Acute TNFα levels predict cognitive impairment 6-9 months after COVID-19 infection.

BACKGROUND: A neurocognitive phenotype of post-COVID-19 infection has recently been described that is characterized by a lack of awareness of memory impairment (i.e., anosognosia), altered functional connectivity in the brain's default mode and limbic networks, and an elevated monocyte count. However, the relationship between these cognitive and brain functional connectivity alterations in the chronic phase with the level of cytokines during the acute phase has yet to be identified. AIM: Determine whether acute cytokine type and levels is associated with anosognosia and functional patterns of brain connectivity 6-9 months after infection. METHODS: We analyzed the predictive value of the concentration of acute cytokines (IL-1RA, IL-1ß, IL-6, IL-8, IFNγ, G-CSF, GM-CSF) (cytokine panel by multiplex immunoassay) in the plasma of 39 patients (mean age 59 yrs, 38-78) in relation to their anosognosia scores for memory deficits via stepwise linear regression. Then, associations between the different cytokines and brain functional connectivity patterns were analyzed by MRI and multivariate partial least squares correlations for the whole group. RESULTS: Stepwise regression modeling allowed us to show that acute TNFα levels predicted (R2 = 0.145; ß = -0.38; p = .017) and were associated (r = -0.587; p < .001) with scores of anosognosia for memory deficits observed 6-9 months post-infection. Finally, high TNFα levels were associated with hippocampal, temporal pole, accumbens nucleus, amygdala, and cerebellum connectivity. CONCLUSION: Increased plasma TNFα levels in the acute phase of COVID-19 predict the presence of long-term anosognosia scores and changes in limbic system functional connectivity.

SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model (preprint)

Despite being largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and long-lasting phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster infection model to characterize the effects of SARS-CoV-2 versus Influenza A virus (IAV) infection on the sensory nervous system. Efforts to detect the presence of virus in the cervical/thoracic spinal cord and dorsal root ganglia (DRGs) demonstrated detectable levels of SARS-CoV-2 by quantitative PCR and RNAscope uniquely within the first 24 hours of infection. SARS-CoV-2-infected hamsters demonstrated mechanical hypersensitivity during acute infection; intriguingly, this hypersensitivity was milder, but prolonged when compared to IAV-infected hamsters. RNA sequencing (RNA-seq) of thoracic DRGs from acute infection revealed predominantly neuron-biased signaling perturbations in SARS-CoV-2-infected animals as opposed to type I interferon signaling in tissue derived from IAV-infected animals. RNA-seq of 31dpi thoracic DRGs from SARS-CoV-2-infected animals highlighted a uniquely neuropathic transcriptomic landscape, which was consistent with substantial SARS-CoV-2-specific mechanical hypersensitivity at 28dpi. Ontology analysis of 1, 4, and 30dpi RNA-seq revealed novel targets for pain management, such as ILF3. Meta-analysis of all SARS-CoV-2 RNA-seq timepoints against preclinical pain model datasets highlighted both conserved and unique pro-nociceptive gene expression changes following infection. Overall, this work elucidates novel transcriptomic signatures triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities while also highlighting several therapeutic targets for alleviation of infection-induced hypersensitivity.

Brain thermal kinetics at brain-eyelid thermal tunnels overcoming COVID-19 thermometry limitations for automated asymptomatic infection detection in concert with physical and biological principles (preprint)

