Spatiotemporal analysis of SARS-CoV-2 infection reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance in hamster lungs (preprint)

Factors of the innate immune response to SARS-CoV-2 in the lungs are pivotal for the ability of the host to deal with the infection. In humans, excessive macrophage infiltration is associated with disease severity. Using 3D spatiotemporal analysis of optically cleared hamster lung slices in combination with virological, immunohistochemical and RNA sequence analyses, we visualized the spread of SARS-CoV-2 through the lungs and the rapid anti-viral response in infected lung epithelial cells, followed by a wave of monocyte-derived macrophage (MDM) infiltration and virus elimination from the tissue. These SARS-CoV-2 induced innate immune processes are closely related to the onset of necrotizing inflammatory and consecutive remodelling responses in the lungs, which manifests as extensive cell death, vascular damage, thrombosis, and cell proliferation. Here we show that MDM are directly linked to virus clearance, and appear in connection with tissue injury and blood vessel damage. Rapid initiation of prothrombotic factor upregulation, tissue repair and alveolar cell proliferation results in tissue remodelling, which is followed by fibrosis development despite a decrease in inflammatory and anti-viral activities. Thus, although the hamsters are able to resolve the infection following the MDM influx and repair lung tissue integrity, longer-term alterations of the lung tissues arise as a result of concurrent tissue damage and regeneration processes.

Stuttering-Like Dysfluencies as a Consequence of Long COVID-19.

PURPOSE: We present two patients who developed neurogenic stuttering after long COVID-19 related to SARS-CoV-2 infection. METHODS AND RESULTS: Both patients experienced both physical (e.g., fatigue) and cognitive difficulties, which led to impaired function of attention, lexical retrieval, and memory consolidation. Both patients had new-onset stuttering-like speech dysfluencies: Blocks and repetitions were especially evident at the initial part of words and sentences, sometimes accompanied by effortful and associated movements (e.g., facial grimaces and oro-facial movements). Neuropsychological evaluations confirmed the presence of difficulties in cognitive tasks, while neurophysiological evaluations (i.e., electroencephalography) suggested the presence of "slowed" patterns of brain activity. Neurogenic stuttering and cognitive difficulties were evident for 4-5 months after negativization of SARS-CoV-2 nasopharyngeal swab, with gradual improvement and near-to-complete recovery. CONCLUSIONS: It is now evident that SARS-CoV-2 infection may significantly involve the central nervous system, also resulting in severe and long-term consequences, even if the precise mechanisms are still unknown. In the present report, long COVID-19 resulted in neurogenic stuttering, as the likely consequence of a "slowed" metabolism of (pre)frontal and sensorimotor brain regions (as suggested by the present and previous clinical evidence). As a consequence, the pathophysiological mechanisms related to the appearance of neurogenic stuttering have been hypothesized, which help to better understand the broader and possible neurological consequences of COVID-19.

Deep Learning-Based Assessment of Cerebral Microbleeds in COVID-19 (preprint)

Cerebral Microbleeds (CMBs), typically captured as hypointensities from susceptibility-weighted imaging (SWI), are particularly important for the study of dementia, cerebrovascular disease, and normal aging. Recent studies on COVID-19 have shown an increase in CMBs of coronavirus cases. Automatic detection of CMBs is challenging due to the small size and amount of CMBs making the classes highly imbalanced, lack of publicly available annotated data, and similarity with CMB mimics such as calcifications, irons, and veins. Hence, the existing deep learning methods are mostly trained on very limited research data and fail to generalize to unseen data with high variability and cannot be used in clinical setups. To this end, we propose an efficient 3D deep learning framework that is actively trained on multi-domain data. Two public datasets assigned for normal aging, stroke, and Alzheimer's disease analysis as well as an in-house dataset for COVID-19 assessment are used to train and evaluate the models. The obtained results show that the proposed method is robust to low-resolution images and achieves 78% recall and 80% precision on the entire test set with an average false positive of 1.6 per scan.

Cerebrovascular radiological features of COVID-19 positive patients.

