In silico design of miniprotein to inhibit SARS-CoV-2 variant Omicron spike protein.

Omicron is a novel variant of SARS-CoV-2 that is currently spreading globally as the dominant strain. The virus first enters the host cell through the receptor binding domain (RBD) of the spike protein by interacting with the angiotensin-converting enzyme 2 (ACE2). Thus, the RBD protein is an ideal target for the design of drugs against the Omicron variant. Here, we designed several miniprotein inhibitors in silico to combat the SARS-CoV-2 Omicron variant using single- and double-point mutation approaches, based on the structure of the initial inhibitor AHB2. Also, two parallel molecular dynamics (MD) simulations were performed for each system to reproduce the calculated results, and the binding free energy was evaluated with the MM/PBSA method. The evaluated values showed that all inhibitors, including AHB2, M7E, M7E + M43W, and M7E + M43Y, were energetically more beneficial to the binding with the RBD than ACE2. In particular, the mutant inhibitor M7E + M43Y possessed the highest binding affinity to RBD and was selected as the most promising "best" inhibitor among all inhibitors. In addition, the combination of multiple analysis methods, such as free energy landscape analysis (FEL), principal component analysis (PCA), dynamic cross-correlation matrix analysis (DCCM), and hydrogen bond, salt bridge, and hydrophobic interaction analysis, also demonstrated that the mutations significantly affect the dynamical behavior and binding pattern of the inhibitor binding to the RBD protein. The current work suggested that miniprotein inhibitors can form stable complex structures with the RBD protein and exert a blocking or inhibitory effect on the SARS-CoV-2 variant Omicron. In conclusion, this study has identified several novel mutant inhibitors with enhanced affinity to the RBD protein, and provided potential guidance and insights for the rational design of therapeutic approaches for the new SARS-CoV-2 variant Omicron.

Diagnostic accuracy of splinter haemorrhages in patients referred for suspected infective endocarditis.

OBJECTIVE: Splinter haemorrhages are an examination finding that has classically been associated with infective endocarditis (IE), but are not included in current diagnostic algorithms. Splinter haemorrhages have not been evaluated as a diagnostic tool using modern definitions of IE. We determined their sensitivity and specificity in patients with suspected IE and investigated their inclusion in the Duke criteria. METHODS: This is a retrospective diagnostic accuracy study using data from 1119 patients with suspected IE referred to the IE service. Patients were categorised according to the Duke criteria, the current diagnostic gold standard, into Duke 'rejected', 'possible' or 'definite' groups. Definite cases (n=451) served as the true positives and rejected cases (n=486) as the true negatives against which splinter haemorrhages were compared. Duke possible cases (n=182) were used the assess the clinical impact of adding splinter haemorrhages to the Duke criteria. RESULTS: In clinically suspected cases of IE and using the Duke criteria as the gold standard comparator, splinter haemorrhages had a sensitivity of 26% (95% CI 22 to 31) (119 out of 451) and a specificity of 83% (95% CI 79 to 86) (403 out of 486). Inclusion of splinter haemorrhages as a minor vascular phenomenon in the Duke criteria would result in a reclassification of 12% of cases from Duke rejected to possible and 13% from Duke possible to definite. CONCLUSION: Splinter haemorrhages are an insensitive tool in the diagnosis of IE, but their high specificity indicates they do have clinical value in patients with suspected infection. Their inclusion in the Duke criteria as a minor vascular criterion reduces diagnostic uncertainty for some Duke possible cases, while increasing it for a similar proportion of Duke rejected cases.

Investigation on the interaction mechanism of different SARS-CoV-2 spike variants with hACE2: insights from molecular dynamics simulations.

