While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous ...infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection.
In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures.
Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio HR ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease.
Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection.
National Institutes of Health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders.
To identify risk factors associated with COVID-19, severe COVID-19, and ...SARS-CoV-2 infection.
This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023.
Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment.
Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection.
A total of 57 692 participants (median range age, 51 18-95 years; 11 720 participants 20.3% aged ≥65 years; 31 058 participants 53.8% assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 95% CI, 1.16-1.58; medium vs low: aHR, 1.41 95% CI, 1.21-1.65; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 95% CI, 1.21-1.66; medium vs low risk: aHR, 1.19 95% CI, 1.08-1.32; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 95% CI, 0.09-0.19; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 95% CI, 0.50-0.64; P < .001) and Black or African American race (aHR vs White race, 0.78 95% CI, 0.67-0.91; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 95% CI, 1.85-3.69; multiracial vs White: aHR, 2.19 95% CI, 1.50-3.20; P < .001), diabetes (aHR, 1.54 95% CI, 1.14-2.08; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 95% CI, 1.09-1.76; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 95% CI, 1.32-2.31; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 95% CI, 1.38-2.83; Black or African American vs White: aHR, 1.49 95% CI, 1.03-2.14; multiracial: aHR, 1.81 95% CI, 1.21-2.69; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 95% CI, 1.01-1.04; P = .001), and diabetes (aHR, 1.85 95% CI, 1.37-2.49; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 95% CI, 0.01-0.14; P < .001).
In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.
To characterize the 'anti-ischemic' effects of adenosine metabolism inhibition in ischemic-reperfused myocardium.
Perfused C57/B16 mouse hearts were subjected to 20 min ischemia 40 min reperfusion in ...the absence or presence of adenosine deaminase inhibition (50 microM erythro-2-(2-hydroxy-3-nonyl)adenine; EHNA) adenosine kinase inhibition (10 microM iodotubercidin; IODO), or 10 microM adenosine. Hearts overexpressing A(1) adenosine receptors (A(1)ARs) were also studied.
EHNA treatment reduced ischemic contracture and post-ischemic diastolic pressure (14+/-2 vs. 20+/-1 mmHg), increased recovery of developed pressure (66+/-3 vs. 53+/-2%) and reduced LDH efflux (8.9+/-1.6 vs. 18.0+/-1.7 I.U./g). IODO also improved functional recovery (to 60+/-2%) and reduced LDH efflux (5.3+/-1.7 I.U./g), as did treatment with 10 microM adenosine. Protection with EHNA was reversed by co-infusion of IODO or 50 microM 8-rho-sulfophenyltheophylline (adenosine receptor antagonist), but unaltered by 20 microM inosine+10 microm hypoxanthine. Similarly, effects of iodotubercidin were inhibited by EHNA and 8-rho-sulfophenyltheophylline. A(1)AR overexpression exerted similar effects to EHNA and EHNA or IODO alone enhanced recovery while EHNA+IODO reduced recovery in transgenic hearts. Functional recoveries and xanthine oxidase reactant levels were unrelated in the groups studied.
Adenosine deaminase or kinase inhibition protects from ischemia-reperfusion. Cardioprotection via these enzyme inhibitors requires a functioning purine salvage pathway and involves enhanced adenosine receptor activation. Reduced formation of inosine is unimportant in EHNA-mediated protection.
