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Aim: To assess and compare the effect of mouthwash containing 0.3% Aegle marmelos (Bael) leaves extract with other herbal mouthwashes containing 0.3% Cinnamomum zeylanicum (Cinnamon) barks extract and 0.3% Azadirachta indica (Neem) leaves extract and with 0. 2% chlorhexidine mouthwash on dental plaque, gingival health and salivary p H among adults. Materials and Methods: A triple blinded randomized controlled trial with concurrent parallel study design was carried out. Around, 48 young adults were randomly allotted to four groups - Group A (Chlorhexidine), Group B (Cinnamon), Group C (Bael) and Group D ( Neem) by simple randomization technique. They were advised to rinse with 10 ml of their respected mouthwashes twice daily for 1 minute for a period of 28 days. The dental plaque score and gingival inflammation score were recorded using Plaque index and Gingival index at the baseline, 15th day, 22nd day and 29th day. Statistical analysis were done using ANOVA and repeated measure ANOVA for the plaque and gingival scores and Paired sample t test for p H Results: Mouthwashes containing Bael, Neem and Chlorhexidine showed a stastistically significant reduction in the plaque levels at the end of second week (mean difference from baseline to 2nd week = 0. 158, 0. 100 and 0. 108 respectively with p value < 0. 05). However, at all the time points considered in the study, Bael was more effective in reducing the gingivitis. Conclusion: Bael extract mouthwash is as effective as the gold standard Chlorhexidine mouthwash in reducing the plaque and gingivitis and opens new perspectives for its use. [ABSTRACT FROM AUTHOR]

Background: This cross-sectional study aimed to identify the prevalence of Candida albicans and Malassezia globosa in children with severe early childhood caries and caries-free children in Hong Kong. Methods: This study first recruited a total of 80 children aged between 48 and 72 months old, 40 children with severe early childhood caries, and 40 caries-free children. The children were then further divided into four groups, with 20 children in each group: Group 1: Severe early childhood caries—C. albicans, Group 2: Severe early childhood caries—M. globosa, Group 3: Caries-free—C. albicans and Group 4: Caries-free—M. globosa. Saliva, plaque, and caries lesion samples were collected from participants with severe early childhood caries, while only saliva and plaque samples were collected from caries-free participants. Caries status of the primary molars was assessed using WHO's decayed, missing, and filled tooth index, and the severity of cavitated lesions was determined based on International Caries Diagnosis and Assessment System criteria as caries code 5 or 6. The samples were analyzed using an Internal Transcribed Space and Quantitative Real-Time Polymerase Chain Reaction. Results:C. albicans was more prevalent in saliva and plaque samples of severe early childhood caries than in the caries-free group. Proportion of C. albicans in both saliva and plaque samples differed significantly between severe early childhood caries and caries-free groups (p < 0.05). Within the severe early childhood caries group, the proportion of children with C. albicans varied between 6 and 46%. No significant difference in M. globosa load was found between plaque samples of the severe early childhood caries and caries-free groups (p = 0.159). Conversely, no significant difference in M. globosa load was observed between saliva samples of severe early childhood caries and caries-free groups (p = 0.051). Conclusions: This study demonstrated a strong association between C. albicans and severe early childhood caries. M. globosa was detected in both the caries-free and severe early childhood caries groups, albeit at low levels. [ABSTRACT FROM AUTHOR]

The rupture of unstable plaques is a major cause of acute cardiovascular events. The early assessment of carotid plaques can significantly reduce the cardiovascular risks, so developing evaluation models suitable for data from different centers is of great clinical importance. This study leverages plaque datasets from multiple centers to develop a Weighted multi-source carotid artery plaque Unsupervised Classification Framework (WUCF). The multi-source domain adaptation module of the WUCF focuses on maintaining feature consistency between each independent source and target center, while also integrating a specialized domain discriminator expert. This ensures that the knowledge from each source center is effectively learned and combined for accurate predictions in the target domain. The experimental evaluation of WUCF, using datasets from three centers, has demonstrated the method's superiority and robustness. [ABSTRACT FROM AUTHOR]