Since the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), SARS-CoV-2 has evolved by acquiring genomic mutations, resulting in the recent emergence of several SARS-CoV-2 variants with improved transmissibility and infectivity relative to the original strain. An underlying mechanism may be the increased ability of the mutants to bind the receptor proteins and infect the host cell. In this work, we implemented all-atom molecular dynamics (MD) simulations to study the binding and interaction of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein singly (D614G), doubly (D614G + L452R and D614G + N501Y), triply (D614G + N501Y + E484K), and quadruply (D614G + N501Y + E484K + K417T) mutated variants with the human angiotensin-converting enzyme 2 (hACE2) receptor protein in the host cell. A combination of multiple analysis approaches elucidated the effects of mutations and the extent of molecular divergence from multiple perspectives, including the dynamic correlated motions, interaction patterns, dominant motions, free energy landscape, and charge distribution on the electrostatic potential surface between the hACE2 and all RBD variants. Moreover, free energy calculations using the MM/PBSA method evaluated the binding affinity between these RBD variants and hACE2. The results showed that the D614G + N501Y + E484K variant possessed the lowest free energy value (highest affinity) compared to the D614G + N501Y + E484K + K417T, D614G + L452R, D614G + N501Y, and D614G mutants. The residue-based energy decomposition also indicated that the energy contribution of residues at the mutation site to the total binding energy was highly variable. The interaction mechanisms between the different RBD variants and hACE2 elucidated in this study will provide some insights into the development of drugs targeting the new SARS-CoV-2 variants.

Computational Design of Miniprotein Inhibitors Targeting SARS-CoV-2 Spike Protein.

The ongoing pandemic of COVID-19 caused by SARS-CoV-2 has become a global health problem. There is an urgent need to develop therapeutic drugs, effective therapies, and vaccines to prevent the spread of the virus. The virus first enters the host cell through the interaction between the receptor binding domain (RBD) of spike protein and the peptidase domain (PD) of the angiotensin-converting enzyme 2 (ACE2). Therefore, blocking the binding of RBD and ACE2 is a promising strategy to inhibit the invasion and infection of the virus in the host cell. In the study, we designed several miniprotein inhibitors against SARS-CoV-2 by single/double/triple-point mutant, based on the initial inhibitor LCB3. Molecular dynamics (MD) simulations and trajectory analysis were performed for an in-depth analysis of the structural stability, essential protein motions, and per-residue energy decomposition involved in the interaction of inhibitors with the RBD. The results showed that the inhibitors have adapted the protein RBD in the binding interface, thereby forming stable complexes. These inhibitors display low binding free energy in the MM/PBSA calculations, substantiating their strong interaction with RBD. Moreover, the binding affinity of the best miniprotein inhibitor, H6Y-M7L-L17F mutant, to RBD was ∼45 980 times (ΔG = RT ln Ki) higher than that of the initial inhibitor LCB3. Following H6Y-M7L-L17F mutant, the inhibitors with strong binding activity are successively H6Y-L17F, L17F, H6Y, and F30Y mutants. Our research proves that the miniprotein inhibitors can maintain their secondary structure and have a highly stable blocking (binding) effect on SARS-CoV-2. This study proposes novel miniprotein mutant inhibitors with enhanced binding to spike protein and provides potential guidance for the rational design of new SARS-CoV-2 spike protein inhibitors.

Childhood trauma and suicide risk in schizophrenia inpatients: the sequential mediating roles of COVID-19 related psychological impact, sleep quality, and emotional distress (preprint)

Purpose The stressful global situation due to the COVID-19 pandemic has had a tremendous impact on mental health in hospitalized patients with schizophrenia. The mediating roles of psychological impacts related to COVID-19 sleep quality and emotional distress were investigated in the association between childhood trauma and suicide risk in inpatients with schizophrenia. Methods A total of 270 participants, including 125 in-patients with schizophrenia and 145 healthy controls (HCs) were enrolled. Childhood trauma, psychological impact related to COVID-19, global sleep quality, and psychological distress were measured using the Childhood Trauma Questionnaires (CTQ), Impact of Event Scale-Revised (IES-R), Pittsburgh Sleep Quality Index (PSQI), and Depression, Anxiety and Stress Scale (DASS-21), respectively. Results The total score and subtype scores of CTQ and the mean scores of the IES-R, PSQI, and DASS-21 in patients with schizophrenia were higher than those in HCs (all p < 0.001). Hierarchical linear regression analyses showed that a history of childhood trauma or schizophrenia was a good predictor of psychological impact, global sleep quality, and emotional distress (all p < 0.01). Moreover, the chain mediation model showed that the effect of childhood trauma on suicide risk in hospitalized patients with schizophrenia was totally sequentially mediated by thepsychological impact of COVID-19, sleep quality, and emotional distress. Conclusions It is important for clinicians to recognize the increased suicide risk associated with COVID-19-related psychological distress in patients with schizophrenia with a history of childhood trauma.