OBJECTIVE: To investigate acute cerebrovascular diseases (stroke and intracranial hemorrhage) by cranial radiologic examinations of patients infected with coronavirus disease 2019 (COVID-19) and with neurological signs. PATIENTS AND METHODS: Between March 2020 and May 2021, patients who were admitted to the Emergency Department and had a positive reverse transcription-polymerase chain reaction (RT-PCR) test and underwent Multidetector Computed Tomography (MDCT) and/or Magnetic Resonance Images (MRI), and/or diffusion MRI due to neurological findings were included in the study. RESULTS: The study reviewed a total of 925 patients, including 404 (43.67%) female and 521 (56.32%) male patients. The distribution of imaging methods was as follows: 805 (71%) patients had cranial MDCT, 71 (6.35%) patients had MRI, and 241 (21.57%) patients had diffusion MRI. Of the total 925 patients, 128 (13.8%) patients were detected with cerebrovascular diseases, 92 (9.9%) patients were detected with ischemic or hemorrhagic stroke, 37 (4%) patients were detected with intraparenchymal hemorrhage, 10 (1.1%) patients were detected with subarachnoid hemorrhage, and four (0.43%) patients were detected with subdural hemorrhage. There was no statistically significant difference in the incidence of subdural, subarachnoid, parenchymal hemorrhage, and stroke in terms of gender. While there was a significant difference in stroke according to age, there was no statistically significant difference in subdural, subarachnoid, and parenchymal hemorrhagic. Three (0.32%) patients were diagnosed with acute disseminated encephalomyelitis (ADEM)'s-like demyelinating lesions. CONCLUSIONS: Cerebrovascular diseases, which may cause severe disability and even threaten the patient's life, should be kept in mind, especially in COVID-19 patients who present with neurological symptoms.

Coexistence of SARS-CoV-2 and cerebrovascular diseases: does COVID-19 positivity trigger cerebrovascular pathologies?

The objectives of this study were to determine the prevalence of cerebrovascular diseases caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and to assess the pharmacological agents used in such cases as reported in the literature. Patient files were retrospectively scanned to determine the prevalence of neurological symptoms of the central nervous system (headache, dizziness, lack of smell and taste, numbness in arms and legs, change in consciousness, muscle weakness, loss of urine and stool control) and cerebrovascular diseases (ischemic cerebrovascular diseases, cerebral venous sinus thrombosis, intracerebral hemorrhage, subarachnoid/subdural hemorrhage) in 2019 novel coronavirus (2019-nCoV) disease (COVID-19) cases (n = 20,099). The diagnostic laboratory, radiology examinations and treatments applied to these cases were recorded. The data from studies presenting cerebrovascular diseases associated with SARS-Cov-2, which constituted 0.035% of all cases, were systematically evaluated from electronic databases. During the treatment of cerebrovascular diseases, it was discovered that high doses of enoxaparin sodium anti-Xa are combined with apixaban or acetylsalicylic acid or clopidogrel or piracetam, and mannitol, in addition to SARS-CoV-2 treatment modalities. While neurological symptoms of the central nervous system are uncommon in cases of SARS-CoV-2 infection, cerebrovascular diseases are far less common, according to the findings of this study. Acute cerebral ischemia was discovered to be the most common cerebrovascular disease associated with SARS-CoV-2. The mortality rate increases with the association between SARS-CoV-2 and cerebrovascular disease.

Impact of dementia, living in a long-term care facility, and physical activity status on COVID-19 severity in older adults (preprint)

