SARS-CoV-2 vaccination induced cerebral venous sinus thrombosis: Do megakaryocytes, platelets and lipid mediators make up the orchestra?

The COVID-19 vaccines comprised of adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2 are highly effective but associated with rare thrombotic complications. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein expressed locally stimulates neutralizing antibody and cellular immune responses. These vaccines have been associated with thromboembolic events including cerebral venous sinus thrombosis (CVST). S glycoprotein stimulates the expression of cyclooxygenase-2 (COX-2) and leads to massive generation of thromboxane A2 in COVID-19. Megakaryocytes express CAR and we postulate that S glycoprotein stimulated generation of thromboxane A2 leads to megakaryocyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinuses express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses could be further activated by thromboxane A2-dependent podoplanin-CLEC2 signaling, leading to CVST. A prothrombotic hormonal milieu, and increased generation of thromboxane A2 and platelet activation in healthy females compared to males is consistent with increased risk for CVST observed in women. We propose that antiplatelet agents targeting thromboxane A2 receptor signaling such as low-dose aspirin merit consideration for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to young adults at risk of thrombosis provided there are no contraindications.

Prediction models based on miRNA-disease relationship: Diagnostic relevance to multiple diseases including COVID-19.

BACKGROUND: Small, non-coding microRNAs, usually of 20-25 nucleotides, are known to regulate the post-transcriptional gene expression, which has a significant role in human biological processes, including immune-biogenesis, homeostasis and infection control as differential expression of such miRNAs is responsible for fine-tuning the organismic development. METHODS: A search of bibliographic databases was carried out with a focused question on microRNA-Disease Prediction. A deductive qualitative content analysis approach was further employed to assess the research's overall outcomes, review articles on prediction tools in miRNA-Diseases, and analyse the interventions. RESULTS: Diagnosis and therapeutics of diseases and miRNA prediction methods hold importance in identifying the regulatory mechanisms. Collections of efficient miRNA prediction methods to identify miRNA-mRNA-disease regulatory relationships have been presented through this review, consolidating the potential of miRNAs as a diagnostic and prognostic biomarker of multiple diseases, including COVID-19. CONCLUSIONS: The role of miRNA in the aetiology and pathogenesis of wide-range of pathologies, including viral, bacterial to chronic diseases such as cancer, is quite feasible through the modern tools in bioinformatics which has been elaborated focusing upon miRNA-disease prediction methods and their application potential establishing miRNAs as a robust and reliable biomarker in clinico-medical studies.

COVID-19 detection using AIE-active iridium complexes.

The highly contagious COVID-19, caused by the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is commonly diagnosed using reverse transcription polymerase chain reaction (RT-PCR). However, despite being highly sensitive, RT-PCR is also time consuming and quite complex, which limits its use for point-of-care (POC) testing. We have developed a simple single-step fluorescence assay for SARS-CoV-2 RNA detection based on the principle of aggregation-induced emission (AIE) using iridium complexes. Our smartly designed iridium probes fluorescently "turn-on" in the presence of SARS-CoV-2 RNA and give specific results at room temperature within 10 min. The lower limit of detection (LOD) is 1.84 genome copies per reaction, and the sensitivity and specificity of the assay in 20 clinical samples are found to be 90% and 80%, respectively.

Time series analysis of animal bite cases attending anti-rabies clinic.

Background: Rabies is a disease transmitted mostly through animal bites in humans, and seasonal variation in animal bites has been reported by different studies. There has been no study in India using time series analysis for studying monthly variation in animal bite cases. Aim: (a) To find out long-term trends and monthly variations in new animal bite cases. (b) To make projections for new animal bite cases. (c) To find out the difference between actual and projected new animal bite cases following the COVID-19 pandemic. Methodology: A retrolective, record-based study was conducted in a tertiary care facility, Jaipur, and data of new Category II and Category III animal bite cases were taken from January 2007 to December 2021. A multiplicative model was used for conducting time series analysis. The projected monthly number of cases was estimated using the line of best fit based on the least square method. Result: An increasing trend in the annual number of animal bite cases was observed from 7,982 in 2007 to 10,134 in 2019. The monthly index was lowest for the months July to November (0.88 to 0.95), peaked in January (1.14), remained higher from January to June, and fell in July (0.95). The monthly number of new animal bite cases from April 2020 to December 2021 was significantly lower than the projected number (P-value < 0.001). Conclusion: Because the monthly index of animal bite cases was high from January onward, information education and communication (IEC) activities should be increased in the preceding months (November onward) for making people aware of immediate care to be provided to animal bite cases and seek prompt medical care.