Clinical applications of machine learning in the survival prediction and classification of sepsis: coagulation and heparin usage matter.

BACKGROUND: Sepsis is a life-threatening syndrome eliciting highly heterogeneous host responses. Current prognostic evaluation methods used in clinical practice are characterized by an inadequate effectiveness in predicting sepsis mortality. Rapid identification of patients with high mortality risk is urgently needed. The phenotyping of patients will assistant invaluably in tailoring treatments. METHODS: Machine learning and deep learning technology are used to characterize the patients' phenotype and determine the sepsis severity. The database used in this study is MIMIC-III and MIMIC-IV ('Medical information Mart for intensive care') which is a large, public, and freely available database. The K-means clustering is used to classify the sepsis phenotype. Convolutional neural network (CNN) was used to predict the 28-day survival rate based on 35 blood test variables of the sepsis patients, whereas a double coefficient quadratic multivariate fitting function (DCQMFF) is utilized to predict the 28-day survival rate with only 11 features of sepsis patients. RESULTS: The patients were grouped into four clusters with a clear survival nomogram. The first cluster (C_1) was characterized by low white blood cell count, low neutrophil, and the highest lymphocyte proportion. C_2 obtained the lowest Sequential Organ Failure Assessment (SOFA) score and the highest survival rate. C_3 was characterized by significantly prolonged PTT, high SIC, and a higher proportion of patients using heparin than the patients in other clusters. The early mortality rate of patients in C_3 was high but with a better long-term survival rate than that in C_4. C_4 contained septic coagulation patients with the worst prognosis, characterized by slightly prolonged partial thromboplastin time (PTT), significantly prolonged prothrombin time (PT), and high septic coagulation disease score (SIC). The survival rate prediction accuracy of CNN and DCQMFF models reached 92% and 82%, respectively. The models were tested on an external dataset (MIMIC-IV) and achieved good performance. A DCQMFF-based application platform was established for fast prediction of the 28-day survival rate. CONCLUSION: CNN and DCQMFF accurately predicted the sepsis patients' survival, while K-means successfully identified the phenotype groups. The distinct phenotypes associated with survival, and significant features correlated with mortality were identified. The findings suggest that sepsis patients with abnormal coagulation had poor outcomes, abnormal coagulation increase mortality during sepsis. The anticoagulation effects of appropriate heparin sodium treatment may improve extensive micro thrombosis-caused organ failure.

The collateral damage of COVID-19 to cardiovascular services: a meta-analysis.

AIMS: The effect of the COVID-19 pandemic on care and outcomes across non-COVID-19 cardiovascular (CV) diseases is unknown. A systematic review and meta-analysis was performed to quantify the effect and investigate for variation by CV disease, geographic region, country income classification and the time course of the pandemic. METHODS AND RESULTS: From January 2019 to December 2021, Medline and Embase databases were searched for observational studies comparing a pandemic and pre-pandemic period with relation to CV disease hospitalisations, diagnostic and interventional procedures, outpatient consultations, and mortality. Observational data were synthesised by incidence rate ratios (IRR) and risk ratios (RR) for binary outcomes and weighted mean differences for continuous outcomes with 95% confidence intervals. The study was registered with PROSPERO (CRD42021265930). A total of 158 studies, covering 49 countries and 6 continents, were used for quantitative synthesis. Most studies (80%) reported information for high-income countries (HICs). Across all CV disease and geographies there were fewer hospitalisations, diagnostic and interventional procedures, and outpatient consultations during the pandemic. By meta-regression, in low-middle income countries (LMICs) compared to HICs the decline in ST-segment elevation myocardial infarction (STEMI) hospitalisations (RR 0.79, 95% confidence interval [CI] 0.66-0.94) and revascularisation (RR 0.73, 95% CI 0.62-0.87) was more severe. In LMICs, but not HICs, in-hospital mortality increased for STEMI (RR 1.22, 95% CI 1.10-1.37) and heart failure (RR 1.08, 95% CI 1.04-1.12). The magnitude of decline in hospitalisations for CV diseases did not differ between the first and second wave. CONCLUSIONS: There was substantial global collateral CV damage during the COVID-19 pandemic with disparity in severity by country income classification.

