SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies

The development and application of a high-sensitivity immunoassay for cardiac myosin-binding protein C

Cardiac troponins (cTns) are released and cleared slowly after myocardial injury. Cardiac myosin–binding protein C (cMyC) is a similar cardiac-restricted protein that has more rapid release and clearance kinetics. Direct comparisons are hampered by the lack of an assay for cMyC that matches the sensitivity of the contemporary assays for cTnI and cTnT. Using a novel pair of monoclonal antibodies, we generated a sensitive assay for MyC on the Erenna platform (Singulex) and compared serum concentrations with those of cTnI (Abbott) and cTnT (Roche) in stable ambulatory cardiac patients without evidence of acute cardiac injury or significant coronary artery stenoses. The assay for cMyC had a lower limit of detection of 0.4 ng/L, a lower limit of quantification (LLoQ) of 1.2 ng/L (LLoQ at 20% coefficient of variation [CV]) and reasonable recovery (107.1 ± 3.7%; mean ± standard deviation), dilutional linearity (101.0 ± 7.7%), and intraseries precision (CV, 11 ± 3%) and interseries precision (CV, 13 ± 3%). In 360 stable patients, cMyC was quantifiable in 359 patients and compared with cTnT and cTnI measured using contemporary high-sensitivity assays. cMyC concentration (median, 12.2 ng/L; interquartile range [IQR], 7.9–21.2 ng/L) was linearly correlated with those for cTnT (median, <3.0 ng/L; IQR, <3.0–4.9 ng/L; R = 0.56, P < 0.01) and cTnI (median, 2.10 ng/L; IQR, 1.3–4.2 ng/L; R = 0.77, P < 0.01) and showed similar dependencies on age, renal function, and left ventricular function. We have developed a high-sensitivity assay for cMyC. Concentrations of cMyC in clinically stable patients are highly correlated with those of cTnT and cTnI. This high correlation may enable ratiometric comparisons between biomarkers to distinguish clinical instability

Forecasting aortic aneurysm rupture: a systematic review of seasonal and atmospheric associations

Background: Abdominal aortic aneurysms (AAAs) represent a significant burden of disease worldwide, and their rupture, without treatment, has an invariably high mortality rate. Whereas some risk factors for ruptured AAAs (rAAAs) are well established, such as hypertension, smoking, and female sex, the impact of seasonal and meteorologic variables is less clear. We systematically reviewed the literature to determine whether these variables are associated with rAAA. Methods: Review methods were according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We calculated pooled proportions and incidence rate ratios (IRRs) for the different months and seasons. Funnel plots were constructed to assess for publication bias. Given the poor methodologic quality of included studies, a sensitivity analysis was performed on better-quality studies, which scored 6 and above of 9 in the author-modified Newcastle-Ottawa Scale. Results: The pooled proportion of rAAA was highest in the autumn season (incidence rate, 26.6%; 95% confidence interval [CI], 25.6%-27.7%; I = 15.4%), followed by winter (incidence rate, 26.2%; 95% CI, 24.1%-28.2%; I = 72.4%), and lowest in summer (incidence rate, 21.1%; 95% CI, 19.3%-23.0%; I = 70.4%). The IRRs of rAAA were −6.9% (95% CI, −9.8% to −3.9%), −19.5% (95% CI, −22% to −16.8%), +10.5% (95% CI, 7.2%-13.9%), and +18.1% (95% CI, 15%-22%) in spring, summer, autumn, and winter compared with the remaining seasons, respectively (all P < .0001), thus affirming existence of seasonal variation. The pooled proportion of rAAA was highest in December (incidence rate, 8.9%; 95% CI, 7.1%-10.9%; I = 54.5%) but lowest in July (incidence rate, 5.7%; 95% CI, 4.2%-7.3%; I = 54.5%). The IRR was significantly the highest in January (IRR, 1.14; 95% CI, 1.01-1.29; P = .031) but lowest in July (IRR, 0.75; 95% CI, 0.65-0.87; P < .0001). There is also some evidence for a possible association with atmospheric pressure. Associations with temperature and daylight hours, however, are at best speculative. Conclusions: Autumn and winter are significantly associated with a higher incidence of rAAAs, and autumn is associated with the highest rupture incidence of all the seasons. However, the inability to appropriately control for other confounding factors known to increase the risk of AAA rupture precludes any additional recommendations to alter current provision of vascular services on the basis of these data

A single centre prospective cohort study addressing the effect of a rule-in/rule-out troponin algorithm on routine clinical practice

Aims: In 2015, the European Society of Cardiology introduced new guidelines for the diagnosis of acute coronary syndromes in patients presenting without persistent ST-segment elevation. These guidelines included the use of high-sensitivity troponin assays for ‘rule-in’ and ‘rule-out’ of acute myocardial injury at presentation (using a ‘0 hour’ blood test). Whilst these algorithms have been extensively validated in prospective diagnostic studies, the outcome of their implementation in routine clinical practice has not been described. The present study describes the change in the patient journey resulting from implementation of such an algorithm in a busy innercity Emergency Department. Methods and results: Data were prospectively collected from electronic records at a large Central London hospital over seven months spanning the periods before, during and after the introduction of a new high-sensitivity troponin rapid diagnostic algorithm modelled on the European Society of Cardiology guideline. Over 213 days, 4644 patients had high-sensitivity troponin T measured in the Emergency Department. Of these patients, 40.4% could be ‘ruled-out’ based on the high-sensitivity troponin T concentration at presentation, whilst 7.6% could be ‘ruled-in’. Adoption of the algorithm into clinical practice was associated with a 37.5% increase of repeat high-sensitivity troponin T measurements within 1.5 h for those patients classified as ‘intermediate risk’ on presentation. Conclusions: Introduction of a 0 hour ‘rule-in’ and ‘rule-out’ algorithm in routine clinical practice enables rapid triage of 48% of patients, and is associated with more rapid repeat testing in intermediate risk patients. </jats:sec

Direct Comparison of Cardiac Myosin-Binding Protein C with Cardiac Troponins for the Early Diagnosis of Acute Myocardial Infarction

Cardiac myosin-binding protein C (cMyC) is a cardiac-restricted protein that is more abundant than cardiac troponins (cTn) and is released more rapidly after acute myocardial infarction (AMI). We evaluated cMyC as an adjunct or alternative to cTn in the early diagnosis of AMI.Unselected patients (N=1954) presenting to the emergency department with symptoms suggestive of AMI, concentrations of cMyC, and high-sensitivity (hs) and standard-sensitivity cTn were measured at presentation. The final diagnosis of AMI was independently adjudicated using all available clinical and biochemical information without knowledge of cMyC. The prognostic end point was long-term mortality.Final diagnosis was AMI in 340 patients (17%). Concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 237 ng/L versus 13 ng/L

Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. METHODS: Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. RESULTS: Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. CONCLUSIONS: These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (-1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies