originally developed to describe disease morbidity, is commonly used to predict in-hospital mortality. During the COVID-19 pandemic, many protocols for crisis standards of care used the SOFA score to select patients to be deprioritized due to a low likelihood of survival. A prior study found that age outperformed the SOFA score for mortality prediction in patients with COVID-19, but was limited to a small cohort of intensive care unit (ICU) patients and did not address whether their findings were unique to patients with COVID-19. Moreover, it is not known how well these measures perform across races. In this retrospective study, we compare the performance of age and SOFA scores in predicting in-hospital mortality across two cohorts: a cohort of 2,648 consecutive adult patients diagnosed with COVID-19 who were admitted to a large academic health system in the northeastern United States over a 4-month period in 2020 and a cohort of 75,601 patients admitted to one of 335 ICUs in the eICU database between 2014 and 2015. Among the COVID-19 cohort, age (area under receiver-operating characteristic curve (AU-ROC) 0.795, 95% CI 0.762, 0.828) had a significantly better discrimination than SOFA score (AU-ROC 0.679, 95% CI 0.638, 0.721) for mortality prediction. Conversely, age (AU-ROC 0.628 95% CI 0.608, 0.628) underperformed compared to SOFA score (AU-ROC 0.735, 95% CI 0.726, 0.745) in non-COVID-19 ICU patients in the eICU database. There was no difference between Black and White COVID-19 patients in performance of either age or SOFA Score. Our findings bring into question the utility of SOFA score-based resource allocation in COVID-19 crisis standards of care.

Effectiveness and durability of protection against future SARS-CoV-2 infection conferred by COVID-19 vaccination and previous infection; findings from the UK SIREN prospective cohort study of healthcare workers March 2020 to September 2021 (preprint)

BackgroundUnderstanding the duration and effectiveness of infection and vaccine-acquired SARS-CoV-2 immunity is essential to inform pandemic policy interventions, including the timing of vaccine-boosters. We investigated this in our large prospective cohort of UK healthcare workers undergoing routine asymptomatic PCR testing. MethodsWe assessed vaccine effectiveness (VE) (up to 10-months after first dose) and infection-acquired immunity by comparing time to PCR-confirmed infection in vaccinated and unvaccinated individuals using a Cox regression-model, adjusted by prior SARS-CoV-2 infection status, vaccine-manufacturer/dosing-interval, demographics and workplace exposures. ResultsOf 35,768 participants, 27% (n=9,488) had a prior SARS-CoV-2 infection. Vaccine coverage was high: 97% had two-doses (79% BNT162b2 long-interval, 8% BNT162b2 short-interval, 8% ChAdOx1). There were 2,747 primary infections and 210 reinfections between 07/12/2020 and 21/09/2021. Adjusted VE (aVE) decreased from 81% (95% CI 68%-89%) 14-73 days after dose-2 to 46% (95% CI 22%-63%) >6-months; with no significant difference for short-interval BNT162b2 but significantly lower aVE (50% (95% CI 18%-70%) 14-73 days after dose-2 from ChAdOx1. Protection from infection-acquired immunity showed evidence of waning in unvaccinated follow-up but remained consistently over 90% in those who received two doses of vaccine, even in those infected over 15-months ago. ConclusionTwo doses of BNT162b2 vaccination induce high short-term protection to SARS-CoV-2 infection, which wanes significantly after six months. Infection-acquired immunity boosted with vaccination remains high over a year after infection. Boosters will be essential to maintain protection in vaccinees who have not had primary infection to reduce infection and transmission in this population. Trial registration numberISRCTN11041050

Comparing lateral flow testing with a rapid RT-PCR method for SARS-CoV-2 detection in the UK (preprint)

In late 2019, SARS-CoV-2 emerged in the Wuhan province of China. Rapid global spread led to the Covid-19 pandemic. Rapid and accurate detection of SARS-CoV-2 has become a vitally important tool in controlling the spread of the virus. Lateral flow devices (LFDs) offer the potential advantage of speed and on-site testing. The sensitivity of these devices compared to the gold standard RT-PCR has been questioned. We compared the performance of the Innova lateral flow kit, recommended by the UK government, with our rapid in-house RT-PCR protocol using stored positive patient samples. The LFD device was found to be 6,000-10,000 times less sensitive than RT-PCR for the detection of SARS-CoV-2. Overall, the LFD detected 46.2% of the positives detected by RT-PCR. 50% of the LFD results were observed to be weak positives, only visible after careful examination by experienced laboratory staff. At lower viral loads, such as 10,000-100,000 RNA copies/ml, the LFD detected 22.2% of positives. In addition, two strong positives (3 and 1.5 million RNA copies/ml) were not detected by the LFD. The argument for use of LFD kits, despite their lack of sensitivity, is that they detect infectious virus and hence contagious individuals. At present, there is a lack of scientific evidence supporting this claim. The LFD used in the UK fails to identify individuals with considerable viral loads and has been subject to a class I recall by the US FDA but is still approved and recommended for use by the UK government. We believe that using LFD testing for assessing SARS-CoV-2 infection risk is a strategy which has risks that outweigh any benefits.