Research progress of epigallocatechin-3-gallate (EGCG) on anti-pathogenic microbes and immune regulation activities.

At the end of 2019, the COVID-19 virus spread worldwide, infecting millions of people. Infectious diseases induced by pathogenic microorganisms such as the influenza virus, hepatitis virus, and Mycobacterium tuberculosis are also a major threat to public health. The high mortality caused by infectious pathogenic microorganisms is due to their strong virulence, which leads to the excessive counterattack by the host immune system and severe inflammatory damage of the immune system. This paper reviews the efficacy, mechanism and related immune regulation of epigallocatechin-3-gallate (EGCG) as an anti-pathogenic microorganism drug. EGCG mainly shows both direct and indirect anti-infection effects. EGCG directly inhibits early infection by interfering with the adsorption on host cells, inhibiting virus replication and reducing bacterial biofilm formation and toxin release; EGCG indirectly inhibits infection by regulating immune inflammation and antioxidation. At the same time, we reviewed the bioavailability and safety of EGCG in vivo. At present, the bioavailability of EGCG can be improved to some extent using nanostructured drug delivery systems and molecular modification technology in combination with other drugs. This study provides a theoretical basis for the development of EGCG as an adjuvant drug for anti-pathogenic microorganisms.

Bordetella avium-associated endophthalmitis: case report.

BACKGROUND: Bordetella avium, an aerobic bacterium that rarely causes infection in humans, is a species of Bordetella that generally inhabits the respiratory tracts of turkeys and other birds. It causes a highly contagious bordetellosis. Few reports describe B. avium as a causative agent of eye-related infections. CASE PRESENTATION: We report a case of acute infectious endophthalmitis associated with infection by B. avium after open trauma. After emergency vitrectomy and subsequent broad-spectrum antibiotic treatment, the infection was controlled successfully, and the patient's vision improved. CONCLUSIONS: B. avium can cause infection in the human eye, which can manifest as acute purulent endophthalmitis. Nanopore targeted sequencing technology can quickly identify this organism. Emergency vitrectomy combined with lens removal and silicone oil tamponade and the early application of broad-spectrum antibiotics are key for successful treatment.

Quality of acute myocardial infarction care in England and Wales during the COVID-19 pandemic: linked nationwide cohort study.

BACKGROUND AND OBJECTIVE: The impact of the COVID-19 pandemic on the quality of care for patients with acute myocardial infarction (AMI) is uncertain. We aimed to compare quality of AMI care in England and Wales during and before the COVID-19 pandemic using the 2020 European Society of Cardiology Association for Acute Cardiovascular Care quality indicators (QIs) for AMI. METHODS: Cohort study of linked data from the AMI and the percutaneous coronary intervention registries in England and Wales between 1 January 2017 and 27 May 2020 (representing 236 743 patients from 186 hospitals). At the patient level, the likelihood of attainment for each QI compared with pre COVID-19 was calculated using logistic regression. The date of the first national lockdown in England and Wales (23 March 2020) was chosen for time series comparisons. RESULTS: There were 10 749 admissions with AMI after 23 March 2020. Compared with before the lockdown, patients admitted with AMI during the first wave had similar age (mean 68.0 vs 69.0 years), with no major differences in baseline characteristics (history of diabetes (25% vs 26%), renal failure (6.4% vs 6.9%), heart failure (5.8% vs 6.4%) and previous myocardial infarction (22.9% vs 23.7%)), and less frequently had high Global Registry of Acute Coronary Events risk scores (43.6% vs 48.6%). There was an improvement in attainment for 10 (62.5%) of the 16 measured QIs including a composite QI (43.8% to 45.2%, OR 1.06, 95% CI 1.02 to 1.10) during, compared with before, the lockdown. CONCLUSION: During the first wave of the COVID-19 pandemic in England and Wales, quality of care for AMI as measured against international standards did not worsen, but improved modestly.

Substantial decline in hospital admissions for heart failure accompanied by increased community mortality during COVID-19 pandemic.