With combined microdialysis and hydrogen clearance techniques for simultaneous local delivery of drugs and blood-flow measurement in the rat hindlimb sensorymotor cortex, we examined the role of ...nitric oxide in cerebral blood-flow regulation during sciatic nerve stimulation. Infusion of 1 mM nitric oxide synthase antagonist, Nη-nitro-L-arginine methyl ester (L-NAME), blocked the cortical blood-flow response to sciatic nerve stimulation (152 ± 43 ml·min-1·100 g-1of tissue in controls and 73 ± 11 ml·min-1·100 g-1in the presence of L-NAME; P$<$0.05). Addition of 10 mM L-arginine to the dialysate containing L-NAME partially restored the hyperemic response to nerve stimulation (125 ml·min-1·100 g-1). L-NAME also produced a decrease in baseline cerebral blood flow when compared with the control (66 ± 14 ml·min-1·100 g-1vs. 93 ± 25 ml·min-1·100 g-1). We conclude that nitric oxide from activated neurons participates in the local regulation of cortical blood flow in response to sciatic nerve stimulation and also in the maintenance of basal cortical blood flow.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity.
To characterize VL at COVID-19 ...diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease.
This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023.
Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis.
Among 1667 participants studied (886 53.1% male; 995 59.7% enrolled in the US; mean SD age, 46.7 14.7 years; 204 12.2% aged 65 years or older; 196 11.8% American Indian or Alaska Native, 150 9% Black or African American, 1112 66.7% White; 762 45.7% Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity.
In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.
While inhibition of ischaemic contracture was one of the first documented cardioprotective actions of exogenously applied adenosine, it is not known whether this is a normal function of endogenous ...adenosine generated during ischaemic stress. Additionally, the relevance of delayed contracture to postischaemic outcome is unclear. We tested the ability of endogenous versus exogenous adenosine to modify contracture (and postischaemic outcomes) in C57/Bl6 mouse hearts. During ischaemia, untreated hearts developed peak contracture (PC) of 85 ± 5 mmHg at 8.9 ± 0.8 min, with time to reach 20 mmHg (time to onset of contracture; TOC) of 4.4 ± 0.3 min. Adenosine (50 μm) delayed TOC to 6.7 ± 0.6 min, as did pretreatment with 10 μm 2‐chloroadenosine (7.2 ± 0.5 min) or 50 nm of A1 adenosine receptor (AR) agonist N6‐cyclohexyladenosine (CHA) (6.7 ± 0.3 min), but not A2AAR or A3AR agonists (20 nm 2‐4‐(2‐carboxyethyl) phenethylamino‐5′ N‐methylcarboxamidoadenosine (CGS21680) or 150 nm 2‐chloro‐N6‐(3‐iodobenzyl)‐adenosine‐5′‐N‐methyluronamide (Cl‐IB‐MECA), respectively). Adenosinergic contracture inhibition was eliminated by A1AR gene knockout (KO), mimicked by A1AR overexpression, and was associated with preservation of myocardial ATP. This adenosine‐mediated inhibition of contracture was, however, only evident after prolonged (10 or 15 min) and not brief (3 min) pretreatment. Ischaemic contracture was also insensitive to endogenously generated adenosine, since A1AR KO, and non‐selective and A1AR‐selective antagonists (50 μm 8‐sulphophenyltheophylline and 150 nm 8‐cyclopentyl‐1, 3‐dipropylxanthine (DPCPX), respectively), all failed to alter intrinsic contracture development. Finally, delayed contracture with A1AR agonism/overexpression or ischaemic 2,3‐butanedione monoxime (BDM; 5 μm to target Ca2+ cross‐bridge formation) was linked to enhanced postischaemic outcomes. In summary, adenosinergic inhibition of contracture is solely A1AR mediated; the response is ‘supraphysiological’, evident only with significant periods of pre‐ischaemic AR agonism (or increased A1AR density); and ischaemic contracture appears insensitive to locally generated adenosine, potentially owing to the rapidity of contracture development versus the finite time necessary for expression of AR‐mediated cardioprotection.