Background: Japan is fast becoming an extremely aged society and older adults are known to be at risk of severe COVID-19. However, the impact of risk factors specific to this population for severe COVID-19 caused by the Omicron variant of concern (VOC) are not yet clear. Methods: We performed an exploratory analysis using logistic regression to identify risk factors for severe COVID-19 illness among 4,868 older adults with a positive SARS-CoV-2 test result who were admitted to a healthcare facility between 1 January 2022 and 16 May 2022. We then conducted one-to-one propensity score (PS) matching for three factors-dementia, admission from a long-term care facility, and poor physical activity status-and used Fisher's exact test to compare the proportion of severe COVID-19 cases in the matched data. We also estimated the average treatment effect on treated (ATT) in each PS matching analysis. Results: Of the 4,868 cases analyzed, 1,380 were severe. Logistic regression analysis showed that age, male sex, cardiovascular disease, cerebrovascular disease, chronic lung disease, renal failure and/or dialysis, physician-diagnosed obesity, admission from a long-term care facility, and poor physical activity status were risk factors for severe disease. Vaccination and dementia were identified as factors associated with non-severe illness. The ATT for dementia, admission from a long-term care facility, and poor physical activity status was -0.04 (95% confidence interval -0.07, -0.01), 0.09 (0.06, 0.12), and 0.17 (0.14, 0.19), respectively. Conclusions: Our results suggest that poor physical activity status and living in a long-term care facility have a substantial impact on the risk of severe COVID-19 caused by the Omicron VOC, while dementia might be associated with non-severe illness.

Analysis of Thromboembolic and Thrombocytopenic Events After the AZD1222, BNT162b2, and MRNA-1273 COVID-19 Vaccines in 3 Nordic Countries.

Importance: Vaccinations are paramount to halt the COVID-19 pandemic, and safety data are essential to determine the risk-benefit ratio of each COVID-19 vaccine. Objective: To evaluate the association between the AZD1222, BNT162b2, and mRNA-1273 vaccines and subsequent thromboembolic and thrombocytopenic events. Design, Setting, and Participants: This self-controlled case series used individual-level data from national registries in Norway, Finland, and Denmark. Participants included individuals with hospital contacts because of coronary artery disease, coagulation disorders, or cerebrovascular disease between January 1, 2020, and May 16, 2021. Exposures: AZD1222, BNT162b2, or mRNA-1273 vaccine. Main Outcomes and Measure: Relative rate (RR) of hospital contacts for coronary artery disease, coagulation disorders, or cerebrovascular disease in a 28-day period following vaccination compared with the control period prior to vaccination. Results: We found 265 339 hospital contacts, of whom 112 984 [43%] were for female patients, 246 092 [93%] were for patients born in 1971 or earlier, 116 931 [44%] were for coronary artery disease, 55 445 [21%] were for coagulation disorders, and 92 963 [35%] were for cerebrovascular disease. In the 28-day period following vaccination, there was an increased rate of coronary artery disease following mRNA-1273 vaccination (RR, 1.13 [95% CI, 1.02-1.25]), but not following AZD1222 vaccination (RR, 0.92 [95% CI, 0.82-1.03]) or BNT162b2 vaccination (RR, 0.96 [95% CI, 0.92-0.99]). There was an observed increased rate of coagulation disorders following all 3 vaccines (AZD1222: RR, 2.01 [95% CI, 1.75-2.31]; BNT162b2: RR, 1.12 [95% CI, 1.07-1.19]; and mRNA-1273: RR, 1.26 [95% CI, 1.07-1.47]). There was also an observed increased rate of cerebrovascular disease following all 3 vaccines (AZD1222: RR, 1.32 [95% CI, 1.16-1.52]; BNT162b2: RR, 1.09 [95% CI, 1.05-1.13]; and mRNA-1273: RR, 1.21 [95% CI, 1.09-1.35]). For individual diseases within the main outcomes, 2 notably high rates were observed: 12.04 (95% CI, 5.37-26.99) for cerebral venous thrombosis and 4.29 (95% CI, 2.96-6.20) for thrombocytopenia, corresponding to 1.6 (95% CI, 0.6-2.6) and 4.9 (95% CI, 2.9-6.9) excess events per 100 000 doses, respectively, following AZD1222 vaccination. Conclusions and Relevance: In this self-controlled case series, there was an increased rate of hospital contacts because of coagulation disorders and cerebrovascular disease, especially for thrombocytopenia and cerebral venous thrombosis, following vaccination with AZD1222. Although increased rates of several thromboembolic and thrombocytopenic outcomes following BNT162b2 and mRNA-1273 vaccination were observed, these increases were less than the rates observed after AZD1222, and sensitivity analyses were not consistent. Confirmatory analysis on the 2 mRNA vaccines by other methods are warranted.

Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction (preprint)

Persistent cognitive impairment and neuropsychiatric disorders are prevalent sequelae of SARS-CoV-2-induced COVID-19 in middle-aged adults. To model age-related neurological vulnerability to COVID-19, we induced respiratory SARS-CoV-2 MA10 infections by nasal inoculation in young (2 months) and middle-aged (12 months) mice. We hypothesized that aging and SARS-CoV-2 synergistically damage the blood-brain barrier (BBB). Indeed, the combined action of aging and SARS-CoV-2 infection caused more fibrinogen leakage, T cell infiltration, and neuroinflammation in middle-aged SARS-CoV-2-infected mice than in similarly inoculated young adults. Mechanistically, SARS-CoV-2 exacerbated age-related increases in Caveolin-1 BBB transcellular permeability and loss of Wnt/β-catenin ligands, with no apparent changes in tight junction proteins. Finally, SARS-CoV-2 infection induced age-dependent neuropsychiatric abnormalities including bradykinesia and obsessive-compulsive-like behavior. These observations indicate that cerebrovascular aging, including loss of Wnt suppression of Caveolin-1, heightens vulnerability to SARS-CoV-2-induced neuroinflammation and neuropsychiatric sequalae. Our work suggests that modulation of Wnt signaling or its downstream effectors at the BBB could be potential interventional strategies for Long COVID. Highlights To our knowledge, we have for the first time used a small animal model to experimentally test the impact of age on SARS-CoV-2 neuropathology. Aged mice were uniquely vulnerable to neuropsychiatric signs after SARS-CoV-2 infection Middle-age increased gliosis, cerebrovascular inflammation, BBB permeability, and T cell infiltration in SARS-CoV-2 infected mice BBB permeability was related to loss of Wnt7a suppression of Caveolin-1

The protective effect of TND1128, with self-redox ability, on Ca2+ overloaded mouse brain slice and its comparison with β-NMN. (preprint)

Background: and purpose: We have no definitive treatment for dementia characterized by prolonged neuronal death due to cerebrovascular degeneration or the enormous accumulation of foreign matters, such as β-amyloid. Since these diseases develop slowly, we may be able to delay the onset and improve these symptoms by enhancing the energy metabolism of individual neurons to assist their viabilities. We examined the effect of TND1128, a derivative of 5-deazaflavin, proven to have the self-redox ability as a possible candidate for a direct activator for mitochondrial energy synthesis. Experimental Approach: We prepared brain slices obtained from mice 22 ± 2 hours pretreated with TND1128 or β−ΝΜΝ used as an active control. We measured Ca2+ concentrations in the cytoplasm ([Ca2+]cyt) and mitochondria ([Ca2+]mit) by using fluorescence Ca2+ indicators, Fura4F, and X-rhod-1, respectively, and examined the protective effects of TND1128 and β−ΝΜΝ on overloaded cytosolic and mitochondrial Ca2+ by repeating 80K exposure. Key Results: TND1128 (0.01, 0.1, and 1 mg/kg s.c.) mitigates the dynamics of both [Ca2+]cyt and [Ca2+]mit in a dose-dependent manner. β−ΝΜΝ (10, 30, and 100mg/kg s.c.) showed significant dose-dependent facilitatory effects on the recovery of [Ca2+]cyt during washing for 5 minutes. However, there was no significant effect on the [Ca2+]mit dynamics. Conclusion and implications: TND1128 works as a cofactor for activating cellular energy production machinery. TND1128 would rescue deteriorating neurons in various cerebrovascular disorder-related diseases, including Alzheimer’s disease and Parkinson’s disease. Furthermore, TND1128 will rescue patients with disorders of respiratory organs, such as pulmonary emphysema and COVID-19, which causes respiratory disability

Clinical prediction rules for adverse outcomes in patients with SARS COV-2 infection by the omicron variant (preprint)