AIMS: We hypothesized that a decline in admissions with heart failure during COVID-19 pandemic would lead to a reciprocal rise in mortality for patients with heart failure in the community. METHODS AND RESULTS: We used National Heart Failure Audit data to identify 36 974 adults who had a hospital admission with a primary diagnosis of heart failure between February and May in either 2018, 2019, or 2020. Hospital admissions for heart failure in 2018/19 averaged 160/day but were much lower in 2020, reaching a nadir of 64/day on 27 March 2020 [incidence rate ratio (IRR): 0.40, 95% confidence interval (CI): 0.38-0.42]. The proportion discharged on guideline-recommended pharmacotherapies was similar in 2018/19 compared to the same period in 2020. Between 1 February-2020 and 31 May 2020, there was a 29% decrease in hospital deaths related to heart failure (IRR: 0.71, 95% CI: 0.67-0.75; estimated decline of 448 deaths), a 31% increase in heart failure deaths at home (IRR: 1.31, 95% CI: 1.24-1.39; estimated excess 539), and a 28% increase in heart failure deaths in care homes and hospices (IRR: 1.28, 95% CI: 1.18-1.40; estimated excess 189). All-cause, inpatient death was similar in the COVID-19 and pre-COVID-19 periods [odds ratio (OR): 1.02, 95% CI: 0.94-1.10]. After hospital discharge, 30-day mortality was higher in 2020 compared to 2018/19 (OR: 1.57, 95% CI: 1.38-1.78). CONCLUSION: Compared with the rolling daily average in 2018/19, there was a substantial decline in admissions for heart failure but an increase in deaths from heart failure in the community. Despite similar rates of prescription of guideline-recommended therapy, mortality 30 days from discharge was higher during the COVID-19 pandemic period.

Indirect Impact of the COVID-19 Pandemic on Activity and Outcomes of Transcatheter and Surgical Treatment of Aortic Stenosis in England.

[Figure: see text].

International Prospective Registry of Acute Coronary Syndromes in Patients With COVID-19.

BACKGROUND: Published data suggest worse outcomes in acute coronary syndrome (ACS) patients and concurrent coronavirus disease 2019 (COVID-19) infection. Mechanisms remain unclear. OBJECTIVES: The purpose of this study was to report the demographics, angiographic findings, and in-hospital outcomes of COVID-19 ACS patients and compare these with pre-COVID-19 cohorts. METHODS: From March 1, 2020 to July 31, 2020, data from 55 international centers were entered into a prospective, COVID-ACS Registry. Patients were COVID-19 positive (or had a high index of clinical suspicion) and underwent invasive coronary angiography for suspected ACS. Outcomes were in-hospital major cardiovascular events (all-cause mortality, re-myocardial infarction, heart failure, stroke, unplanned revascularization, or stent thrombosis). Results were compared with national pre-COVID-19 databases (MINAP [Myocardial Ischaemia National Audit Project] 2019 and BCIS [British Cardiovascular Intervention Society] 2018 to 2019). RESULTS: In 144 ST-segment elevation myocardial infarction (STEMI) and 121 non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients, symptom-to-admission times were significantly prolonged (COVID-STEMI vs. BCIS: median 339.0 min vs. 173.0 min; p < 0.001; COVID NSTE-ACS vs. MINAP: 417.0 min vs. 295.0 min; p = 0.012). Mortality in COVID-ACS patients was significantly higher than BCIS/MINAP control subjects in both subgroups (COVID-STEMI: 22.9% vs. 5.7%; p < 0.001; COVID NSTE-ACS: 6.6% vs. 1.2%; p < 0.001), which remained following multivariate propensity analysis adjusting for comorbidities (STEMI subgroup odds ratio: 3.33 [95% confidence interval: 2.04 to 5.42]). Cardiogenic shock occurred in 20.1% of COVID-STEMI patients versus 8.7% of BCIS patients (p < 0.001). CONCLUSIONS: In this multicenter international registry, COVID-19-positive ACS patients presented later and had increased in-hospital mortality compared with a pre-COVID-19 ACS population. Excessive rates of and mortality from cardiogenic shock were major contributors to the worse outcomes in COVID-19 positive STEMI patients.

Racial differences in management and outcomes of acute myocardial infarction during COVID-19 pandemic.