For centuries, temperature measurement deficiencies attributable to biological barriers and low thermo-conductivity ( k ) have precluded accurate surface-based fever assessment. At this stage of the pandemic, infection detection in children (who due to immature immune system may not effectively respond to vaccines) is critical because children can be readily infected and also become a large mutation reservoir. We reveal hitherto-unrecognized worldwide body temperature measurements (T°), in children and adults, over tissue typified by low- k  similar to wood that may reach 6.8°C in thermal variability, hampering thereby COVID-19 control. Brain-eyelid thermal tunnels’ (BTT) integration of low- k  and high- k  regions creating a thermal pathway for undisturbed heat transmission from hypothalamus to high- k  skin eliminates current shortcomings and makes the brain indispensable for defeating COVID-19 given that brain thermoregulatory signals are not limited by mutations. Anatomo-histologic, emissive, physiologic, and thermometric bench-to-bedside studies characterized and overcome biophysical limitations of thermometry through high- k  eyelid-enabled brain temperature measurements in children and adults. BTT eyelid features fat-free skin (~900 µm) and unique light emission through a blood/fat configuration in the underlying tunnel. Contrarily, forehead features variable and thick dermis (2000–2500 µm) and variable fat layers (1100–2800 µm) resulting in variable low- k  as well as temperatures 1.97 °C lower than BTT temperature (BTT°). Highest emission present in only ~3.1% of forehead averaged 1.08±0.49 °C (mean±SD) less than BTT° ( p =0.008). Environmental and biological impacts during fanning revealed thermal imaging limitations for COVID-19 screening. Comparison of paired measurements for 100 pediatric patients showed that in the children subgroup above 37°C, BTT° exceeded body core temperature (Core°) in 60/72 patients; the average difference in the 72 patients was 0.62±0.7°C  (p<0.001 by unpaired t-test); and in the subgroup beyond 37.5°C, BTT° exceeded Core° in 30/32 patients. Delineating hypothalamic activity in children facilitates early infection detection, which is essential because children’s immunogenicity prevents effective vaccination and causes accelerated viral evolution. Capturing hypothalamic thermal signals from BTT was further supported by brain thermal kinetics via BTT using wearables during anesthesia, sedation, sleep, brain injury, exercise, and asymptomatic infection, which revealed brain/core discordance and enabled automated noninvasive afebrile infection detection for interrupting asymptomatic human-to-human transmission. BTT-based spot-check thermometry can be harmlessly implemented for children worldwide without undue burden and costs; meanwhile, continuous brain-eyelid T° in concert with biological and physical principles affords a new dimension for combating pandemics. The “detection–vaccination” pair solution presented is required to mitigate COVID-19 from spreading indefinitely through mutations and vaccine evasion while opening a viable path for eradicating COVID-19.

Coagulopathy is Initiated with Endothelial Dysfunction and Disrupted Fibrinolysis in Patients with COVID-19 (preprint)

Background: A substantial group of patients suffer coagulopathy of Covid-19 (CAC) and are presented with thrombosis. The pathogenesis involved in CAC is not fully understood. Objectives: We evaluated the hemostatic and inflammatory parameters of 51 hospitalized Covid-19 adult patients and 21 controls. The parameters analyzed were danger signal molecule (High molecular weight group box protein-1/HMGBP-1), platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, fibrinogen, endothelial protein C receptor (EPCR), soluble E-selectin, soluble P-selectin, thrombomodulin, tissue plasminogen activator (TPA), plasminogen activator inhibitor-1 (PAI-1), soluble fibrin monomer complex (SFMC), platelet-derived microparticles (PDMP), β-thromboglobulin, antithrombin and protein C. The main objective of our study was to investigate which part of the hemostatic system was mostly affected at the admission of Covid-19 patients and whether these parameters could differentiate intensive care unit (ICU) and non-ICU patients. Patients and Methods: In this prospective case-control study, 51 patients ≥18 years who are hospitalized with the diagnosis of Covid-19 and 21 healthy control subjects were included. We divided the patients into two groups according to their medical progress, either into ICU and non-ICU group. Regarding the outcome, patients were again categorized as survivor and non-survivor groups. Blood samples were collected from patients at admission at the time of hospitalization before administration of any treatment for Covid-19. The analyzes of the study were made with the IBM SPSS V22 program. p < 0.05 was considered statistically significant. Results: : A total of 51 adult patients (F/M: 24/27) (13 ICU and 38 non-ICU) were included in the study cohort. The mean age of the patients was 68.1 ± 14.4 years. The control group consisted of 21 age and sex-matched healthy individuals. All of the patients were hospitalized, in a group of 13 patients, Covid-19 progressed to severe form and were hospitalized at ICU. We found out that the levels of fibrinogen, prothrombin time (PT), endothelial protein-C receptor (EPCR), D-dimer, soluble E-selectin, soluble P-selectin, plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (TPA) were increased; whereas, the levels of soluble fibrin monomer complex (SFMC), platelet-derived microparticles (PDMP), antithrombin and protein-C were decreased in Covid-19 patients compared to the control group at hospital admission. Tissue plasminogen activator was the only marker that had a significantly different median level between ICU and non-ICU groups (p<0.001). Conclusions: : In accordance with the previous literature, we showed that Covid-19 associated coagulopathy is distinct from sepsis-induced DIC with prominent early endothelial involvement and fibrinolytic shut-down. Reconstruction of endothelial function at early stages of infection may protect patients to progress to ICU hospitalization. We believe that after considering the patient’s bleeding risk, early administration of LMWH therapy at Covid-19 even in at outpatient setting may be useful both for restoring endothelial function and anticoagulation. The intensity of anticoagulation in non-ICU and ICU Covid-19 patients should be clarified with further studies.