Background: Factors related to an adverse evolution in COVID19 infection are needed for proper decision making. We try to identify factors related to hospitalization, ICU admission, and mortality related to the infection. Methods. Retrospective cohort study of patients with SARS-CoV-2 infection from March 1st 2020 to January 9th 2022. The sample was randomly divided into two subsamples, for the purposes of derivation and validation of the prediction rule, until omicron variant appearance and afterwards, respectively. Data collected for this study included sociodemographic data, baseline comorbidities and treatments, and other background data. Multivariable logistic regression models using Lasso logistic regression were used . Results. In the multivariable models, older age, male, peripheral vascular disease, heart failure, heart disease, cerebrovascular, dementia, liver, kidney, diabetes, hemiplegia, interstitial pulmonary disease, cystic fibrosis, malignant tumors, as well as diuretics and the chronic systemic use of steroids were common predictive factors of death. Similar predictors, except liver disease, plus arterial hypertension, were also related to adverse evolution. Similar predictors to the previous, including liver disease, plus dyslipidemia, inflammatory bowel disease, respiratory diseases, and the basal prescription of NSAIDs, heparin, bronchodilators, or immunosuppressants were related to hospital admission. All risk scores developed had AUCs from 0.79 (hospital admission) to 0.94 (death) in the validation in the omicron sample. Conclusions. We propose three risk scales for adverse outcomes and hospital admission easy to calculate and with high predictive capacity, which also work with the current omicron variant, which can help manage patients in primary, emergency, and hospital care.

Microbial Pattern and Antibiotic Resistance of Severe Pneumonia in A National Referral Hospital in Indonesia (preprint)

Background: Patients hospitalized in the intensive care unit (ICU) have a higher susceptibility to infections. Respiratory infections are the most common nosocomial infections. Rising antibiotic resistance due to indiscriminate use of antibiotics and poor adherence to standard precaution in healthcare facilities compounds the problem. The main aim of this study is to assess microbial patterns and antibiotic resistance from bronchoalveolar lavage specimens in severe pneumonia patients. Methods: This retrospective study was conducted in an Indonesian tertiary care hospital from January 2016-December 2020. Written and verbal informed consent was obtained prior to bronchoscopy procedures. Patients were enrolled if they had severe community-acquired pneumonia (CAP) according to American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) criteria, had high-risk hospital-acquired pneumonia (HAP), late-onset ventilator-associated pneumonia (VAP), or pneumonia caused by Coronavirus disease (COVID-19). Respiratory specimens via bronchoscopy were inoculated on general semi-sloid thioglycolate media. Testing for antibiotic susceptibility was done using the disk diffusion method. Results: Two hundred and one patients’ data were analyzed. The majority of patients were males (65,17%) and above 60 years of age. The most common type of pneumonia was CAP (39,3%). Neurologic/cerebrovascular disease was the most common comorbidity (35,32%). Acinetobacter baumannii was the most frequently isolated microorganism. Ampicillin/sulbactam and amikacin were found to yield lower microbial resistance. Conclusion: Combination of ampicillin/sulbactam and amikacin appeared effective as initial empirical therapy in severe pneumonia patients. Further studies are needed to evaluate the feasibility and effectiveness of this combined therapy.

Direct and indirect mortality impacts of the COVID-19 pandemic in the US, March 2020-April 2021 (preprint)