OBJECTIVE: There are concerns that healthcare and outcomes of black, Asian and minority ethnic (BAME) communities are disproportionately impacted by the COVID-19 pandemic. We investigated admission rates, treatment and mortality of BAME with acute myocardial infarction (AMI) during COVID-19. METHODS: Using multisource national healthcare records, patients hospitalised with AMI in England during 1 February-27 May 2020 were included in the COVID-19 group, whereas patients admitted during the same period in the previous three consecutive years were included in a pre-COVID-19 group. Multilevel hierarchical regression analyses were used to quantify the changes in-hospital and 7-day mortality in BAME compared with whites. RESULTS: Of 73 746 patients, higher proportions of BAME patients (16.7% vs 10.1%) were hospitalised with AMI during the COVID-19 period compared with pre-COVID-19. BAME patients admitted during the COVID-19 period were younger, male and likely to present with ST-elevation acute myocardial infarction. COVID-19 BAME group admitted with non-ST-elevation acute myocardial infarction less frequently received coronary angiography (86.1% vs 90.0%, p<0.001) and had a longer median delay to reperfusion (4.1 hours vs 3.7 hours, p<0.001) compared with whites. BAME had higher in-hospital (OR 1.68, 95% CI 1.27 to 2.28) and 7-day mortality (OR 1.81 95% CI 1.31 to 2.19) during COVID-19 compared with pre-COVID-19 period. CONCLUSION: In this multisource linked cohort study, compared with whites, BAME patients had proportionally higher hospitalisation rates with AMI, less frequently received guidelines indicated care and had higher early mortality during COVID-19 period compared with pre-COVID-19 period. There is a need to develop clinical pathways to achieve equity in the management of these vulnerable populations.

Incidence and mortality due to thromboembolic events during the COVID-19 pandemic: Multi-sourced population-based health records cohort study.

BACKGROUND: Evidence supports an excess of deaths during the COVID-19 pandemic. We report the incidence and mortality of thrombo-embolic events (TE) during the COVID-19 pandemic. METHODS: Multi-sourced nationwide cohort study of adults (age ≥18 years) admitted to hospital with TE and deaths from TE in England (hospital and community) between 1st February 2018 and 31st July 2020. Relative risks, adjusted for age, sex, atrial fibrillation, co-morbidities and time trend comparing before and during the COVID-19 pandemic were estimated using Poisson regression. FINDINGS: Of 272,423 patients admitted with TE to 195 hospitals, 86,577 (31.8%) were admitted after 2nd March 2020 (first COVID-19 death in the UK). The incidence of TE hospitalised increased during the COVID-19 pandemic from 1090 to 1590 per 100,000 (absolute risk change 45.9% [95% CI 45.1-46.6%], adjusted relative risk [ARR] 1.43 [95% CI 1.41-1.44]) driven particularly by pulmonary embolism; 1.49, 95% CI 1.46-1.52. TE were more frequent among those with COVID-19; 1.9% vs. 1.6%, absolute risk change 21.7%, 95% CI 21.0-22.4%, ARR 1.20, 95% CI 1.18-1.22. There was an increase in the overall mortality from TE during the pandemic (617, 6.7% proportional increase compared with the historical baseline), with more TE deaths occurring in the community compared with the historical rate (44% vs. 33%). INTERPRETATION: The COVID-19 pandemic has resulted in an increase in the incidence of hospitalised TE. There were more deaths from TE in the community highlighting a number of mechanisms including the hypercoagulable state associated with COVID-19 infection and potential impact of delays in seeking help. RESEARCH IN CONTEXT: Evidence before this study We searched PubMed on 16 November 2020 for articles that documented the incidence and mortality of thrombo-embolic events (TE) during the COVID-19 pandemic using the search terms "COVID-19" OR "Coronavirus*" OR "2019-nCOV" OR "SARS-CoV" AND ("Thromboembolism" OR "Venous Thromboembolism" OR "thromboembol*") with no language or time restrictions. The majority of data on TE in COVID-19 pertains to hospitalised patients from retrospective cohort studies. One study found that TE in hospitalised patients was associated with an increased mortality rate (adjusted hazard ratio 1.82; 95% CI 1.54-2.15). A systematic review and meta-analysis of 35 studies in 9249 hospitalised patients calculated an overall pooled incidence of TE of 17.8% (95% CI: 9.9-27.4%), rising to 22.9% (95% CI: 14.5-32.4%) in patients admitted to intensive care (ICU). The most contemporary data are from a cohort of 1114 patients (715 outpatient, 399 hospitalised, 170 admitted to ICU). With robust COVID-19-specific therapies and widespread thromboprophylaxis the prevalence of venous TE in ICU patients was reported as 7% (n = 12) when catheter-/device-related events were excluded, and among the outpatients there was no TE reported. No published studies have used nationwide data to investigate TE during the pandemic or the effect of the pandemic on outcomes of patients with TE but without Covid-19. Added value of this study This retrospective multi-sourced nationwide unlinked cohort study compares the overall incidence and mortality of TE prior to and during the COVID-19 pandemic. We found an increased incidence of TE despite only a small proportion having a diagnosis of COVID-19. This may highlight the lack of testing, particularly in the community during the initial phase of the pandemic, and the possibility of other factors contributing to TE risk, such as decreased daily activity mandated by home quarantine and alterations in medication concordance. Mortality from TE was higher in the community during the pandemic and this highlights that adverse societal effects of the pandemic, such as aversion to seeking medical assessment, may precipitate worse outcomes related to TE. Implications of all the available evidence Evidence suggests that COVID-19 produces a hypercoagulable state and thromboprophylaxis is recommended in hospitalised patients to prevent excess mortality from TE. Whether to anticoagulate non-hospitalised ambulatory patients with COVID-19 will be answered by ongoing trials. Clinicians should consider the risks posed by decreased daily activity and fear of medical contact, and provide appropriate advice to patients.