Comparison of Laboratory Parameters in Patients with COVID-19 (preprint)

Background: The novel coronavirus strain disease that started in December 2019, in Wuhan, China became a pandemic and life-threatening disease worldwide. Despite COVID-19 vaccination in some parts of the world, social distances, lockdown, and more policies the disease is rising, the disease would continue for some while, especially in poor and developing countries. To extend our knowledge about severely and critically ill patients with COVID-19, we compared laboratory values about these patients with the control group.Methods: In this single-center, observational study, we enrolled 143 participants that 103 patients who were severely or critically ill patients with confirmed SARS-CoV-2 pneumonia who admitted to Imam Khomeini Hospital Complex (Tehran, Iran) and included 40 healthy individuals as the control group. Data were analyzed for demographic data, laboratory values, and clinical outcomes. Data were also compared between survivors and non-survivors.Findings: Of 143 participants, we enrolled 54 patients in the severe group and 49 patients in the critical group. The average age of the cases was 53.5 years. 52.4% were men, non-survivors were older than survivors (55 years vs 53.2). Prothrombin time, partial thromboplastin time, the international normalized ratio, and D-dimer were significant in the critical group and the severe group compared to the control group. The blood cell parameters (include WBC, RBC, Hb, HCT, neutrophils, lymphocytes) were significant in the critical and severe groups compared to the control group. Renal function tests (BUN, Cr) and liver function tests (ALT, AST, ALK) were significant in the patient groups compared with the control group. Inflammatory indicator tests like erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were higher in the patient groups compared to the control group. Significant elevation of lactate dehydrogenase (LDH) levels in the patient groups in comparison to the control group showed that tissues damaged deeply in the patient groups. We also carried out a comparison between survivors and non-survivors and revealed that PT, PTT, D-dimer, ESR, FBS, urea, creatinine, LDH, lymphocyte, and neutrophil count were significant. Findings showed coagulopathy and organ failure are the main reason for the mortality of patients.Interpretation: Rapid blood tests, including prothrombin time, D-dimer, FBS, urea, creatinine, LDH, neutrophil, and lymphocyte counts can help clinicians like biomarkers to assess severity, organ failure, and prognosis of patients with COVID-19. Nevertheless, more investigations are needed to find the applicability of biomarkers in predicting the risk of severity and mortality in 2019-nCoV infection.Funding Statement: This study was funded and supported by Tehran university of medical sciences (TUMS); Grant no.47635Declaration of Interests: We declare no competing interests.Ethics Approval Statement: This study was approved by the Iran National Committee for Ethics in Biomedical Research (IR.TUMS.VCR.REC.1399.260) was done in Imam Khomeini Hospital Complex (Tehran, Iran).

Thermal Camera detection of High Temperature for mass COVID Screening (preprint)

The COVID-19 [SARS-COV-2] pandemic has had a devastating global impact, with both the human and socio economic costs being severe. One result of the COVID-19 pandemic is the emergence of an urgent requirement for effective techniques and technologies for screening individuals showing symptoms of infection in a non-invasive and non-contact way. Systems that exploit thermal imaging technology to screen individuals show promise to satisfy the desired criteria, including offering a non-contact, non-invasive method of temperature measurement. Furthermore, the potential for mass and passive screening makes thermal imaging systems an attractive technology where current 'standard of care' methods are not practical. Critically, any fever screening solution must be capable of accurate temperature measurement and subsequent prediction of core temperature. This is essential to ensure a high sensitivity in identifying fever while maintaining a low rate of false positives. This paper discusses the results and analysis of a clinical trial undertaken by Thales UK Ltd and the Queen Elizabeth University Teaching Hospital in Glasgow to assess the accuracy and operation of the High Temperature Detection (HTD) system developed by Thales UK Ltd when used in a clinical setting. Results of this single centre prospective observational cohort study show that the measured laboratory accuracy of the Thales HTD system (RMSE=0.1{degrees}C) is comparable to the accuracy when used in a clinical setting (RMSE=0.15{degrees}C) when measuring a calibrated blackbody source at typical skin temperature. For measurement of forehead skin temperature, the system produced results commensurate with close contact measurement methods (R=0.86, Mean error = 0.05{degrees}C). Compared to measured tympanic temperatures, measurement of the forehead skin temperature by the HTD system showed a moderate correlation (R=0.43), which is stronger than close contact IR forehead thermometers (R=0.20, 0.35). An improved correlation was observed between the maximum facial temperature measured by the HTD system and measured tympanic temperatures (R=0.53), which is significantly stronger than the close contact methods. A linear predictive model for tympanic temperature based on the measured maximum facial temperatures resulted in a root mean square error (RMSE=0.50{degrees}C) that is marginally larger than what is expected as a compound of errors in the measuring devices (RMSE=0.45{degrees}C). The study demonstrates that the HTD could be applied in the clinical and non-clinical setting as a screening mechanism to detect citizens with raised temperature. This approach would enable high volume surveillance and identification of individuals that contribute to further spread of COVID-19. Deployment of the HTD system could be implemented as part of a screening tool to support measures to enhance public safety and confidence in areas of high throughput, such as airports, shopping centres or places of work.