Excess mortality studies provide crucial information regarding the health burden of pandemics and other large-scale events. Here, we used time series approaches to separate the direct contribution of SARS-CoV-2 infections on mortality from the indirect consequences of pandemic interventions and behavior changes in the United States. We estimated deaths occurring in excess of seasonal baselines stratified by state, age, week and cause (all causes, COVID-19 and respiratory diseases, Alzheimer’s disease, cancer, cerebrovascular disease, diabetes, heart disease, and external causes, including suicides, opioids, accidents) from March 1, 2020 to April 30, 2021. Our estimates of COVID-19 excess deaths were highly correlated with SARS-CoV-2 serology, lending support to our approach. Over the study period, we estimate an excess of 666,000 (95% Confidence Interval (CI) 556000, 774000) all-cause deaths, of which 90% could be attributed to the direct impact of SARS-CoV-2 infection, and 78% were reflected in official COVID-19 statistics. Mortality from all disease conditions rose during the pandemic, except for cancer. The largest direct impacts of the pandemic were seen in mortality from diabetes, Alzheimer’s, and heart diseases, and in age groups over 65 years. In contrast, the largest indirect consequences of the pandemic were seen in deaths from external causes, which increased by 45,300 (95% CI 30,800, 59,500) and were statistically linked to the intensity of non-pharmaceutical interventions. Within this category, increases were most pronounced in mortality from accidents and injuries, drug overdoses, and assaults and homicides, while the rate of death from suicides remained stable. Younger age groups suffered the brunt of these indirect effects. Overall, on a national scale, the largest consequences of the COVID-19 pandemic are attributable to the direct impact of SARS-CoV-2 infections; yet, the secondary impacts dominate among younger age groups, in periods of stricter interventions, and in mortality from external causes. Further research on the drivers of indirect mortality is warranted to optimize interventions in future pandemics.

Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study (preprint)

Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. Here we assess cerebrovascular health in 45 hospitalised patients using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode, as indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. Exploratory analysis suggests that the level of cerebrovascular dysfunction is associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.

Contextualizing adverse event following immunization data of coronavirus disease 2019 (COVID-19) vaccines in VigiAccess: An approach for reducing COVID-19 vaccine hesitancy (preprint)

Introduction: Vaccination features high among the public health interventions that have contributed significantly to global health. Following the March 2020 declaration by the World Health Organization that coronavirus 2019 (COVID-19) is a global pandemic, several vaccines have been developed and administered to curb the spread of COVID-19. One of the threats to attaining adequate vaccination uptake for these relatively new vaccines are concerns people have about the adverse event following immunization (AEFI) information. This study sought to assess AEFIs reported on COVID-19 vaccines approved for use so far in VigiAccess and to make a case for why AEFIs data in the database must be interpreted with caution. Methods: The study followed a cross-sectional quantitative study design. VigiAccess was searched on November 10, 2021 for AEFIs reported so far for all the 12 approved COVID-19 vaccines. Data were captured among age groups, sex and continents of the world. Descriptive data were summarized using tables. Frequencies and percentages were used to categorize descriptive variables. No ethical approval was obtained before the commencement of the study as this was essentially a secondary data analysis of AEFI reports which cannot be linked to any individual. Consequently, there was no need for the informed consent process. Results: Overall, 2,457,386 AEFIs had been reported in VigiAccess. AEFIs were found to be highest among the 18-44 age group (39.7%) and lowest in vaccine recipients below 12 years (0.1%). AEFIs were more common in females than male vaccine recipients with over two-thirds of the vaccine recipients being females. Among the continents of the world, AEFI reports were highest for Europe (50%) and lowest for Africa (3%). The top 10 commonly reported AEFI types were as follows: general disorders and vaccine administrative site conditions (1,481,549, 60.1%), nervous system disorders (1,046,928, 42.6%), musculoskeletal and connective tissue disorders (704,657, 28.6%), gastrointestinal disorders (495,997, 20.2%), investigations with undesirable outcomes (341,677, 13.9%), skin and subcutaneous tissue disorders (335,932, 13.6%), respiratory, thoracic and mediastinal disorders (262,158, 10.6%), infections and infestations (180,873, 7.3%), vascular disorders (132,533, 5.3%) and injury, poisoning and procedural complications (122,519, 5%). Conclusion: The study showed that over 2 million COVID-19 AEFIs were spontaneously reported in VigiAccess, however, no causal relationships could be established between the vaccines and the AEFIs. The public accessing VigiAccess data should be made aware of this lack of association so that they may make well informed health decisions.