Place and Underlying Cause of Death During the COVID-19 Pandemic: Retrospective Cohort Study of 3.5 Million Deaths in England and Wales, 2014 to 2020.

OBJECTIVE: To describe the place and cause of death during the coronavirus disease 2019 (COVID-19) pandemic to assess its impact on excess mortality. METHODS: This national death registry included all adult (aged ≥18 years) deaths in England and Wales between January 1, 2014, and June 30, 2020. Daily deaths during the COVID-19 pandemic were compared against the expected daily deaths, estimated with use of the Farrington surveillance algorithm for daily historical data between 2014 and 2020 by place and cause of death. RESULTS: Between March 2 and June 30, 2020, there was an excess mortality of 57,860 (a proportional increase of 35%) compared with the expected deaths, of which 50,603 (87%) were COVID-19 related. At home, only 14% (2267) of the 16,190 excess deaths were related to COVID-19, with 5963 deaths due to cancer and 2485 deaths due to cardiac disease, few of which involved COVID-19. In care homes or hospices, 61% (15,623) of the 25,611 excess deaths were related to COVID-19, 5539 of which were due to respiratory disease, and most of these (4315 deaths) involved COVID-19. In the hospital, there were 16,174 fewer deaths than expected that did not involve COVID-19, with 4088 fewer deaths due to cancer and 1398 fewer deaths due to cardiac disease than expected. CONCLUSION: The COVID-19 pandemic has resulted in a large excess of deaths in care homes that were poorly characterized and likely to be the result of undiagnosed COVID-19. There was a smaller but important and ongoing excess in deaths at home, particularly from cancer and cardiac disease, suggesting public avoidance of hospital care for non-COVID-19 conditions.

Outcomes of COVID-19-positive acute coronary syndrome patients: A multisource electronic healthcare records study from England.

BACKGROUND: Patients with underlying cardiovascular disease and coronavirus disease 2019 (COVID-19) infection are at increased risk of morbidity and mortality. OBJECTIVES: This study was designed to characterize the presenting profile and outcomes of patients hospitalized with acute coronary syndrome (ACS) and COVID-19 infection. METHODS: This observational cohort study was conducted using multisource data from all acute NHS hospitals in England. All consecutive patients hospitalized with diagnosis of ACS with or without COVID-19 infection between 1 March and 31 May 2020 were included. The primary outcome was in-hospital and 30-day mortality. RESULTS: A total of 12 958 patients were hospitalized with ACS during the study period, of which 517 (4.0%) were COVID-19-positive and were more likely to present with non-ST-elevation acute myocardial infarction. The COVID-19 ACS group were generally older, Black Asian and Minority ethnicity, more comorbid and had unfavourable presenting clinical characteristics such as elevated cardiac troponin, pulmonary oedema, cardiogenic shock and poor left ventricular systolic function compared with the non-COVID-19 ACS group. They were less likely to receive an invasive coronary angiography (67.7% vs 81.0%), percutaneous coronary intervention (PCI) (30.2% vs 53.9%) and dual antiplatelet medication (76.3% vs 88.0%). After adjusting for all the baseline differences, patients with COVID-19 ACS had higher in-hospital (adjusted odds ratio (aOR): 3.27; 95% confidence interval (CI): 2.41-4.42) and 30-day mortality (aOR: 6.53; 95% CI: 5.1-8.36) compared to patients with the non-COVID-19 ACS. CONCLUSION: COVID-19 infection was present in 4% of patients hospitalized with an ACS in England and is associated with lower rates of guideline-recommended treatment and significant mortality hazard.

