PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis

BACKGROUND Oxidation-specific epitopes (OSEs) are proinflammatory, and elevated levels in plasma predict cardiovascular events. OBJECTIVES The purpose of this study was to develop novel positron emission tomography (PET) probes to noninvasively image OSE-rich lesions. METHODS An antigen-binding fragment (Fab) antibody library was constructed from human fetal cord blood. After multiple rounds of screening against malondialdehyde-acetaldehyde (MAA) epitopes, the Fab LA25 containing minimal nontemplated insertions in the CDR3 region was identified and characterized. In mice, pharmacokinetics, biodistribution, and plaque specificity studies were performed with Zirconium-89 (Zr-89)-labeled LA25. In rabbits, Zr-89-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. F-18-fluorodeoxyglucose PET and dynamic contrast-enhanced MR imaging were used to evaluate vessel wall inflammation and plaque neovascularization, respectively. Extensive ex vivo validation was carried out through a combination of gamma counting, near infrared fluorescence, autoradiography, immunohistochemistry, and immunofluorescence. RESULTS LA25 bound specifically to MAA epitopes in advanced and ruptured human atherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of Zr-89-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. F-18-fluorodeoxyglucose PET, dynamic contrastenhanced MR imaging, and near-infrared fluorescence signals were also significantly higher in atherosclerotic rabbit aortas compared with control aortas. Enhanced liver uptake was also noted in atherosclerotic animals, confirmed by the presence of MAA epitopes by immunostaining. CONCLUSIONS Zr-89-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions. (c) 2018 by the American College of Cardiology Foundatio

PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis.

BackgroundOxidation-specific epitopes (OSEs) are proinflammatory, and elevated levels in plasma predict cardiovascular events.ObjectivesThe purpose of this study was to develop novel positron emission tomography (PET) probes to noninvasively image OSE-rich lesions.MethodsAn antigen-binding fragment (Fab) antibody library was constructed from human fetal cord blood. After multiple rounds of screening against malondialdehyde-acetaldehyde (MAA) epitopes, the Fab LA25 containing minimal nontemplated insertions in the CDR3 region was identified and characterized. In mice, pharmacokinetics, biodistribution, and plaque specificity studies were performed with Zirconium-89 (89Zr)-labeled LA25. In rabbits, 89Zr-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. 18F-fluorodeoxyglucose PET and dynamic contrast-enhanced MR imaging were used to evaluate vessel wall inflammation and plaque neovascularization, respectively. Extensive ex vivo validation was carried out through a combination of gamma counting, near infrared fluorescence, autoradiography, immunohistochemistry, and immunofluorescence.ResultsLA25 bound specifically to MAA epitopes in advanced and ruptured human atherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of 89Zr-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. 18F-fluorodeoxyglucose PET, dynamic contrast-enhanced MR imaging, and near-infrared fluorescence signals were also significantly higher in atherosclerotic rabbit aortas compared with control aortas. Enhanced liver uptake was also noted in atherosclerotic animals, confirmed by the presence of MAA epitopes by immunostaining.Conclusions89Zr-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions

Efficacy of different preoperative skin antiseptics on the incidence of surgical site infections: a systematic review, GRADE assessment, and network meta-analysis

Background: Surgical site infection (SSI) is the most common postoperative complication and substantially increases health-care costs. Published meta-analyses and international guidelines differ with regard to which preoperative skin antiseptic solution and concentration has the highest efficacy. We aimed to compare the efficacy of different skin preparation solutions and concentrations for the prevention of SSIs, and to provide an overview of current guidelines. Methods: This systematic review and network meta-analysis compared different preoperative skin antiseptics in the prevention of SSIs in adult patients undergoing surgery of any wound classification. We searched for randomised controlled trials (RCTs) in MEDLINE, Embase, and Cochrane CENTRAL, published up to Nov 23, 2021, that directly compared two or more antiseptic agents (ie, chlorhexidine, iodine, or olanexidine) or concentrations in aqueous and alcohol-based solutions. We excluded paediatric, animal, and non-randomised studies, and studies not providing standard preoperative intravenous antibiotic prophylaxis. Studies with no SSIs in both groups were excluded from the quantitative analysis. Two reviewers screened and reviewed eligible full texts and extracted data. The primary outcome was the occurrence of SSI (ie, superficial, deep, and organ space). We conducted a frequentist random effects network meta-analysis to estimate the network effects of the skin preparation solutions on the prevention of SSIs. A risk-of-bias and Grading of Recommendations, Assessment, Development, and Evaluation assessment were done to determine the certainty of the evidence. This study is registered with PROSPERO, CRD42021293554. Findings: Overall, 2326 articles were identified, 33 studies were eligible for the systematic review, and 27 studies with 17 735 patients reporting 2144 SSIs (overall incidence of 12·1%) were included in the quantitative analysis. Only 2·0–2·5% chlorhexidine in alcohol (relative risk 0·75, 95% CI 0·61–0·92) and 1·5% olanexidine (0·49, 0·26–0·92) significantly reduced the rate of SSIs compared with aqueous iodine. For clean surgery, we found no difference in efficacy between different concentrations of chlorhexidine in alcohol. Seven RCTs were at high risk of bias, 24 had some concerns, and two had low risk of bias. Heterogeneity across the studies was moderate (I2=27·5%), and netsplitting did not show inconsistencies between direct and indirect comparisons. Five of ten studies that mentioned adverse events related to the skin preparation solutions reported no adverse events, and five reported a total of 56 mild events (mainly erythema, pruritus, dermatitis, skin irritation, or mild allergic symptoms); none reported a substantial difference in adverse events between groups. Interpretation: For adult patients undergoing a surgical procedure of any wound classification, skin preparation using either 2·0–2·5% chlorhexidine in alcohol or 1·5% olanexidine is most effective in the prevention of SSIs. For clean surgery, no specific concentration of chlorhexidine in alcohol can be recommended. The efficacy of olanexidine was established by a single randomised trial and further investigation is needed. Funding: Dutch Association for Quality Funds Medical Specialists

