Plaque instability biomarkers: a comparison between acute coronary syndrome and chronic stable angina patients

Biomarkers play a pivotal role in the diagnosis and management of patients with acute coronary syndrome (ACS). Some biomarkers, such as C-reactive protein (CRP), soluble CD40 ligand (sCD40L), placental growth factor (PlGF) and myeloperoxidase (MPO) have been reported to be involved in plaque destabilization. The levels of these biomarkers were studied in ACS and chronic stable angina (CSA) patients aged ≤ 45 years and aged > 45 years. The relationship between these biomarkers in the coronary circulation and peripheral circulation was also investigated. This study was the first attempt to investigate the expression of peroxisome proliferator-activated receptors (PPARs) in ACS. A total of 79 patients (ACS: n = 39, CSA: n = 40) was recruited. The blood was sampled from the occluded coronary artery (coronary circulation) and also from the median cubital vein antecubital fossa (peripheral circulation). The serum protein levels of CRP, sCD40L and PlGF and plasma levels of MPO were measured using ELISA. The intracellular levels of PPARs were semiquantified using Western blot. The mRNA levels of the biomarkers were measured by real-time PCR. All ACS patients that underwent six months clinical follow-up was assessed for major adverse cardiac events (MACE) after the acute event. The peripheral levels of CRP, MPO, sCD40L and PlGF were significantly increased in ACS compared to CSA patients. Furthermore, the peripheral concentrations of these biomarkers were significantly correlated with the concentrations found in the coronary circulation. The patients aged below 45 years and above 45 years shared similar profiles of biomarkers. The expression of PPAR-γ was significantly increased in the ACS patients and correlated with both sCD40L and MPO. Serum CRP demonstrated the highest area under the curve value of 0.79 (p < 0.001) in discriminating ACS, followed by PlGF, MPO and sCD40L. In addition, the biomarkers also showed their promising prognostic abilities in predicting 30-day and six-month MACE in ACS patients. In conclusion, this study provided additional information on the proteins and gene expression profiles of plaque instability markers in both CSA and ACS patients. The biomarkers contribute to the formation of unstable plaque by triggering vascular inflammation, firous cap thinning and formation of large lipid core in coronary plaque. Their accuracies in discriminating ACS and predicting MACE also showed promising results

Does prior experience really matter for disaster preparedness?

Climate change and transition toward urbanization had resulted in more frequent and severe disasters in the last decade. While urbanization is potential driver of change and economic growth, climate change had exacerbated resource scarcity and exposed local communities to greater and more frequent disasters. The local communities in Malaysia are of no exception. The most common types of disasters in Malaysia are landslide, flash flood and haze. This study explores the extent to which prior experience affects the level of preparedness among Malaysian communities before occurrence of natural disasters. Although previous studies have proven prior experience aided better handling of preparedness, yet some researchers have not found significant correlation between prior experience and preparedness. Having inconclusive results and with the rise of unexpected disaster events, has lead this present study to investigate the link in the Malaysian context. Questionnaire surveys were distributed to more than 1,000 respondents and face-to-face interviews were conducted with 12 local communities from Klang Valley, Malaysia. The results indicated that prior experience does contribute towards the level of disaster preparedness among the local communities in Malaysia. Hence, the findings of this present study may reduce the impact of disasters and thus could help local communities to effectively cope with the events of disasters

Safety and potential efficacy of cyclooxygenase-2 inhibitors in coronavirus disease 2019

Objectives While the safety of non‐steroidal anti‐inflammatory drugs in COVID‐19 has been questioned, they may be beneficial given the hyper‐inflammatory immune response associated with severe disease. We aimed to assess the safety and potential efficacy of cyclooxygenase‐2 (COX‐2) selective inhibitors in high‐risk patients. Methods Retrospective study of patients with COVID‐19 pneumonia and aged ≥ 50 years who were admitted to hospital. Adverse outcomes analysed included supplemental oxygen use, intensive care unit admission, mechanical ventilation and mortality, with the primary endpoint a composite of any of these. Plasma levels of inflammatory cytokines and chemokines were measured in a subset. Results Twenty‐two of 168 (13.1%) in the cohort received COX‐2 inhibitors [median duration 3 days, interquartile range (IQR) 3–4.25]. Median age was 61 (IQR 55–67.75), 44.6% were female, and 72.6% had at least one comorbidity. A lower proportion of patients receiving COX‐2 inhibitors met the primary endpoint: 4 (18.2%) versus 57 (39.0%), P = 0.062. This difference was less pronounced after adjusting for baseline difference in age, gender and comorbidities in a multivariate logistic regression model [adjusted odds ratio (AOR) 0.45, 95% CI 0.14–1.46]. The level of interleukin‐6 declined after treatment in five of six (83.3%) treatment group patients [compared to 15 of 28 (53.6%) in the control group] with a greater reduction in absolute IL‐6 levels (P‐value = 0.025). Conclusion Treatment with COX‐2 inhibitors was not associated with an increase in adverse outcomes. Its potential for therapeutic use as an immune modulator warrants further evaluation in a large randomised controlled trial

Differential Cytokine Responses in Hospitalized COVID-19 Patients Limit Efficacy of Remdesivir

A significant proportion of COVID-19 patients will progress to critical illness requiring invasive mechanical ventilation. This accentuates the need for a therapy that can reduce the severity of COVID-19. Clinical trials have shown the effectiveness of remdesivir in shortening recovery time and decreasing progression to respiratory failure and mechanical ventilation. However, some studies have highlighted its lack of efficacy in patients on high-flow oxygen and mechanical ventilation. This study uncovers some underlying immune response differences between responders and non-responders to remdesivir treatment. Immunological analyses revealed an upregulation of tissue repair factors BDNF, PDGF-BB and PIGF-1, as well as an increase in ratio of Th2-associated cytokine IL-4 to Th1-associated cytokine IFN-γ. Serological profiling of IgG subclasses corroborated this observation, with significantly higher magnitude of increase in Th2-associated IgG2 and IgG4 responses. These findings help to identify the mechanisms of immune regulation accompanying successful remdesivir treatment in severe COVID-19 patients