Hypercoagulation detected by Rotational Thromboelastometry predicts mortality in COVID-19: A risk model based on a prospective observational study (preprint)

ABSTRACT Background Severe disease due to COVID-19 has been shown to be associated with hypercoagulation. Early identification of prothrombotic patients may help guiding anticoagulant treatment and improve survival. The aim of this study was to assess Rotational Thromboelastmetry (ROTEM ® ) as a marker of coagulopathy in hospitalized COVID-19 patients. Methods This was a prospective, observational study. Patients hospitalized due to a COVID-19 infection were eligible for inclusion. Conventional coagulation tests and ROTEM were taken after hospital admission, and patients were followed for 30 days. Patient characteristics and outcome variables were collected, and a prediction model including variables age, respiratory frequency and ROTEM EXTEM-MCF, was developed using logistic regression to evaluate the probability of death. Results Out of the 141 patients included, 18 (13%) died within 30 days. D-dimer (p=0.01) and Activated Partial Thromboplastin Time (APTT) (p=0.002) were increased, and ROTEM EXTEM-/INTEM-CT (p<0.001) were prolonged in non-survivors. In the final prediction model, the risk of death within 30 days for a patient hospitalized due to COVID-19 was increased with increased age, respiratory frequency and EXTEM-MCF. Longitudinal ROTEM data in the severely ill subpopulation showed enhanced hypercoagulation. In our in vitro analysis, no heparin effect on EXTEM-CT was observed, supporting a SARS-CoV-2 effect on initiation of coagulation. Conclusions Here we show that hypercoagulation measured with ROTEM predicts 30-day mortality in COVID-19. Longitudinal ROTEM data strengthen the hypothesis of hypercoagulation as a driver of severe disease in COVID-19. Thus, ROTEM may be a useful tool to assess disease severity in COVID-19, and could potentially guide anticoagulation therapy.

Advancing Efficient and Timely Community Access to SARS-CoV-2 Serology Testing in Europe: a Multi-stakeholder Consensus (preprint)

Background: Currently there is no clear consensus on the use, value, benefits, and impact of serology testing as part of a comprehensive SARS-CoV-2 testing strategy. The lack of clarity on the use of this strategy in policies and guidelines may have serious implications on the efforts to curb the pandemic. The aim of this paper is to elaborate an experts and community consensus on the use of serology testing as an effective method to respond to and mitigate the impact of the pandemic. The recommendations herein can help build community awareness and guide advocacy strategies. Methods: : A desk review was conducted to inform a working document that was subject to a multistage process of validation and feedback by a group of renowned experts. The multi-stakeholder group of experts, representing the European and international levels, convened to inform and validate the recommendations. Results: : The consensus offered eight policy recommendations organized in two main themes. The first group of recommendations provides guidance on the role and value of serology testing to contain and understand the COVID-19 pandemic. The second group targets health system strengthening aspects necessary to support the appropriate delivery of serology testing. Conclusions: : Recommendations seek to indicate how SARS-CoV-2 serology testing may positively impact national health systems, country economies and local communities. The pertinence of the recommendations is to communities in Europe, and beyond, and relevant to multiple stakeholders. Given the rapidly changing scenario, this set of recommendations should be considered a live document.

Efficacy and Complications of Regional Citrate Anticoagulation During Continuous Renal Replacement Therapy in Critically Ill Patients with COVID-19 (preprint)

Background: Enhanced coagulation in coronavirus disease 2019 (COVID-19) patients is considered a major obstacle for continuous renal replacement therapy (CRRT), but systematic analyses are sparse. We compared filter survival and citrate-induced complications during CRRT with regional citrate anticoagulation (RCA) in COVID-19 and Non-COVID-19 patients. Methods: : In this retrospective study we included all consecutive adult patients (n=97) with acute kidney injury (AKI) treated with RCA-CRRT at seven ICUs of a tertiary university hospital over the tree month period. Medical data were collected to compare the efficacy and complications of RCA-CRRT between COVID-19 (n=44) and Non-COVID-19 patients (n=53). Results: : There was no significant difference in the number of CRRT filters used per patient in COVID-19 vs. Non-COVID-19 patients (median 5 vs 3 filters, p=0.103). Mean filter run-time was significantly higher in COVID-19 patients compared to Non-COVID-19 patients (68.4 (95%CI 67.0-69.9) vs. 65.2 (95%CI 63.2-67.2) hours, respectively; log-rank 0.014). COVID-19 patients showed significantly higher activated partial thromboplastin time (aPTT) throughout the CRRT due to systemic anticoagulation compared to Non-COVID-19 patients (54 (IQR 45 – 61) vs. 47 (IQR 41 - 58) seconds, respectively; p<0.001). A significantly higher incidence of combined metabolic disturbances (metabolic alkalosis, hypercalcemia and hypernatremia), consistent with reduced filter patency and citrate overload during RCA, was observed in COVID-19 patients compared to Non-COVID-19 patients (19.1% vs. 12.7%, respectively; p=0.04). These metabolic disarrangements were resistant to per-protocol adjustments and disappeared after replacement of the CRRT-filter. Conclusions: : In contrast to initial concerns, adequate filter life-span can be achieved with RCA during CRRT in COVID-19 patients. However, close monitoring of the acid-base balance appears warranted, as these patients tend to develop reduced filter patency leading to a higher incidence of citrate overload and metabolic disturbances. Trial Registration (local authority): EA1/285/20 (Ethikkommission der Charité - Universitätsmedizin Berlin); date of registration 08.10.2020.

Temperature Dependent Viral Tropism (TDVT): Understanding Viral Seasonality and Pathogenicity as Applied to the Avoidance and Treatment of Endemic Viral Respiratory Illnesses (preprint)

This review seeks to explain four features of viral respiratory illnesses that have perplexed generations of virologists: (1) the seasonal timing of respiratory illness; (2) the common viruses causing respiratory illness worldwide, including year-round disease in the Tropics; (3) the rapid response of outbreaks to weather, specifically temperature; (4) the rapid arrival and termination of epidemics caused by influenza and other viruses. The inadequacy of the popular explanations of seasonality is discussed, and a simple hypothesis is proposed, called Temperature Dependent Viral Tropism (TDVT), that is compatible with the above features of respiratory illness. TDVT notes that viruses can transmit themselves more effectively if they moderate their pathogenicity (thereby maintaining host mobility) and suggests that endemic respiratory viruses accomplish this by developing thermal sensitivity within a range that supports organ-specific viral tropism within the human body, whereby they replicate most rapidly at temperatures below body temperature. This allows them to confine themselves to the upper respiratory tract and to avoid infecting the lungs, heart, gut etc. Biochemical and tissue-culture studies show that “wild” respiratory viruses show such natural thermal sensitivity. The typical early autumn surge of colds and the existence of respiratory illness in the Tropics year-round at intermediate levels are explained by the tendency for strains to adapt their thermal sensitivity to their local climate and season. The TDVT hypothesis has important practical implications for preventing and treating respiratory illness including Covid-19. TVDT is testable with many options for experiments to increase our understanding of viral seasonality and pathogenicity.

Autopsy and Statistical Evidence of Disturbed Hemostasis Progress in COVID-19: Medical Records from 407 Patients (preprint)