Factors influencing attitudes toward vaccine safety and vaccine effectiveness amongst UK healthcare professionals prior to and at the time of COVID-19 vaccine rollout: Insights from the CoPE-HCP cohort study.

Given the potential for nosocomial outbreaks, we must understand factors associated with negative vaccine attitudes amongst healthcare professionals (HCPs) before the rollout of a newly developed vaccine in a pandemic setting. The aim of this prospective cohort study was to study the impact of preexisting and prevailing mental health on United Kingdom HCPs' attitudes towards a newly developed COVID-19 vaccine. Two online surveys were distributed: first during vaccine development (July-September, 2020) and second during nationwide vaccine rollout (December 2020-March 2021). Mental health (PHQ-9 for depression; GAD-7 for anxiety) was assessed in both surveys. Negative attitude regarding vaccine safety and vaccine effectiveness was assessed at vaccine rollout. A series of logistic regression models were developed relating mental health (preexisting during vaccine development, ongoing and new-onset during rollout, and changes in symptom severity) to negative vaccine attitudes. In 634 HCPs, the presence of depression and/or anxiety during vaccine development was associated with elevated negative attitude towards vaccine safety (adj. OR 1.74 [95% CI 1.10-2.75], p = .02), but not vaccine effectiveness (1.13 [0.77-1.66], p = .53) at rollout. This was independent of other characteristics: age, ethnicity, professional role, and history of contracting COVID-19. Ongoing depression and/or anxiety (1.72 [1.10-2.69], p = .02) was associated with elevated negative attitude regarding vaccine effectiveness, but not vaccine safety. Worsened combined symptom scores over time were associated with elevated negative vaccine effectiveness attitudes (1.03 [1.00-1.05], p < .05), but not vaccine safety. Overall, adverse mental health can impact on HCPs' attitudes towards a newly developed vaccine. Further work is required to understand how this translates to vaccine uptake.

Thrombo-Inflammation in COVID-19 and Sickle Cell Disease: Two Faces of the Same Coin.

People with sickle cell disease (SCD) are at greater risk of severe illness and death from respiratory infections, including COVID-19, than people without SCD (Centers for Disease Control and Prevention, USA). Vaso-occlusive crises (VOC) in SCD and severe SARS-CoV-2 infection are both characterized by thrombo-inflammation mediated by endothelial injury, complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion, and activation of the coagulation cascade. Notably, lipid mediators, including thromboxane A2, significantly increase in severe COVID-19 and SCD. In addition, the release of thromboxane A2 from endothelial cells and macrophages stimulates platelets to release microvesicles, which are harbingers of multicellular adhesion and thrombo-inflammation. Currently, there are limited therapeutic strategies targeting platelet-neutrophil activation and thrombo-inflammation in either SCD or COVID-19 during acute crisis. However, due to many similarities between the pathobiology of thrombo-inflammation in SCD and COVID-19, therapies targeting one disease may likely be effective in the other. Therefore, the preclinical and clinical research spurred by the COVID-19 pandemic, including clinical trials of anti-thrombotic agents, are potentially applicable to VOC. Here, we first outline the parallels between SCD and COVID-19; second, review the role of lipid mediators in the pathogenesis of these diseases; and lastly, examine the therapeutic targets and potential treatments for the two diseases.

Perceived workplace support and mental health, well-being and burnout among health care professionals during the COVID-19 pandemic: a cohort analysis.