Utilisation of tracheostomy in patients with COVID-19 in England: patient characteristics, timing and outcomes (preprint)

Objectives: We aimed to characterise the use of tracheostomy procedures for all COVID-19 critical care patients in England and to understand how patient factors and timing of tracheostomy affected outcomes. Design: A retrospective observational study using exploratory analysis of hospital administrative data. Setting: All 500 National Health Service hospitals in England. Participants: All hospitalised COVID-19 patients aged ≥ 18 years in England between March 1st and October 31st, 2020 were included. Main outcomes and measures: This was a retrospective exploratory analysis using the Hospital Episode Statistics administrative dataset. Multilevel modelling was used to explore the relationship between demographic factors, comorbidity and use of tracheostomy and the association between tracheostomy use, tracheostomy timing and the outcomes. Results: In total, 2,200 hospitalised COVID-19 patients had a tracheostomy. Tracheostomy utilisation varied substantially across the study period, peaking in April-June 2020. In multivariable modelling, for those admitted to critical care, tracheostomy was most common in those aged 40-79 years, in males and in people of Black and Asian ethnic groups and those with a history of cerebrovascular disease. In critical care patients, tracheostomy was associated with lower odds of mortality (OR: 0.514 (95% CI 0.443 to 0.596), but greater length of stay (OR: 41.143 (95% CI 30.979 to 54.642). In patients that survived, earlier timing of tracheostomy (≤ 14 days post admission to critical care) was significantly associated with shorter length of stay. Conclusions: Tracheostomy is safe and advantageous for critical care COVID-19 patients. Early tracheostomy may be associated with better outcomes, such as shorter length of stay, compared to late tracheostomy.

Cardiac and Other Presentation and Clinical Outcomes of COVID-19 Pandemic among Different Ethnic and Religious Populations in The City of Jerusalem (preprint)

Background: The COVID‑19 pandemic is an ongoing global pandemic. Jerusalem with its 919,400 inhabitants has a wide variety of populations, of which 62% are Jews (36% ultra-orthodox; 64% non-ultraorthodox) and 38% Arabs which were largely affected by the pandemic. The aim of our study was to understand the different presentations, course and clinical outcomes in these different ethnical and cultural groups in Jerusalem in the COVID-19 pandemic. Methods: : We performed a cohort study of all COVID-19 patients admitted between March 9 - July 16, 2020 to the two university medical centers in Jerusalem. Patients were divided according to their religion and ethnicity into 3 main groups: 1) Ultra-Orthodox Jews; 2) other (non-Ultra-Orthodox) Jews and 3) Arabs. Results: : Six hundred and two patients comprised the study population. Of them the 361 (60%) were Ultra-Orthodox Jews; 166 (27.5%) non-Ultra-Orthodox Jews and 75 (12.5%) Arabs. The Arab patients were younger than the Ultra-Orthodox Jews and the non-Ultra-Orthodox Jews (51±18 year-old vs. 57±21 and 59±19, respectively, p<0.01), but suffered from significantly more co-morbidities. Moreover, hemodynamic shock, ischemic ECG changes and pathological chest x-ray were all more frequent in the Ultra-Orthodox patients as compared the other groups of patients. Being an Ultra-Orthodox was independently associated with significantly higher rate of Major Adverse Cardiovascular Events (MACE) [OR=1.96; 95% CI (1.03-3.71), p<0.05]. Age was the only independent risk factor associated with increased mortality rate [OR=1.10; 95% CI (1.07 - 1.13), p<0.001]. Conclusions: : The COVID-19 first phase in Jerusalem, affected different ethnical and cultural groups differently, with the Ultra-Orthodox Jews mostly affected by admission rates, presenting symptoms clinical course and MACE (Acute coronary syndrome, shock, cerebrovascular event or venous thromboembolism). It is conceivable that vulnerable populations need special attention and health planning in time of pandemic, to prevent rapid distribution and severe morbidity.