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We investigated whether A(1) adenosine receptor stimulation affects expression of genes involved in calcium homeostasis, including sarcolemmal L-type Ca(2+) channel, Na(+)/Ca(2+) exchanger, ...sarcoplasmic reticulum (SR) Ca(2+)-ATPase, phospholamban, or ryanodine receptor. Three models of A(1) stimulation were used: i) an acute model, i.e. isolated perfused rat hearts treated for 120 min with 15 nM R-phenylisopropyladenosine (R-PIA), an A(1) receptor agonist; ii) a subacute model, i.e. rats treated with 1.5 mg/kg R-PIA e.v. and sacrificed after 24 h; iii) a transgenic model, i.e. mice overexpressing A(1) adenosine receptors. In all models gene expression was determined by RT-PCR, and oxalate-supported Ca(2+) uptake, representing SR Ca(2+) uptake, was measured in the crude homogenate. Significant increase in the expression of the phospholamban gene was observed in each model of A(1) stimulation, while the expression of the other four genes was not significantly modified. In the acute model, SR Ca(2+) uptake was unaffected, however in the subacute and transgenic models uptake rate was significantly reduced. In parallel experiments, hearts obtained from the subacute model demonstrated a significant reduction in irreversible tissue injury from 30 min of ischemia and 120 min of reperfusion. Increased resistance to ischemia has already been reported also in our transgenic model. In conclusion, A(1) adenosine receptor stimulation up-regulates phospholamban gene expression, which leads within 24 h to a reduced rate of SR Ca(2+) uptake. Changes in Ca(2+) homeostasis might contribute to the delayed cardioprotective effect of adenosine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Cold ischemic storage of hearts for transplantation is limited to 4-6 h, and therefore the development of strategies to extend preservation time may increase the donor pool of hearts. Overexpression ...of A
1
-adenosine receptors (A
1
AR) can protect hearts from acute ischemic injury, and the purpose of this study was to test the hypothesis that overexpression of A
1
AR will improve tolerance to longer periods of cold ischemic preservation. Hearts from 18 wild type and 16 transgenic mice with overexpression of A
1
AR (A
1
AR Trans) were isolated and perfused, and then subjected to 18 h of preservation in 5 °C University of Wisconsin solution followed by 2 h of reperfusion. Left ventricular end diastolic pressure and left ventricular developed pressure were measured as indices of ventricular function. Cell viability was assessed by determination of infarct size and myocardial cell apoptosis. A
1
AR Trans hearts showed improved function following 18 h of ischemia, as shown by lower end diastolic pressure (p < 0.05) and higher recovery of left ventricular developed pressure (p < 0.05) during reperfusion. A
1
AR Trans hearts had markedly reduced infarct size (p < 0.05) and decreased apoptosis (p < 0.05). Overexpression of cardiac A
1
AR imparts cardioprotection during long-term cold ischemic preservation.
Key words: cardiac preservation, myocardial protection, g-protein coupled receptors, transgenic mice, heart transplantation.
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DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The goal of the present study was to compare two common types of isolated working mouse heart models, setting afterload either with (1) a hydrostatic fluid column, or (2) a mechanical resistor. ...Cardiovascular function in both models was determined by volume- and pressure-loading protocols. During volume loading, both models demonstrated a fixed degree of outflow resistance from the 20-gauge rigid aortic cannula resulting in a small predictable rise in left-ventricular pressure. In the mechanical resistor model, volume loading resulted in a marked increase in afterload, with a >50% increase from baseline aortic pressure. This altered ventricular mechanics, resulting in twice the expected change in dP/dtduring volume loading. Additionally, coronary flow in the mechanical resistor model rose by more than four-fold in parallel to the increased preload. When using the fluid column model, however, aortic pressure was unchanged and coronary flow remained stable. During pressure loading, no significant differences in ventricular mechanics or coronary flow between the mechanical resistor and fluid column models were noted. When mouse hemodynamic data were compared to that from larger species, mouse hearts had similar cardiac function and efficiency with higher MVO2and coronary flows. In summary, the hydrostatic fluid column isolated working mouse heart model is preferred over the mechanical resistor model for studying murine cardiac function. Further, use of this model provides hemodynamic data that is consistent with larger species, albeit with higher MVO2and basal coronary flow, and should allow relevant study of mouse cardiac physiology.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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