BACKGROUND: Little is known about the relationship between workplace support and mental health and burnout among health care professionals (HCPs) during the COVID-19 pandemic. In this cohort study, we sought to evaluate the association between perceived level of (and changes to) workplace support and mental health and burnout among HCPs, and to identify what constitutes perceived effective workplace support. METHODS: Online surveys at baseline (July-September 2020) and follow-up 4 months later assessed the presence of generalized anxiety disorder (using the 7-item Generalized Anxiety Disorder scale [GAD-7]), clinical insomnia, major depressive disorder (using the 9-item Patient Health Questionnaire), burnout (emotional exhaustion and depersonalization) and mental well-being (using the Short Warwick-Edinburgh Mental Wellbeing Score). Both surveys assessed self-reported level of workplace support (single-item Likert scale). For baseline and follow-up, independently, we developed separate logistic regression models to evaluate the association of the level of workplace support (tricohotomized as unsupported, neither supported nor unsupported and supported) with mental health and burnout. We also developed linear regression models to evaluate the association between the change in perceived level of workplace support and the change in mental health scores from baseline and follow-up. We used thematic analyses on free-text entries of the baseline survey to evaluate what constitutes effective support. RESULTS: At baseline (n = 1422) and follow-up (n = 681), HCPs who felt supported had reduced risk of anxiety, depression, clinical insomnia, emotional exhaustion and depersonalization, compared with those who felt unsupported. Among those who responded to both surveys (n = 681), improved perceived level of workplace support over time was associated with significantly improved scores on measures of anxiety (adjusted ß -0.13, 95% confidence interval [CI] -0.25 to -0.01), depression (adjusted ß -0.17, 95% CI -0.29 to -0.04) and mental well-being (adjusted ß 0.19, 95% CI 0.10 to 0.29), independent of baseline level of support. We identified 5 themes constituting effective workplace support, namely concern or understanding for welfare, information, tangible qualities of the workplace, leadership and peer support. INTERPRETATION: We found a significant association between perceived level of (and changes in) workplace support and mental health and burnout of HCPs, and identified potential themes that constitute perceived workplace support. Collectively, these findings can inform changes in guidance and national policies to improve mental health and burnout among HCPs. Trial registration: ClinicalTrials.gov, no. NCT04433260.

Improved lifestyle is associated with improved depression, anxiety and well-being over time in UK healthcare professionals during the COVID-19 pandemic: insights from the CoPE-HCP cohort study.

Background: One potential modifiable factor to improve the mental health of healthcare professionals (HCPs) during the pandemic is lifestyle. Aims: This study aimed to assess whether an improved lifestyle during the pandemic is associated with improved mental health symptoms and mental well-being in HCPs over time. Methods: This was a cohort study involving an online survey distributed at two separate time points during the pandemic (baseline (July-September 2020) and follow-up (December 2020-March 2021)) to HCPs working in primary or secondary care in the UK. Both surveys assessed for major depressive disorder (MDD) (Patient Health Questionnaire-9 (PHQ-9)), generalised anxiety disorder (GAD) (Generalised Anxiety Disorder-7 (GAD-7)), mental well-being (Short Warwick-Edinburgh Mental Well-being Score (SWEMWBS)) and self-reported lifestyle change (compared with the start of the pandemic) on multiple domains. Cumulative scores were calculated to estimate overall lifestyle change compared with that before the pandemic (at both baseline and follow-up). At each time point, separate logistic regression models were constructed to relate the lifestyle change score with the presence of MDD, GAD and low mental well-being. Linear regression models were also developed relating the change in lifestyle scores from baseline to follow-up to changes in PHQ-9, GAD-7 and SWEMWBS scores. Results: 613 HCPs completed both baseline assessment and follow-up assessment. Consistent significant cross-sectional associations between increased lifestyle change scores and a reduced risk of MDD, GAD and low mental well-being were observed at both baseline and follow-up. Over the study period, a whole unit increase in the change in novel scores (ie, improved overall lifestyle) over 4 months was inversely associated with changes in PHQ-9 (adjusted coefficient: -0.51, 95% confidence interval (CI): -0.73 to -0.30, p<0.001) and GAD-7 scores (adjusted coefficient: -0.32, 95% CI: -0.53 to -0.10, p=0.004) and positively associated with the change in SWEMWBS scores (adjusted coefficient: 0.37, 95% CI: 0.18 to 0.55, p<0.001). Conclusions: Improved lifestyle over time is associated with improved mental health and mental well-being in HCPs during the pandemic. Improving lifestyle could be a recommended intervention for HCPs to help mitigate the mental health impact during the current and future pandemics. Trial registration number: NCT04433260.