Background: Life's Essential 8 (LE8), the recently updated construct for quantifying cardiovascular health, is related to the risks of cardiovascular events. The present study aimed to evaluate associations of LE8 score with the multi-territorial extent of atherosclerosis in a community-dwelling population. Methods: Data were derived from the baseline cross-sectional survey of the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in Lishui City. The LE8 included overall, medical and behavior LE8 scores, and were categorized as low (< 60), moderate (60-<80), and high (≥ 80) groups. Vascular magnetic resonance imaging was used to evaluate intracranial and extracranial arteries; thoracoabdominal computed tomography angiography to evaluate coronary, subclavian, aorta, renal, ilio-femoral arteries; and ankle-brachial index to evaluate peripheral arteries. The presence of atherosclerotic plaque or stenosis in any territory was defined as plaque or vascular stenosis with 1 territory affected or more in these arteries. The extent of atherosclerotic plaques or stenosis was assessed according to the number of these 8 vascular sites affected, and graded as four grades (none, single territory, 2–3 territories, 4–8 territories). Results: Of 3065 included participants, the average age was 61.2 ± 6.7 years, and 53.5% were women (n = 1639). The moderate and high overall LE8 groups were associated with lower extent of multi-territorial plaques [common odds ratio (cOR) 0.44, 95% confidence interval (CI), 0.35–0.55; cOR 0.16, 95%CI, 0.12–0.21; respectively] and stenosis (cOR 0.51, 95%CI, 0.42–0.62; cOR 0.16, 95%CI, 0.12–0.21; respectively) after adjustment for potential covariates. Similar results were observed for medical LE8 score with the extent of multi-territorial plaques and stenosis (P < 0.05). We also found the association between behavior LE8 score and the extent of multi-territorial stenosis (P < 0.05). Conclusions: The higher LE8 scores, indicating healthier lifestyle, were associated with lower presence and extent of atherosclerotic plaque and stenosis in southern Chinese adults. Prospective studies are needed to further validate these findings. [ABSTRACT FROM AUTHOR]

Definition: The Pandemic Equation describes multiple pandemic waves and has been applied to describe the COVID-19 pandemic. Using the generalized approaches of solid-state physics, we derive the Pandemic Equation, which accounts for the effects of pandemic mitigation measures and multiple pandemic waves. The Pandemic Equation uses slow and fast time scales for "curve flattening" and describing vaccination and mitigation measures and the Scaled Fermi–Dirac distribution functions for describing transitions between pandemic waves. The Pandemic Equation parameters extracted from the pandemic curves can be used for comparing different scenarios of the pandemic evolution and for extrapolating the pandemic evolution curves for the periods of time on the order of the instantaneous Pandemic Equation characteristic time constant. The parameter extraction for multiple locations could also allow for uncertainty quantification for such pandemic evolution predictions. [ABSTRACT FROM AUTHOR]

This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health concern. Atherosclerosis is characterized by the accumulation of lipids and inflammation within arterial walls, leading to significant morbidity and mortality through cardiovascular diseases such as myocardial infarction and stroke. Traditional therapeutic approaches have primarily focused on modulating risk factors such as hypertension and hyperlipidemia, with emerging evidence highlighting the pivotal role of inflammation. PDT, leveraging a photosensitizer, specific-wavelength light, and oxygen, offers targeted treatment by inducing cell death in diseased tissues while sparing healthy ones. This specificity, combined with advancements in nanoparticle technology for improved delivery, positions PDT as a promising alternative to traditional interventions. The review explores the mechanistic basis of PDT, its efficacy in preclinical studies, and the potential for enhancing plaque stability and reducing macrophage density within plaques. It also addresses the need for further research to optimize treatment parameters, mitigate adverse effects, and validate long-term outcomes. By detailing past developments, current progress, and future directions, this paper aims to highlight PDT's potential in revolutionizing atherosclerosis treatment, bridging the gap from experimental research to clinical application. [ABSTRACT FROM AUTHOR]