Comorbidities and COVID-19 Status Influence the Survival Rate of Geriatric Patients in Intensive Care Units: a Prospective Cohort Study From the Indonesian Society of Anaesthesiology and Intensive Therapy (preprint)

Background: With the more advanced science in the field of medicine and disease management, the population of geriatric intensive care patients is increasing. The COVID-19 pandemic has impacted healthcare management around the globe, especially on critically-ill elderly patients. We aim to analyse the relationship between underlying illnesses, including COVID-19, and the survival rate of elderly patients who are treated in the intensive care setting. Methods: : We conducted a prospective cohort study at 14 teaching hospitals for Anaesthesiology and Intensive Therapy Education in Indonesia. We selected all subjects with 60 years of age or older in the period between February to May 2021. Variables recorded included subject characteristics, comorbidities, and COVID-19 status. Subjects were followed for 30-day mortality as an outcome. We analysed the data using Kaplan-Meier survival analysis. Results: : We recruited 982 elderly patients, and 728 subjects were in the final analysis (60.7% male; 68.0 ± 6.6 years old). The 30-day mortality was 38.6%. The top five comorbidities are hypertension (21.1%), diabetes (16.2%), moderate or severe renal disease (10.6%), congestive heart failure (9.2%), and cerebrovascular disease (9.1%). Subjects with Charlson's Comorbidity Index Score >5 experienced 66% death. Subjects with COVID-19 who died were 57.4%. Subjects with comorbidities and COVID-19 had lower survival rates than subjects without those conditions (p < 0.005). Conclusion: Approximately one in four elderly intensive care patients die, and the number is increasing with comorbidities and COVID-19 status.

Clinical Characteristics and Risk Factors for COVID-19 Infection and Disease Severity: A Nationwide Observational Study in Estonia (preprint)

Background: COVID-19 pandemic has required overloading of health systems all over the world. For reliable risk stratification, knowledge on factors predisposing to SARS-CoV-2 infection and to severe COVID-19 disease course is needed for decision-making at the individual, provider, and government levels. Data to identify these factors should be easily obtainable.Methods: Retrospective cohort study of nationwide e-health databases in Estonia. We used longitudinal health records from 66,295 people tested positive for SARS-CoV-2 RNA from 26 February 2020 to 28 February 2021 and 254,958 randomly selected controls from the reference population with no known history of SARS-CoV-2 infection or clinical COVID-19 diagnosis (case to control ratio 1:4) to predict risk factors of infection and severe course of COVID-19. We analysed sociodemographic and health characteristics of study participants.Findings: The SARS-CoV-2 infection risk was slightly higher among women, and was higher among those with comorbid conditions or obesity. Dementia (RRR 3.77, 95%CI 3.30⎼4.31), renal disease (RRR 1.88, 95%CI 1.56⎼2.26), and cerebrovascular disease (RRR 1.81, 95%CI 1.64⎼2.00) increased the risk of infection. Of all SARS-CoV-2 infected people, 92% had a non-severe disease course, 4.8% severe disease (requiring hospitalisation), 1.7% critical disease (needing intensive care), and 1.5% died. Male sex, increasing age and comorbid burden contributed significantly to more severe COVID-19, and the strength of association for male sex increased with the increasing severity of COVID-19 outcome. The strongest contributors to critical illness (expressed as RRR with 95% CI) were renal disease (7.71, 4.71⎼12.62), the history of previous myocardial infarction (3.54, 2.49⎼5.02) and obesity (3.56, 2.82⎼4.49). The strongest contributors to a lethal outcome were renal disease (6.48, 3.74⎼11.23), cancer (3.81, 3.06⎼4.75), liver disease (3.51, 1.36⎼9.02) and cerebrovascular disease (3.00, 2.31⎼3.89).Interpretation: We found divergent effect of age and gender on infection risk and severity of COVID-19 ⎼ age and gender did not contribute substantially to infection risk, but did so for the risk of severe disease. Co-morbid health conditions, especially those affecting renin-angiotensin system, had impact on both, the risk of infection and severe disease course. Age and male sex had the most significant impact on the risk of severe COVID-19.Funding Information: Research was carried out with the support of Estonian Research Council, European Regional Development Fund and European Social Fund via IT Academy programme.Declaration of Interests: The authors declared no potential conflicts of interest.Ethics Approval Statement: The study was approved by the Research Ethics Committee of the University of Tartu.