Assessment of National Program for Prevention and Control of Cancer, Diabetes, CVD and Stroke (NPCDCS): An observational study in rural Jaipur, Rajasthan.

Introduction: Non-communicable diseases (NCDs) are increasing in trend and associated with modifiable risk factors and subsequently reducing physical activity; hence the Government of India (GOI) has launched a National Programme for Prevention and Control of Cancers, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS) in 2010 to curb increasing prevalence. The present study was planned for assessment of the activities conducted under NPCDCS in rural Jaipur. Methods and Material: This observational study was conducted in rural Jaipur. NPCDCS reports, status of logistics and manpower were assessed for 1 year. Field level cross-checking survey was done to assess the gap between the actual screening work done and the work reported. All staffs were assessed for the level of awareness regarding NCDs as well as NPCDCS programs. Data were entered and analysed in Microsoft excel. Result: Around 48% (6674/13917) of persons >30 years were screened during 1 year study period. Around 51.5% of the screened persons had one or more NCDs (13.5% newly screened NCDs cases and 38% were prediagnosed of NCD cases). Status reports that 10 (83.33%) out of the total 12 expected reports were sent regularly on a monthly basis. Reason for not sending reports was a sudden lockdown due to COVID-19. Conclusion: The study concludes that the implementation of NPCDCS program activities is not in synch with the health staff awareness level. IEC activities were deficient and no work was done for adoption of behavioural change and healthy lifestyle. Actual cases of hypertension were more while cases of diabetes were less than the reported cases found on cross-check survey.

Longitudinal comparisons of mental health, burnout and well-being in patient-facing, non-patient-facing healthcare professionals and non-healthcare professionals during the COVID-19 pandemic: findings from the CoPE-HCP study.

BACKGROUND: The COVID-19 pandemic may disproportionately affect the mental health of healthcare professionals (HCPs), especially patient-facing HCPs. AIMS: To longitudinally examine mental health in HCPs versus non-HCPs, and patient-facing HCPs versus non-patient-facing HCPs. METHOD: Online surveys were distributed to a cohort at three phases (baseline, July to September 2020; phase 2, 6 weeks post-baseline; phase 3, 4 months post-baseline). Each survey contained validated assessments for depression, anxiety, insomnia, burnout and well-being. For each outcome, we conducted mixed-effects logistic regression models (adjusted for a priori confounders) comparing the risk in different groups at each phase. RESULTS: A total of 1574 HCPs and 147 non-HCPs completed the baseline survey. Although there were generally higher rates of various probable mental health issues among HCPs versus non-HCPs at each phase, there was no significant difference, except that HCPs had 2.5-fold increased risk of burnout at phase 2 (emotional exhaustion: odds ratio 2.50, 95% CI 1.15-5.46, P = 0.021), which increased at phase 3 (emotional exhaustion: odds ratio 3.32, 95% CI 1.40-7.87, P = 0.006; depersonalisation: odds ratio 3.29, 95% CI 1.12-9.71, P = 0.031). At baseline, patient-facing HCPs (versus non-patient-facing HCPs) had a five-fold increased risk of depersonalisation (odds ratio 5.02, 95% CI 1.65-15.26, P = 0.004), with no significant difference in the risk for other outcomes. The difference in depersonalisation reduced over time, but patient-facing HCPs still had a 2.7-fold increased risk of emotional exhaustion (odds ratio 2.74, 95% CI 1.28-5.85, P = 0.009) by phase 3. CONCLUSIONS: The COVID-19 pandemic had a huge impact on the mental health and well-being of both HCPs and non-HCPs, but there is disproportionately higher burnout among HCPs, particularly patient-facing HCPs.

A systematic review of mucormycosis cases in COVID-19: Is it an unholy trilogy of COVID-19, diabetes mellitus, and corticosteroids?