Background: The coronary artery disease‐reporting and data system (CAD‐RADS) 2.0 is used to standardize the reporting of coronary computed tomography angiography (CCTA) results. Artificial intelligence software can quantify the plaque composition, fat attenuation index, and fractional flow reserve. Objective: To analyze plaque features of varying severity in patients with a combination of CAD‐RADS stenosis and plaque burden categorization and establish a random forest classification model. Methods: The data of 100 patients treated between April 2021 and February 2022 were retrospectively collected. The most severe plaque observed in each patient was the target lesion. Patients were categorized into three groups according to CAD‐RADS: CAD‐RADS 1−2 + P0−2, CAD‐RADS 3−4B + P0−2, and CAD‐RADS 3−4B + P3−4. Differences and correlations between variables were assessed between groups. AUC, accuracy, precision, recall, and F1 score were used to evaluate the diagnostic performance. Results: A total of 100 patients and 178 arteries were included. The differences of computed tomography fractional flow reserve (CT‐FFR) (H = 23.921, p < 0.001), the volume of lipid component (H = 12.996, p = 0.002), the volume of fibro‐lipid component (H = 8.692, p = 0.013), the proportion of lipid component volume (H = 22.038, p < 0.001), the proportion of fibro‐lipid component volume (H = 11.731, p = 0.003), the proportion of calcification component volume (H = 11.049, p = 0.004), and plaque type (χ2 = 18.110, p = 0.001) was statistically significant. Conclusion: CT‐FFR, volume and proportion of lipid and fibro‐lipid components of plaques, the proportion of calcified components, and plaque type were valuable for CAD‐RADS stenosis + plaque burden classification, especially CT‐FFR, volume, and proportion of lipid and fibro‐lipid components. The model built using the random forest was better than the clinical model (AUC: 0.874 vs. 0.647). [ABSTRACT FROM AUTHOR]

Early detection of Alzheimer's disease (AD) represents an unmet clinical need. Beta-amyloid (Aβ) plays an important role in AD pathology, and the Aβ42/40 peptide ratio is a good indicator for amyloid deposition. In addition, variants of the apolipoprotein E (APOE) gene are associated with variable AD risk. Here, we describe the development and validation of high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for plasma Aβ40 and Aβ42 quantitation, as well as apolipoprotein E (ApoE) proteotype determination as a surrogate for APOE genotype. Aβ40 and Aβ42 were simultaneously immunoprecipitated from plasma, proteolytically digested, and quantitated by LC-MS/MS. ApoE proteotype status was qualitatively assessed by targeting tryptic peptides from the ApoE2, ApoE3, and ApoE4 proteoforms. Both assays were validated according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Within-run precision was 1.8%–4.2% (Aβ40), 1.9%–7.2% (Aβ42), and 2.6%–8.3% (Aβ42/40 ratio). Between-run precision was 3.5%–5.9% (Aβ40), 3.8%–8.0% (Aβ42), and 3.3%–8.7% (Aβ42/40 ratio). Both Aβ40 and Aβ42 were linear from 10 to 2500 pg/mL. Identified ApoE proteotypes had 100% concordance with APOE genotypes. We have developed a precise, accurate, and sensitive high-throughput LC-MS/MS assay for plasma Aβ40, Aβ42, and proteoforms of ApoE. [ABSTRACT FROM AUTHOR]