Linear B-cell epitopes in the spike and nucleocapsid proteins as markers of SARS-CoV-2 exposure and disease severity

BACKGROUND Given the unceasing worldwide surge in COVID-19 cases, there is an imperative need to develop highly specific and sensitive serology assays to define exposure to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). METHODS Pooled plasma samples from PCR positive COVID-19 patients were used to identify linear B-cell epitopes from a SARS-CoV-2 peptide library of spike (S), envelope (E), membrane (M), and nucleocapsid (N) structural proteins by peptide-based ELISA. Hit epitopes were further validated with 79 COVID-19 patients with different disease severity status, 13 seasonal human CoV, 20 recovered SARS patients and 22 healthy donors. FINDINGS Four immunodominant epitopes, S14P5, S20P2, S21P2 and N4P5, were identified on the S and N viral proteins. IgG responses to all identified epitopes displayed a strong detection profile, with N4P5 achieving the highest level of specificity (100%) and sensitivity (&gt;96%) against SARS-CoV-2. Furthermore, the magnitude of IgG responses to S14P5, S21P2 and N4P5 were strongly associated with disease severity. INTERPRETATION IgG responses to the peptide epitopes can serve as useful indicators for the degree of immunopathology in COVID-19 patients, and function as higly specific and sensitive sero-immunosurveillance tools for recent or past SARS-CoV-2 infections. The flexibility of these epitopes to be used alone or in combination will allow for the development of improved point-of-care-tests (POCTs)

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19

COVID-19 severity is associated with cytokine levels and lymphopenia, but the role of immune cell subsets is not well understood. Here the authors immunophenotype whole blood samples from 54 COVID-19 patients and find that the immature neutrophil-to-VD2 T-cell ratio is associated with severe COVID-19

Association of SARS-CoV-2 clades with clinical, inflammatory and virologic outcomes: An observational study

BACKGROUND: Host determinants of severe coronavirus disease 2019 include advanced age, comorbidities and male sex. Virologic factors may also be important in determining clinical outcome and transmission rates, but limited patient-level data is available. METHODS: We conducted an observational cohort study at seven public hospitals in Singapore. Clinical and laboratory data were collected and compared between individuals infected with different SARS-CoV-2 clades. Firth's logistic regression was used to examine the association between SARS-CoV-2 clade and development of hypoxia, and quasi-Poisson regression to compare transmission rates. Plasma samples were tested for immune mediator levels and the kinetics of viral replication in cell culture were compared. FINDINGS: 319 patients with PCR-confirmed SARS-CoV-2 infection had clinical and virologic data available for analysis. 29 (9%) were infected with clade S, 90 (28%) with clade L/V, 96 (30%) with clade G (containing D614G variant), and 104 (33%) with other clades 'O' were assigned to lineage B.6. After adjusting for age and other covariates, infections with clade S (adjusted odds ratio (aOR) 0·030 (95% confidence intervals (CI): 0·0002-0·29)) or clade O (B·6) (aOR 0·26 (95% CI 0·064-0·93)) were associated with lower odds of developing hypoxia requiring supplemental oxygen compared with clade L/V. Patients infected with clade L/V had more pronounced systemic inflammation with higher concentrations of pro-inflammatory cytokines, chemokines and growth factors. No significant difference in the severity of clade G infections was observed (aOR 0·95 (95% CI: 0·35-2·52). Though viral loads were significantly higher, there was no evidence of increased transmissibility of clade G, and replicative fitness in cell culture was similar for all clades. INTERPRETATION: Infection with clades L/V was associated with increased severity and more systemic release of pro-inflammatory cytokines. Infection with clade G was not associated with changes in severity, and despite higher viral loads there was no evidence of increased transmissibility

Antibody response of heterologous vs homologous mRNA vaccine boosters against the SARS-CoV-2 Omicron variant: interim results from the PRIBIVAC study, A Randomized Clinical Trial

Abstract Background Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity has raised the need for booster vaccinations. However, which combination of COVID-19 vaccines offers the strongest immune response against Omicron variant is unknown. Methods This randomized, subject-blinded, controlled trial assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. 100 BNT162b2-vaccinated individuals were enrolled and randomized 1: 1 to either homologous (BNT162b2 + BNT162b2 + BNT162b2; ‘BBB’) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; ‘BBM’). Primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and VOCs at Day 28. Results 51 participants were allocated to BBB and 49 to BBM; 50 and 48 respectively were analyzed for safety and immunogenicity outcomes. At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22,382  IU/mL 95% CI, 18,210 to 27,517) vs BBM (29,751  IU/mL 95% CI, 25,281 to 35,011, p = 0.034) as was the median level of neutralizing antibodies: BBB 99.0% (IQR 97.9 to 99.3%) vs BBM 99.3% (IQR 98.8 to 99.5%, p = 0.021). On sub-group analysis, significant differences in mean spike antibody titer and live Omicron neutralization titer was only observed in older adults. Median surrogate neutralizing antibody level against all VOCs was also significantly higher with BBM in older adults, and against Omicron was BBB 72.8% (IQR 54.0 to 84.7%) vs BBM 84.3% (IQR 78.1 to 88.7%, p = 0.0073). Both vaccines were well tolerated. Conclusions Heterologous mRNA-1273 booster vaccination induced a stronger neutralizing response against the Omicron variant in older individuals compared with homologous BNT123b2. </jats:sec

Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals.

The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 - 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2