Background: A significant surge of cases of mucormycosis is seen in individuals with COVID-19 with presence of diabetes mellitus (DM) and usage of corticosteroids. We aim to conduct a systematic analysis of the cases involving presence of mucormycosis and to find out its association with COVID-19, diabetes mellitus, and corticosteroids. Method: The electronic records of PubMed, Google Scholar, and Science Direct were searched for the case reports and case series that reported mucormycosis in association of COVID-19. The particulars of each case report and case series were retrieved, stored and analyzed. Results: In this study, 476 cases of mucormycosis were reported. In 346 cases of mucormycosis, the patients were found to be COVID-19 positive. The incidence of diabetes Mellitus (DM) was 67.01%. Corticosteroid was administered in 57.77% of the cases. Mortality was reported in 36.34% of the cases. Conclusion: An immunosuppressive environment created due to the COVID-19, diabetes mellitus, and extensive use of corticosteroid provide a suitable background for the increased incidence of mucormycosis. The COVID task force should adopt an aggressive multidisciplinary approach to optimize the use of corticosteroids and maintain glucose in the optimal range.

The Relationship Between Availability and Changes to Perceived Workplace Support and Their Impact on the Mental Health, Well-being and Burn-Out of Healthcare Professionals (HCP): Insight and Mitigating Strategies From the CoPE-HCP Cohort Study

Aims To examine the relationship between self-reported level of workplace support (WS) and various mental health outcomes in HCPs and non-HCPs at different time-points during the COVID-19 pandemic, and to examine whether improved WS is associated with improved mental health outcomes over time. Lastly, to identify what support healthcare professionals (HCPs) perceive to be most helpful. Methods Cohort survey study at baseline (July-September 2020) and follow-up (approximately four months later). Setting HCPs working in primary or secondary care, from UK and other countries, and non-HCP controls from primarily London-based universities. Participants 1574 HCPs and 147 non-HCPs (academic and research staff at London-based universities). The inclusion criteria for the study were: 1) aged 18 or older, 2) electronic consent given, and 3) identified as HCP or non-healthcare academic staff or self-declared non-HCPs. Main outcome measures Presence of generalized anxiety disorder (assessed using the GAD-7), clinical insomnia (ISI), major depressive disorder (PHQ-9), well-being (SWEMWBS), and burnout (emotional exhaustion and depersonalization;EEDP2Q). Qualitative data exploring what support HCPs perceive as most useful was gathered using free-text inputs. Results At baseline and follow-up, consistently, compared to those who felt unsupported, those who felt supported had significantly reduced risk (odds) of generalized anxiety disorder (baseline: 59% [95% CI of OR, 0.29 to 0.57], follow-up: 41% [0.38 to 0.92]), clinical insomnia (51% [0.34 to 0.69], 66% [0.20 to 0.55]), major depressive disorder (58% [0.31 to 0.58], 54% [0.31 to 0.74]), emotional exhaustion (65% [0.26 to 0.46], 61% [0.27 to 0.56]) and depersonalization (58% [0.28 to 0.61], 68% [0.21 to 0.50]). At follow-up, self-reported improved WS (vs. baseline) was associated with significantly improved GAD-7 (adjusted difference. −1.73 [-2.54 to −0.91]), ISI (-0.96 [-1.88 to −0.04]), PHQ−9 (-1.32 [-2.16 to −0.49]), SWEMWBS (0.97 [0.37 to 1.57]) and EEDP2Q (burnout) (-1.30 [-1.82 to −0.79]) scores, independent of baseline level of support. Five themes were identified constituting WS: ‘managerial support’ was the largest sub-theme. Conclusion A consistent association was observed between level of WS and the mental health of HCPs and non-HCPs. Improved WS was associated with improved mental health scores over a four-month period during the pandemic.

Treatment of COVID-19 Pneumonia and Acute Respiratory Distress With Ramatroban, a Thromboxane A2 and Prostaglandin D2 Receptor Antagonist: A Four-Patient Case Series Report.

Hypoxemia in COVID-19 pneumonia is associated with hospitalization, mechanical ventilation, and mortality. COVID-19 patients exhibit marked increases in fatty acid levels and inflammatory lipid mediators, predominantly arachidonic acid metabolites, notably thromboxane B2 >> prostaglandin E2 > prostaglandin D2. Thromboxane A2 increases pulmonary capillary pressure and microvascular permeability, leading to pulmonary edema, and causes bronchoconstriction contributing to ventilation/perfusion mismatch. Prostaglandin D2-stimulated IL-13 production is associated with respiratory failure, possibly due to hyaluronan accumulation in the lungs. Ramatroban is an orally bioavailable, dual thromboxane A2/TP and prostaglandin D2/DP2 receptor antagonist used in Japan for allergic rhinitis. Four consecutive outpatients with COVID-19 pneumonia treated with ramatroban exhibited rapid relief of dyspnea and hypoxemia within 12-36 h and complete resolution over 5 days, thereby avoiding hospitalization. Therefore, ramatroban as an antivasospastic, broncho-relaxant, antithrombotic, and immunomodulatory agent merits study in randomized clinical trials that might offer hope for a cost-effective pandemic treatment.