AIMS: The totality of atherosclerotic plaque derived from coronary computed tomography angiography (CCTA) emerges as a comprehensive measure to assess the intensity of medical treatment that patients need. This study examines the differences in age onset and prognostic significance of atherosclerotic plaque burden between sexes. METHODS AND RESULTS: From a large multi-center CCTA registry the Leiden CCTA score was calculated in 24 950 individuals. A total of 11 678 women (58.5 ± 12.4 years) and 13 272 men (55.6 ± 12.5 years) were followed for 3.7 years for major adverse cardiovascular events (MACE) (death or myocardial infarction). The age where the median risk score was above zero was 12 years higher in women vs. men (64-68 years vs. 52-56 years, respectively, P < 0.001). The Leiden CCTA risk score was independently associated with MACE: score 6-20: HR 2.29 (1.69-3.10); score > 20: HR 6.71 (4.36-10.32) in women, and score 6-20: HR 1.64 (1.29-2.08); score > 20: HR 2.38 (1.73-3.29) in men. The risk was significantly higher for women within the highest score group (adjusted P-interaction = 0.003). In pre-menopausal women, the risk score was equally predictive and comparable with men. In post-menopausal women, the prognostic value was higher for women [score 6-20: HR 2.21 (1.57-3.11); score > 20: HR 6.11 (3.84-9.70) in women; score 6-20: HR 1.57 (1.19-2.09); score > 20: HR 2.25 (1.58-3.22) in men], with a significant interaction for the highest risk group (adjusted P-interaction = 0.004). CONCLUSION: Women developed coronary atherosclerosis approximately 12 years later than men. Post-menopausal women within the highest atherosclerotic burden group were at significantly higher risk for MACE than their male counterparts, which may have implications for the medical treatment intensity.

Recent studies have found an association between high volumes of physical activity and increased levels of coronary artery calcification (CAC) among older male endurance athletes, yet the underlying mechanisms have remained largely elusive. Potential mechanisms include greater exposure to inflammatory cytokines, reactive oxygen species and oxidised low-density lipoproteins, as acute strenuous physical activity has been found to enhance their systemic release. Other possibilities include post-exercise elevations in circulating parathyroid hormone, which can modify the amount and morphology of calcific plaque, and long-term exposure to non-laminar blood flow within the coronary arteries during vigorous physical activity, particularly in individuals with pre-existing atherosclerosis. Further, although the association has only been identified in men, the role of testosterone in this process remains unclear. This brief review discusses the association between high-volume endurance exercise and CAC in older men, elaborates on the potential mechanisms underlying the increased calcification, and provides clinical implications and recommendations for those at risk.

Calcific aortic valve disease (CAVD) and stenosis have a complex pathogenesis, and no therapies are available that can halt or slow their progression. Several studies have shown the presence of apolipoprotein-related amyloid deposits in close proximity to calcified areas in diseased aortic valves. In this Perspective, we explore a possible relationship between amyloid deposits, calcification and the development of aortic valve stenosis. These amyloid deposits might contribute to the amplification of the inflammatory cycle in the aortic valve, including extracellular matrix remodelling and myofibroblast and osteoblast-like cell proliferation. Further investigation in this area is needed to characterize the amyloid deposits associated with CAVD, which could allow the use of antisense oligonucleotides and/or isotype gene therapies for the prevention and/or treatment of CAVD.

OBJECTIVES: People with HIV have a higher risk of myocardial infarction (MI) than the general population, with a greater proportion of type 2 MI (T2MI) due to oxygen demand-supply mismatch compared with type 1 (T1MI) resulting from atherothrombotic plaque disruption. People living with HIV report a greater prevalence of cigarette and alcohol use than do the general population. Alcohol use and smoking as risk factors for MI by type are not well studied among people living with HIV. We examined longitudinal associations between smoking and alcohol use patterns and MI by type among people living with HIV. DESIGN AND METHODS: Using longitudinal data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort, we conducted time-updated Cox proportional hazards models to determine the impact of smoking and alcohol consumption on adjudicated T1MI and T2MI. RESULTS: Among 13 506 people living with HIV, with a median 4 years of follow-up, we observed 177 T1MI and 141 T2MI. Current smoking was associated with a 60% increase in risk of both T1MI and T2MI. In addition, every cigarette smoked per day was associated with a 4% increase in risk of T1MI, with a suggestive, but not significant, 2% increase for T2MI. Cigarette use had a greater impact on T1MI for men than for women and on T2MI for women than for men. Increasing alcohol use was associated with a lower risk of T1MI but not T2MI. Frequency of heavy episodic alcohol use was not associated with MI. CONCLUSIONS: Our findings reinforce the prioritization of smoking reduction, even without cessation, and cessation among people living with HIV for MI prevention and highlight the different impacts on MI type by gender.