MotionInput v2.0 supporting DirectX: A modular library of open-source gesture-based machine learning and computer vision methods for interacting and controlling existing software with a webcam (preprint)

Touchless computer interaction has become an important consideration during the COVID-19 pandemic period. Despite progress in machine learning and computer vision that allows for advanced gesture recognition, an integrated collection of such open-source methods and a user-customisable approach to utilising them in a low-cost solution for touchless interaction in existing software is still missing. In this paper, we introduce the MotionInput v2.0 application. This application utilises published open-source libraries and additional gesture definitions developed to take the video stream from a standard RGB webcam as input. It then maps human motion gestures to input operations for existing applications and games. The user can choose their own preferred way of interacting from a series of motion types, including single and bi-modal hand gesturing, full-body repetitive or extremities-based exercises, head and facial movements, eye tracking, and combinations of the above. We also introduce a series of bespoke gesture recognition classifications as DirectInput triggers, including gestures for idle states, auto calibration, depth capture from a 2D RGB webcam stream and tracking of facial motions such as mouth motions, winking, and head direction with rotation. Three use case areas assisted the development of the modules: creativity software, office and clinical software, and gaming software. A collection of open-source libraries has been integrated and provide a layer of modular gesture mapping on top of existing mouse and keyboard controls in Windows via DirectX. With ease of access to webcams integrated into most laptops and desktop computers, touchless computing becomes more available with MotionInput v2.0, in a federated and locally processed method.

Clinical Characteristics and Outcomes for 7,995 Patients with SARS-CoV-2 Infection (preprint)

Objective: Severe acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with SARS-CoV-2. Design: This was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository. Setting: Yale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas. Populations: The study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020. Main outcome and performance measures: Primary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support. Results: Of the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 1633 (75.8%) had a discharge disposition at the end of the study period. Of these, 192 (11.8%) required invasive mechanical ventilation and 227 (13.5%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 81.9 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14-1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50-2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups. Conclusions: This observational study identified, among people testing positive for SARS-CoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines.

Coronavirus (COVID-19) infection in children at a specialist centre: outcome and implications of underlying high-risk comorbidities in a paediatric population (preprint)

Background: There is evolving evidence of significant differences in severity and outcomes of coronavirus disease 2019 (COVID-19) in children compared to adults. Underlying medical conditions associated with increased risk of severe disease are based on adult data, but have been applied across all ages resulting in large numbers of families undertaking social shielding (vulnerable group). We conducted a retrospective analysis of children with suspected COVID-19 at a Specialist Childrens Hospital to determine outcomes based on COVID-19 testing status and underlying health vulnerabilities. Methods: Routine clinical data were extracted retrospectively from the Institutions Electronic Health Record system and Digital Research Environment for patients with suspected and confirmed COVID-19 diagnoses. Data were compared between Sars-CoV-2 positive and negative patients (CoVPos / CoVNeg respectively), and in relation to presence of underlying health vulnerabilities based on Public Health England guidance. Findings: Between 1st March and 15th May 2020, 166 children (<18 years of age) presented to a specialist childrens hospital with clinical features of possible COVID-19 infection. 65 patients (39.2%) tested positive for SARS-CoV-2 virus. CoVPos patients were older (median 9 [0.9-14] years vs median 1 [0.1-5.7.5] years respectively, p<0.001). There was a significantly reduced proportion of vulnerable cases (47.7% vs 72.3%, p=0.002), but no difference in proportion of vulnerable patients requiring ventilation (61% vs 64.3%, p = 0.84) between CoVPos and CoVNeg groups. However, a significantly lower proportion of CoVPos patients required mechanical ventilation support compared to CoVNeg patients (27.7 vs 57.4%, p<0.001). Mortality was not significantly different between CoVPos and CoVNeg groups (1.5 vs 4% respectively, p=0.67) although there were no direct COVID-19 related deaths in this highly preselected paediatric population. Interpretation: COVID-19 infection may be associated with severe disease in childhood presenting to a specialist hospital, but does not appear significantly different in severity to other causes of similar clinical presentations. In children presenting with pre-existing COVID-19 vulnerable medical conditions at a specialist centre, there does not appear to be significantly increased risk of either contracting COVID-19 or severe complications, apart from those undergoing chemotherapy, who are over-represented.