Risk Stratification Models for Stroke in Patients Hospitalized with COVID-19 Infection.

OBJECTIVES: To derive models that identify patients with COVID-19 at high risk for stroke. MATERIALS AND METHODS: We used data from the AHA's Get With The Guidelines® COVID-19 Cardiovascular Disease Registry to generate models for predicting stroke risk among adults hospitalized with COVID-19 at 122 centers from March 2020-March 2021. To build our models, we used data on demographics, comorbidities, medications, and vital sign and laboratory values at admission. The outcome was a cerebrovascular event (stroke, TIA, or cerebral vein thrombosis). First, we used Cox regression with cross validation techniques to identify factors associated with the outcome in both univariable and multivariable analyses. Then, we assigned points for each variable based on corresponding coefficients to create a prediction score. Second, we used machine learning techniques to create risk estimators using all available covariates. RESULTS: Among 21,420 patients hospitalized with COVID-19, 312 (1.5%) had a cerebrovascular event. Using traditional Cox regression, we created/validated a COVID-19 stroke risk score with a C-statistic of 0.66 (95% CI, 0.60-0.72). The CANDLE score assigns 1 point each for prior cerebrovascular disease, afebrile temperature, no prior pulmonary disease, history of hypertension, leukocytosis, and elevated systolic blood pressure. CANDLE stratified risk of an acute cerebrovascular event according to low- (0-1: 0.2% risk), medium- (2-3: 1.1% risk), and high-risk (4-6: 2.1-3.0% risk) groups. Machine learning estimators had similar discriminatory performance as CANDLE: C-statistics, 0.63-0.69. CONCLUSIONS: We developed a practical clinical score, with similar performance to machine learning estimators, to help stratify stroke risk among patients hospitalized with COVID-19.

Leveraging human resources for outbreak analysis: lessons from an international collaboration to support the sub-Saharan African COVID-19 response.

Emerging infectious diseases are a growing threat in sub-Saharan African countries, but the human and technical capacity to quickly respond to outbreaks remains limited. Here, we describe the experience and lessons learned from a joint project with the WHO Regional Office for Africa (WHO AFRO) to support the sub-Saharan African COVID-19 response.In June 2020, WHO AFRO contracted a number of consultants to reinforce the COVID-19 response in member states by providing actionable epidemiological analysis. Given the urgency of the situation and the magnitude of work required, we recruited a worldwide network of field experts, academics and students in the areas of public health, data science and social science to support the effort. Most analyses were performed on a merged line list of COVID-19 cases using a reverse engineering model (line listing built using data extracted from national situation reports shared by countries with the Regional Office for Africa as per the IHR (2005) obligations). The data analysis platform The Renku Project ( https://renkulab.io ) provided secure data storage and permitted collaborative coding.Over a period of 6 months, 63 contributors from 32 nations (including 17 African countries) participated in the project. A total of 45 in-depth country-specific epidemiological reports and data quality reports were prepared for 28 countries. Spatial transmission and mortality risk indices were developed for 23 countries. Text and video-based training modules were developed to integrate and mentor new members. The team also began to develop EpiGraph Hub, a web application that automates the generation of reports similar to those we created, and includes more advanced data analyses features (e.g. mathematical models, geospatial analyses) to deliver real-time, actionable results to decision-makers.Within a short period, we implemented a global collaborative approach to health data management and analyses to advance national responses to health emergencies and outbreaks. The interdisciplinary team, the hands-on training and mentoring, and the participation of local researchers were key to the success of this initiative.

Quantifying the Excess Risk of Adverse COVID-19 Outcomes in Unvaccinated Individuals With Diabetes Mellitus, Hypertension, Ischaemic Heart Disease or Myocardial Injury: A Meta-Analysis.