Background: The progression of coagulation in COVID-19 patients with confirmed discharge status and the combination of autopsy with complete hemostasis parameters have not been well studied. Objective: To clarify the thrombotic phenomena and hemostasis state in COVID-19 patients based on epidemiological statistics combining autopsy and statistical analysis. Methods: : Using autopsy results from 9 patients with COVID-19 pneumonia and the medical records of 407 patients, including 39 deceased patients whose discharge status was certain, time-sequential changes in 11 relevant indices within mild, severe and critical infection throughout hospitalization according to the Chinese National Health Commission (NHC) guidelines were evaluated. Statistical tools were applied to calculate the importance of 11 indices and the correlation between those indices and the severity of COVID-19. Results: : At the beginning of hospitalization, platelet (PLT) counts were significantly reduced in critically ill patients compared with severely or mildly ill patients. Blood glucose (GLU), prothrombin time (PT), activated partial thromboplastin time (APTT), and D-dimer levels in critical patients were increased compared with mild and severe patients during the entire admission period. The International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) score was also high in critical patients. In the relatively late stage of nonsurvivors, the temporal changes in PLT count, PT, and D-dimer levels were significantly different from those in survivors. A random forest model indicated that the most important feature was PT followed by D-dimer, indicating their positive associations with disease severity. Autopsy of deceased patients fulfilling diagnostic criteria for DIC revealed microthromboses in multiple organs. Conclusions: Combining autopsy data, time-sequential changes and statistical methods to explore hemostasis-relevant indices among the different severities of the disease helps guide therapy and detect prognosis in COVID-19 infection.

Renin-angiotensin system blockers and mortality in COVID-19: a territory-wide study from Hong Kong (preprint)

Aims Renin–angiotensin system blockers such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase the risk of adverse outcomes in COVID-19. In this study, the relationships between ACEI/ARB use and COVID-19 related mortality were examined. Methods Consecutive patients diagnosed with COVID-19 by RT-PCR at the Hong Kong Hospital Authority between 1 st January and 28 th July 2020 were included. Results This study included 2774 patients. The mortality rate of the COVID-19 positive group was 1.5% (n=42). Those who died had a higher median age (82.3[76.5-89.5] vs. 42.9[28.2-59.5] years old; P<0.0001), more likely to have baseline comorbidities of cardiovascular disease, diabetes mellitus, hypertension, and chronic kidney disease (P<0.0001). They were more frequently prescribed ACEI/ARBs at baseline, and steroids, lopinavir/ritonavir, ribavirin and hydroxychloroquine during admission (P<0.0001). They also had a higher white cell count, higher neutrophil count, lower platelet count, prolonged prothrombin time and activated partial thromboplastin time, higher D-dimer, troponin, lactate dehydrogenase, creatinine, alanine transaminase, aspartate transaminase and alkaline phosphatase (P<0.0001). Multivariate Cox regression showed that age, cardiovascular disease, renal disease, diabetes mellitus, the use of ACEIs/ARBs and diuretics, and various laboratory tests remained significant predictors of mortality. Conclusions We report that an association between ACEIs/ARBs with COVID-19 related mortality even after adjusting for cardiovascular and other comorbidities, as well as medication use. Patients with greater comorbidity burden and laboratory markers reflecting deranged clotting, renal and liver function, and increased tissue inflammation, and ACEI/ARB use have a higher mortality risk. Key Points We report that an association between ACEIs/ARBs with COVID-19 related mortality even after adjusting for cardiovascular and other comorbidities, as well as medication use. Patients with greater comorbidity burden and laboratory markers reflecting deranged clotting, renal and liver function, and increased tissue inflammation, and ACEI/ARB use have a higher mortality risk.

Parkinsonism as a Third Wave of the COVID-19 Pandemic?

Since the initial reports of COVID-19 in December 2019, the world has been gripped by the disastrous acute respiratory disease caused by the SARS-CoV-2 virus. There are an ever-increasing number of reports of neurological symptoms in patients, from severe (encephalitis), to mild (hyposmia), suggesting the potential for neurotropism of SARS-CoV-2. This Perspective investigates the hypothesis that the reliance on self-reporting of hyposmia has resulted in an underestimation of neurological symptoms in COVID-19 patients. While the acute effect of the virus on the nervous system function is vastly overshadowed by the respiratory effects, we propose that it will be important to monitor convalescent individuals for potential long-term implications that may include neurodegenerative sequelae such as viral-associated parkinsonism. As it is possible to identify premorbid harbingers of Parkinson's disease, we propose long-term screening of SARS-CoV-2 cases post-recovery for these expressions of neurodegenerative disease. An accurate understanding of the incidence of neurological complications in COVID-19 requires long-term monitoring for sequelae after remission and a strategized health policy to ensure healthcare systems all over the world are prepared for a third wave of the virus in the form of parkinsonism.