In-Hospital and 30-Day Mortality After Percutaneous Coronary Intervention in England in the Pre-COVID and COVID Eras.

BACKGROUND: Public reporting of percutaneous coronary intervention (PCI) outcomes is a performance metric and a requirement in many healthcare systems. There are inconsistent data on the causes of death after PCI, and the proportion of these deaths that are attributable to cardiac causes. METHODS: All patients undergoing PCI in England between January 1, 2017 and May 10, 2020 (n = 273,141) were retrospectively analyzed according to their outcome from the date of PCI: no death, in-hospital death, postdischarge death, and total 30-day death. The present study examined short-term primary causes of death after PCI in a national cohort before and during COVID-19. RESULTS: The overall rates of in-hospital and 30-day death were 1.9% and 2.8%, respectively. The rate of 30-day death declined between 2017 (2.9%) and February 2020 (2.5%), mainly due to lower in-hospital death (2.1% vs 1.5%), before rising again from March 1, 2020 (3.2%) due to higher rates of postdischarge mortality. Only 59.6% of 30-day deaths were due to cardiac causes, with the most common causes being acute coronary syndrome, cardiogenic shock, and heart failure, and this persisted throughout the study period. In the 30-day death group, 10.4% after March 1, 2020 were due to confirmed COVID-19. CONCLUSIONS: In this nationwide study, we show that 40% of 30-day deaths are due to non-cardiac causes. Non-cardiac deaths have increased even more from the start of the COVID-19 pandemic, with 1 in 10 deaths from March 2020 being COVID-19 related. These findings raise a question of whether public reporting of PCI outcomes should be cause specific.

The Impact of Periodontal Disease on Hospital Admission and Mortality During COVID-19 Pandemic.

Introduction: COVID-19 has had a huge impact on society and healthcare and it has been suggested that people with periodontal disease are at risk of having worse outcomes from the disease. The aim of this study was to quantify the impact of periodontal disease on hospital admission and mortality during the COVID-19 pandemic. Materials and Methods: The study extracted UK Biobank participants who had taken a COVID-19 test between March and June 2020 (n = 13,253), of which 1,616 were COVID-19 positive (12%) and 11,637 were COVID-19 negative (88%). Self-reported oral health indicators of painful or bleeding gums and loose teeth were used as surrogates for periodontal disease, participants who did not report any of the aforementioned indicators were used as controls. Multivariable logistic regressions were used to obtain crude and adjusted odds ratios of COVID-19 infection, subsequent hospital admission and mortality adjusted for demographics, BMI, biomarkers, lifestyle and co-morbidities. Results: Painful gums, bleeding gums and loose teeth were reported in 2.7, 11.2 and 3.3% of participants with COVID-19 infection, respectively. Risk of COVID-19 infection in participants with painful or bleeding gums and loose teeth compared to controls was not increased (odds ratio [OR]: 1.10, 95% CI: 0.72-1.69; OR: 1.15, 95% CI: 0.84-1.59). COVID-19 positive participants with painful or bleeding gums had a higher risk of mortality (OR: 1.71, 95% CI: 1.05-2.72) but not hospital admission (OR: 0.90, 95% CI: 0.59-1.37). Participants with loose teeth did not show higher risk of hospital admission or mortality compared to the control group (OR = 1.55, 95% CI: 0.87-2.77; OR: 1.85; 95% CI: 0.92-2.72). Conclusion: There was insufficient evidence to link periodontal disease with an increased risk of COVID-19 infection. However, amongst the COVID-19 positive, there was significantly higher mortality for participants with periodontal disease. Utilization of linked dental and hospital patient records would improve the understanding of the impact of periodontal disease on COVID-19 related outcomes.