Background: More than 80% of individuals in low and middle-income countries (LMICs) are unvaccinated against coronavirus disease 2019 (COVID-19). In contrast, the greatest burden of cardiovascular disease is seen in LMIC populations. Hypertension (HTN), diabetes mellitus (DM), ischaemic heart disease (IHD) and myocardial injury have been variably associated with adverse COVID-19 outcomes. A systematic comparison of their impact on specific COVID-19 outcomes is lacking. We quantified the impact of DM, HTN, IHD and myocardial injury on six adverse COVID-19 outcomes: death, acute respiratory distress syndrome (ARDS), invasive mechanical ventilation (IMV), admission to intensive care (ITUadm), acute kidney injury (AKI) and severe COVID-19 disease (SCov), in an unvaccinated population. Methodology: We included studies published between 1st December 2019 and 16th July 2020 with extractable data on patients ≥18 years of age with suspected or confirmed SARS-CoV-2 infection. Odds ratios (OR) for the association between DM, HTN, IHD and myocardial injury with each of six COVID-19 outcomes were measured. Results: We included 110 studies comprising 48,809 COVID-19 patients. Myocardial injury had the strongest association for all six adverse COVID-19 outcomes [death: OR 8.85 95% CI (8.08-9.68), ARDS: 5.70 (4.48-7.24), IMV: 3.42 (2.92-4.01), ITUadm: 4.85 (3.94-6.05), AKI: 10.49 (6.55-16.78), SCov: 5.10 (4.26-6.05)]. HTN and DM were also significantly associated with death, ARDS, ITUadm, AKI and SCov. There was substantial heterogeneity in the results, partly explained by differences in age, gender, geographical region and recruitment period. Conclusion: COVID-19 patients with myocardial injury are at substantially greater risk of death, severe disease and other adverse outcomes. Weaker, yet significant associations are present in patients with HTN, DM and IHD. Quantifying these associations is important for risk stratification, resource allocation and urgency in vaccinating these populations. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, registration no: CRD42020201435 and CRD42020201443.

Thymic Dysfunction and Atrophy in COVID-19 Disease Complicated by Inflammation, Malnutrition and Cachexia.

Background: The current COVID-19 pandemic has put millions of people, especially children at risk of protein-energy malnutrition (PEM) by pushing them into poverty and disrupting the global food supply chain. The thymus is severely affected by nutritional deficiencies and is known as a barometer of malnutrition. Aim: The present commentary provides a novel perspective on the role of malnutrition-induced thymic dysfunction, involution and atrophy on the risk and severity of disease in children during the COVID-19 pandemic. Methods: A review of pertinent indexed literature including studies examining the effects of malnutrition on the thymus and immune dysfunction in COVID-19. Results: Protein-energy malnutrition and micronutrient deficiencies of zinc, iron and vitamin A are known to promote thymic dysfunction and thymocyte loss in children. Malnutrition- and infection-induced thymic atrophy and immune dysfunction may increase the risk of first, progression of COVID-19 disease to more severe forms including development of multisystem inflammatory syndrome in children (MIS-C); second, slow the recovery from COVID-19 disease; and third, increase the risk of other infections. Furthermore, malnourished children may be at increased risk of contracting SARS-CoV-2 infection due to socioeconomic conditions that promote viral transmission amongst contacts and create barriers to vaccination. Conclusion: National governments and international organizations including WHO, World Food Program, and UNICEF should institute measures to ensure provision of food and micronutrients for children at risk in order to limit the health impact of the ongoing COVID-19 pandemic.

Secondary infections modify the overall course of hospitalized patients with COVID-19: a retrospective study from a network of hospitals across North India.