Incisional negative pressure wound therapy for the prevention of surgical site infection: an up-to-date meta-analysis and trial sequential analysisResearch in context

Summary: Background: The evidence on prophylactic use of negative pressure wound therapy on primary closed incisional wounds (iNPWT) for the prevention of surgical site infections (SSI) is confusing and ambiguous. Implementation in daily practice is impaired by inconsistent recommendations in current international guidelines and published meta-analyses. More recently, multiple new randomised controlled trials (RCTs) have been published. We aimed to provide an overview of all meta-analyses and their characteristics; to conduct a new and up-to-date systematic review and meta-analysis and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment; and to explore the additive value of new RCTs with a trial sequential analysis (TSA). Methods: PubMed, Embase and Cochrane CENTRAL databases were searched from database inception to October 24, 2022. We identified existing meta-analyses covering all surgical specialties and RCTs studying the effect of iNPWT compared with standard dressings in all types of surgery on the incidence of SSI, wound dehiscence, reoperation, seroma, hematoma, mortality, readmission rate, skin blistering, skin necrosis, pain, and adverse effects of the intervention. We calculated relative risks (RR) with corresponding 95% confidence intervals (CI) using a Mantel-Haenszel random-effects model. We assessed publication bias with a comparison-adjusted funnel plot. TSA was used to assess the risk of random error. The certainty of evidence was evaluated using the Cochrane Risk of Bias-2 (RoB2) tool and GRADE approach. This study is registered with PROSPERO, CRD42022312995. Findings: We identified eight previously published general meta-analyses investigating iNPWT and compared their results to present meta-analysis. For the updated systematic review, 57 RCTs with 13,744 patients were included in the quantitative analysis for SSI, yielding a RR of 0.67 (95% CI: 0.59–0.76, I2 = 21%) for iNPWT compared with standard dressing. Certainty of evidence was high. Compared with previous meta-analyses, the RR stabilised, and the confidence interval narrowed. In the TSA, the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit, confirming the robustness of the summary effect estimate from the meta-analysis. Interpretation: In this up-to-date meta-analysis, GRADE assessment shows high-certainty evidence that iNPWT is effective in reducing SSI, and uncertainty is less than in previous meta-analyses. TSA indicated that further trials are unlikely to change the effect estimate for the outcome SSI; therefore, if future research is to be conducted on iNPWT, it is crucial to consider what the findings will contribute to the existing robust evidence. Funding: Dutch Association for Quality Funds Medical Specialists

Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease

Tissue macrophage numbers vary during health versus disease. Abundant inflammatory macrophages destruct tissues, leading to atherosclerosis, myocardial infarction and heart failure. Emerging therapeutic options create interest in monitoring macrophages in patients. Here we describe positron emission tomography (PET) imaging with 18F-Macroflor, a modified polyglucose nanoparticle with high avidity for macrophages. Due to its small size, Macroflor is excreted renally, a prerequisite for imaging with the isotope flourine-18. The particle's short blood half-life, measured in three species, including a primate, enables macrophage imaging in inflamed cardiovascular tissues. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. In PET/magnetic resonance imaging (MRI) experiments, Macroflor PET imaging detects changes in macrophage population size while molecular MRI reports on increasing or resolving inflammation. These data suggest that Macroflor PET/MRI could be a clinical tool to non-invasively monitor macrophage biology