Estimating the Case Fatality Ratio for COVID-19 using a Time-Shifted Distribution Analysis (preprint)

Estimating the case fatality ratio (CFR) for COVID-19 is an important aspect of public health. However, calculating CFR accurately is problematic early in a novel disease outbreak, due to uncertainties regarding the time course of disease and difficulties in diagnosis and reporting of cases. In this work, we present a simple method for calculating the case fatality ratio using only public case and death data over time by exploiting the correspondence between the time distributions of cases and deaths. The time-shifted distribution (TSD) analysis generates two parameters of interest: the delay time between reporting of cases and deaths and the case fatality ratio. These parameters converge reliably over time once the exponential growth phase has finished. Analysis is performed for early COVID 19 outbreaks in many countries, and we discuss corrections to CFR values using excess-death and seroprevalence data to estimate the infection fatality ratio (IFR). While CFR values range from 0.2-20% in different countries, estimates for IFR are mostly around 0.5-0.8% for countries that experienced moderate outbreaks and 1-3% for severe outbreaks. The simplicity and transparency of TSD analysis enhance its usefulness in characterizing a new disease as well as the state of the health and reporting systems.

The Role of COVID-19 in the Death of SARS-CoV-2–Positive Patients: A Study Based on Death Certificates (preprint)

Background: Death certificates are considered the most reliable source of information to compare cause-specific mortality across countries. Aim of the present study was to examine death certificates of persons who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to a. quantify the number of deaths directly caused by coronavirus 2019 (COVID-19); b. estimate the most common complications leading to death; and c. identify the most common comorbidities.Methods: Death certificates of persons who tested positive for SARS-CoV-2 provided to the National Surveillance system were coded according to the 10th edition of the International Classification of Diseases. Deaths due to COVID-19 were defined as those in which COVID-19 was the underlying cause of death. Complications were defined as those conditions reported as originating from COVID-19, and comorbidities were conditions independent of COVID-19.Findings: A total of 5,311 death certificates of persons dying in March through May 2020 were analysed (16.7% of total deaths). COVID-19 was the underlying cause of death in 88% of cases. Pneumonia and respiratory failure were the most common complications, being identified in 78% and 54% of certificates, respectively. Other complications, including shock, respiratory distress and pulmonary oedema, and heart complications demonstrated a low prevalence, but they were more commonly observed in the 30–59 years age group. Comorbidities were reported in 72% of certificates, with little variation by age and gender. The most common comorbidities were hypertensive heart disease, diabetes, ischaemic heart disease, and neoplasms. Neoplasms and obesity were the main comorbidities among younger people.Interpretation: In most persons dying after testing positive for SARS-CoV-2, COVID-19 was the cause directly leading to death. In a large proportion of death certificates, no comorbidities were reported, suggesting that this condition can be fatal in healthy persons. Respiratory complications were common, but non-respiratory complications were also observed.Funding Statement: None.Declaration of Interests: No financial relationships with any organisation that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.Ethics Approval Statement: On February 27, 2020, the Italian Presidency of the Council of Ministers authorised the collection and scientific dissemination of data related to COVID-19 by the Italian Institute of Health.

A Comparison of Clinical and Laboratory Manifestations of Thrombotic Events in Patients with COVID-19 and Other Respiratory Viral Infections (preprint)

Background: COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and other respiratory viral (non-CoV-2-RV) infections are associated with thrombotic complications. The differences in prothrombotic potential between SARS-CoV-2 and non-CoV-2-RV have not been well characterised. We compared the thrombotic rates between these two groups of patients directly and further delved into their coagulation profiles. Methods: In this single-center, retrospective cohort study, all consecutive COVID-19 and non-CoV-2-RV patients admitted between January 15th and April 10th 2020 were included. Coagulation parameters studied were prothrombin time and activated partial thromboplastin time and its associated clot waveform analysis (CWA) parameter, min1, min2 and max2.Findings: In the COVID-19 (n=181) group there were two (1.0 event/1000-hospital-days) thrombotic events while one (1.8 event/1000-hospital-day) was reported in the non-CoV-2-RV (n=165) group. All of these events were myocardial infarction occurring in the intensive care unit. Coagulation parameters did not differ throughout the course of mild COVID-19. However, CWA parameters were significantly higher in severe COVID-19 compared with mild disease, suggesting hypercoagulability (min1: 6.48%/s vs 5.05%/s, P <0.001; min2: 0.92%/s2 vs 0.74%/s2, P =0.033).Interpretation: The thrombotic rates were low and did not differ between COVID-19 and non-CoV-2-RV patients. The hypercoagulability in COVID-19 is a highly dynamic process with the highest risk occurring when patients were most severely ill. Such changes in haemostasis could be detected by CWA. In our population, a more individualized thromboprophylaxis approach, considering clinical and laboratory factors, is preferred over universal pharmacological thromboprophylaxis for all hospitalized COVID-19 patients and such personalized approach warrants further research. Funding: This research was funded by the SingHealth Duke-NUS Academic Medicine COVID-19 Research Grant.Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: This database is part of a prospective study to characterize emerging infectious diseases and was approved by our institutional review board (CIRB no. 2018/3045).