Objective: To gain better insight into the extent of secondary bacterial and fungal infections in hospitalized patients in India, and to assess how these alter the course of coronavirus disease 2019 (COVID-19) so that control measures can be suggested. Methods: In this retrospective, multicentre study, the data of all patients who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) on reverse transcriptase polymerase chain reaction (RT-PCR), admitted to hospital between March 2020 and July 2021, were accessed from the electronic health records of a network of 10 hospitals across five states in North India. Results: Of 19,852 patients testing positive for SARS-CoV-2 on RT-PCR and admitted to the study hospitals during the study period, 1940 (9.8%) patients developed secondary infections (SIs). Patients with SIs were, on average, 8 years older than patients without SIs (median age 62.6 vs 54.3 years; P<0.001). The risk of SIs was significantly (P<0.001) associated with age, severity of disease at admission, diabetes, admission to the intensive care unit (ICU), and ventilator use. The most common site of infection was urine (41.7%), followed by blood (30.8%) and sputum/bronchoalveolar lavage/endotracheal fluid (24.8%); the least common was pus/wound discharge (2.6%). Gram-negative bacilli (GNB) were the most common organisms (63.2%), followed by Gram-positive cocci (GPC) (19.6%) and fungi (17.3%). Most patients with SIs were on multiple antimicrobials. The most commonly used antibiotics against GNB were beta-lactam/beta-lactamase inhibitors (76.9%), carbapenems (57.7%), cephalosporins (53.9%), and antibiotics against carbapenem-resistant Enterobacteriaceae (47.1%). Empirical use of antibiotics against GPC was seen in 58.9% of patients with SIs, and empirical use of antifungals was observed in 56.9% of patients with SIs. The average length of hospital stay for patients with SIs was almost twice as long as that of patients without SIs (median 13 vs 7 days). Overall mortality among patients with SIs (40.3%) was more than eight times higher than that among patients without SIs (4.6%). Only 1.2% of patients with SIs with mild COVID-19 at admission died, compared with 17.5% of those with moderate COVID-19 at admission and 58.5% of those with severe COVID-19 at admission (P<0.001). The mortality rate was highest in patients with bloodstream infections (49.8%), followed by those with hospital-acquired pneumonia (47.9%), urinary tract infections (29.4%), and skin and soft tissue infections (29.4%). The mortality rate in patients with diabetes with SIs was 45.2%, compared with 34.3% in those without diabetes (P<0.001). Conclusions: SIs complicate the course of patients hospitalized with COVID-19. These patients tend to have a much longer hospital stay, a higher requirement for oxygen and ICU care, and a significantly higher mortality rate compared with those without SIs. The groups most vulnerable to SIs are patients with more severe COVID-19, elderly patients and patients with diabetes. Judicious empirical use of combination antimicrobials in these groups of vulnerable patients can save lives. It is desirable to have region- or country-specific guidelines for appropriate use of antibiotics and antifungals to prevent their overuse.

Ramatroban for chemoprophylaxis and treatment of COVID-19: David takes on Goliath.

INTRODUCTION: In COVID-19 pneumonia, there is a massive increase in fatty acid levels and lipid mediators with a predominance of cyclooxygenase metabolites, notably TxB2 ≫ PGE2 > PGD2 in the lungs, and 11-dehydro-TxB2, a TxA2 metabolite, in the systemic circulation. While TxA2 stimulates thromboxane prostanoid (TP) receptors, 11-dehydro-TxB2 is a full agonist of DP2 (formerly known as the CRTh2) receptors for PGD2. Anecdotal experience of using ramatroban, a dual receptor antagonist of the TxA2/TP and PGD2/DP2 receptors, demonstrated rapid symptomatic relief from acute respiratory distress and hypoxemia while avoiding hospitalization. AREAS COVERED: Evidence supporting the role of TxA2/TP receptors and PGD2/DP2 receptors in causing rapidly progressive lung injury associated with hypoxemia, a maladaptive immune response and thromboinflammation is discussed. An innovative perspective on the dual antagonism of TxA2/TP and PGD2/DP2 receptor signaling as a therapeutic approach in COVID-19 is presented. This paper examines ramatroban an anti-platelet, immunomodulator, and antifibrotic agent for acute and long-haul COVID-19. EXPERT OPINION: Ramatroban, a dual blocker of TP and DP2 receptors, has demonstrated efficacy in animal models of respiratory dysfunction, atherosclerosis, thrombosis, and sepsis, as well as preliminary evidence for rapid relief from dyspnea and hypoxemia in COVID-19 pneumonia. Ramatroban merits investigation as a promising antithrombotic and immunomodulatory agent for chemoprophylaxis and treatment.