Development and validation of the COVID-19 severity index (CSI): a prognostic tool for early respiratory decompensation (preprint)

ObjectiveThe goal of this study was to create a predictive model of early hospital respiratory decompensation among patients with COVID-19. DesignObservational, retrospective cohort study. SettingNine-hospital health system within the Northeastern United States. PopulationsAdult patients ([≥] 18 years) admitted from the emergency department who tested positive for SARS-CoV-2 (COVID-19) up to 24 hours after initial presentation. Patients meeting criteria for respiratory critical illness within 4 hours of arrival were excluded. Main outcome and performance measuresWe used a composite endpoint of critical illness as defined by oxygen requirement (greater than 10 L/min by low-flow device, high-flow device, non-invasive, or invasive ventilation) or death within the first 24 hours of hospitalization. We developed models predicting our composite endpoint using patient demographic and clinical data available within the first four hours of arrival. Eight hospitals (n = 932) were used for model development and one hospital (n = 240) was held out for external validation. Area under receiver operating characteristic (AU-ROC), precision-recall curves (AU-PRC), and calibration metrics were used to compare predictive models to three illness scoring systems: Elixhauser comorbidity index, qSOFA, and CURB-65. ResultsDuring the study period from March 1, 2020 to April 27,2020, 1,792 patients were admitted with COVID-19. Six-hundred and twenty patients were excluded based on age or critical illness within the first 4 hours, yielding 1,172 patients in the final cohort. Of these patients, 144 (12.3%) met the composite endpoint within the first 24 hours. We first developed a bedside quick COVID-19 severity index (qCSI), a twelve-point scale using nasal cannula flow rate, respiratory rate, and minimum documented pulse oximetry. We then created a machine-learning gradient boosting model, the COVID-19 severity index (CSI), using twelve additional variables including inflammatory markers and liver chemistries. Both the qCSI (AU-ROC mean [95% CI]: 0.90 [0.85-0.96]) and CSI (AU-ROC: 0.91 [0.86-0.97]) outperformed the comparator models (qSOFA: 0.76 [0.69-0.85]; Elixhauser: 0.70 [0.62-0.80]; CURB-65: AU-ROC 0.66 [0.58-0.77]) on cross-validation and performed well on external validation (qCSI: 0.82, CSI: 0.76, CURB-65: 0.50, qSOFA: 0.59, Elixhauser: 0.61). We find that a qCSI score of 0-3 is associated with a less than 5% risk of critical respiratory illness, while a score of 9-12 is associated with a 57% risk of progression to critical illness. ConclusionsA significant proportion of admitted COVID-19 patients decompensate within 24 hours of hospital presentation and these events are accurately predicted using bedside respiratory exam findings within a simple scoring system.

Molecular detection of SARS-CoV-2 using a reagent-free approach (preprint)

Shortage of reagents and consumables required for the extraction and molecular detection of SARS-CoV-2 RNA in respiratory samples has led many laboratories to investigate alternative approaches for sample preparation. Fomsgaard et al 20205 recently presented results using heat-processing of respiratory samples prior to RT-qPCR as an economical method enabling an extremely fast streamlining of the processes at virtually no cost. Here, we present our results using this method and highlight some major pitfalls that diagnostics laboratories should be aware of before proceeding with this technique. We first investigated various treatments using different temperatures, incubation times and sample volumes based on the above study to optimise the heat-treatment conditions. Although the initial data confirmed the published results, further investigations revealed unexpected inhibitory properties of some commonly used virus transport media (VTMs) on some commercially available RT-qPCR mixes, emphasising the critical importance of a thorough validation process to determine the most adapted reagents to be used depending on the sample types to be tested. In conclusion, although the method works, with very consistent Ct values and an excellent sensitivity when compared to a conventional RNA extraction method, it is critical to include an internal control to check each sample for potential inhibition.

Performance of temporal artery temperature measurement in ruling out fever: implications for COVID-19 screening. (preprint)

The use of non-invasive temperature testing methods like temporal artery thermometers (TATs) is growing exponentially in the face of the ongoing COVID-19 pandemic. We performed a retrospective analysis of over 1.8 million emergency department electronic health records to identify assess the performance of TAT measurement using patients with near-contemporaneous temperature measurements taken via rectal or oral approaches. Using over 17,000 matched measurements, we show poor fever sensitivity using TAT. We show that sensitivity is significantly improved by lowering the fever threshold and describe limits of agreement between methods of measurement. Our findings suggest that private, public, and healthcare delivery organizations may need to reconsider how we perform high-volume screening during this time of crisis and has implications for return-to-work protocols.