Treatment Delays and In-Hospital Outcomes in Acute Myocardial Infarction During the COVID-19 Pandemic: A Nationwide Study (preprint)

Background: Delay on admission of myocardial infarction (MI) is an important prognostic factor. In this nationwide registry, we compared treatment delays and outcomes of patients with acute MI in Covid-19 pandemic period with a recent pre-pandemic registry conducted at the same centres. Methods: A recent nationwide registry (TURKMI-1) enrolled consecutive patients with acute MI in November 1-15, 2018 in Turkey, and assessed time delay at each step from symptom-onset to treatment and outcomes. Fifty centres were selected using probability sampling. In the present study (TURKMI-2), the same information was obtained from 48 of the same 50 centres during the pandemic between April 17 and May 2, 2020. Findings: In a 2-week period, 991 patients (51·1% NSTEMI, 48·9% STEMI) were admitted to the study centres within the 48-hour of symptom-onset. Compared with the TURKMI-1, admissions decreased by 31·2% in ST-segment elevation MI (STEMI), and 56·4% in non-STEMI (NSTEMI). Median time from symptom-onset to hospital-arrival increased from 295 min to 419 min in NSTEMI, and from 150 min to 185 min in STEMI (p-values <0·001). Door-to-balloon time was similar in the two periods (37 vs. 40 min, p=0·448), however, total ischaemic time increased significantly (195 min vs 245 min, p=0·001) mainly due to patient-related delay. Percutaneous coronary intervention (PCI) was decreased especially in the NSTEMI group (60·3% vs 47·4% in NSTEMI, p<0·001; 94·8% vs 91·1% in STEMI, p=0·013). Major cardiac adverse events (MACE) defined as in-hospital death, heart failure, or cardiogenic shock were significantly higher in the pandemic period compared to non-pandemic (4·8% vs 8·9%; p <0·001). Age and sex adjusted risk of MACE was two times higher during pandemic (Odds ratio [95% confidence interval] was 1·96 [1·20-3·22] for NSTEMI, p=0·007; and 2·08 [1·38-3·13] for STEMI, p<0·001). Interpretation: Besides the overall 47·1% reduction in acute MI admissions, there was a significant patient related treatment delay during the pandemic. Although PCI was performed in a timely fashion, increase in total ischaemic time and decrease in PCI might be responsible for the increased risk of MACE in acute MI. Funding: This investigator-initiated study was funded by the Turkish Society of Cardiology, which received unrestricted grant from Astra-Zeneca Company for this project.Declaration of Interests: Dr. Kayikcioglu reports grants from Astra Zeneca, during the conduct of the study; grants from Aegerion, other from Astra Zeneca, other from Menarini, non-financial support and other from Abbott, outside the submitted work; - Dr. Aktaş reports non-financial support from Astra Zeneca, during the conduct of the study - Dr. Kilickap reports grants from Astra_Zeneca, during the conduct of the study - Dr. Zeybey reports grants from Astra Zeneca, during the conduct of the study - Dr. Inci reports grants from Astra Zeneca , during the conduct of the study - Dr. Er reports grants from Astra Zeneca, during the conduct of the study - Dr. Kahraman reports grants from Astra Zeneca, during the conduct of the study - Dr. Yayla reports grants from Astra Zeneca, during the conduct of the study - Dr. Kafkas reports grants from Astra Zeneca, during the conduct of the study - Dr. Yildirim reports grants from Astra Zeneca, during the conduct of the study - Dr. can reports grants from ASTRA-ZENECA, during the conduct of the study - Dr Erol reports grands from Astra Zeneca, during the conduct of the study, - Dr. Yalcin reports grants from Astra Zeneca, during the conduct of the study - Dr. Guler reports grants from Astra Zeneca, during the conduct of the study - Dr. Arin reports grants from Astra-Zeneca, during the conduct of the study - Dr. Genç reports grants and non-financial support from Astra Zeneca, during the conduct of the studyEthics Approval Statement: The study protocol was approved by the Institutional Review Board (Ankara University Medical School; May 7, 2020; No: i4-225-20) and the Ministry of Health COVID-19 Scientific Board (May 6, 2020 No: 66175679.99.E.110223).