INTRODUCTION: The inositol polyphosphate-5-phosphatase D (INPP5D) gene encodes a dual-specificity phosphatase that can dephosphorylate both phospholipids and phosphoproteins. Single nucleotide polymorphisms in INPP5D impact risk for developing late onset sporadic Alzheimers disease (LOAD). METHODS: To assess the consequences of inducible Inpp5d knockdown in microglia of APPKM670/671NL /PSEN1Δexon9 (PSAPP) mice, we injected 3-month-old Inpp5dfl/fl /Cx3cr1CreER/+ and PSAPP/Inpp5dfl/fl /Cx3cr1CreER/+ mice with either tamoxifen (TAM) or corn oil (CO) to induce recombination. RESULTS: At age 6 months, we found that the percent area of 6E10+ deposits and plaque-associated microglia in Inpp5d knockdown mice were increased compared to controls. Spatial transcriptomics identified a plaque-specific expression profile that was extensively altered by Inpp5d knockdown. DISCUSSION: These results demonstrate that conditional Inpp5d downregulation in the PSAPP mouse increases plaque burden and recruitment of microglia to plaques. Spatial transcriptomics highlighted an extended gene expression signature associated with plaques and identified CST7 (cystatin F) as a novel marker of plaques. HIGHLIGHTS: Inpp5d knockdown increases plaque burden and plaque-associated microglia number. Spatial transcriptomics identifies an expanded plaque-specific gene expression profile. Plaque-induced gene expression is altered by Inpp5d knockdown in microglia. Our plaque-associated gene signature overlaps with human Alzheimers disease gene networks.

Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE3Aβ) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer's Disease (AD) cases, pE3Aβ represents a major constituent of the amyloid plaque. The data show that pE3Aβ formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pE3Aβ accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pE3Aβ3-11 fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in AdvaxCpG adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 105-106 against pE3Aβ and 103-104 against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease.

ObjectiveThe association of sex-specific hormones with coronary computed tomography angiography(CCTA)-based plaque characteristics in women without cardiovascular disease is not well understood. We investigated the association of sex-specific hormones with coronary artery plaque characteristics in a contemporary multiracial cohort with no clinical coronary artery disease (CAD).MethodsIn this cross-sectional analysis, we utilized data from 2,325 individuals with no clinical CAD from the Miami Heart (MiHeart) study. Multivariable logistic regression models were used to investigate the association of sex hormones: sex hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), free and total testosterone, estradiol, with plaque characteristics among women and men.ResultsOf the 1,155 women, 34.2% had any plaque and 3.4% had any high-risk plaque features (HRP) while among men (n = 1170), 63.1% had any plaque and 10.4% had HRP. Among women, estradiol and SHBG were associated with lower odds of any plaque after adjusting for age and race-ethnicity (estradiol OR per SD increase: 0.87, 95%CI: 0.76-0.98; SHBG OR per SD increase: 0.82, 95%CI: 0.72-0.93) but the significance did not persist after adjustment of cardiovascular risk factors. High free testosterone was associated with higher odds of HRP (aOR:3.48, 95%CI:1.07-11.26) but null associations for the other sex hormones with HRP, in the context of limited sample size. Among men, there were no significant associations between sex-specific hormones and plaque or HRP.ConclusionAmong young to middle-aged women with no clinical CAD, increasing estradiol and SHBG were associated with lower odds of any plaque and higher free testosterone was associated with HRP. Larger cohorts may be needed to validate this.

Introduction: Palmoplantar psoriasis (PP) is classified as nonpustular psoriasis (NPPP) or palmoplantar pustulosis (PPP). Objective: We sought to shed light on the phenotypic diversity of nail psoriasis (NP) and conducted a thorough study of the dermoscopic features of nail lesions from patients with NPPP and PPP. Methods: A prospective study included 35 patients with NPPP and 20 patients with PPP who had macroscopic NP changes in at least three of their nails. Demographic and clinical data, such as general characteristics, history, a thorough dermatological examination, and musculoskeletal assessment, were recorded. Each patient had their nails evaluated with video dermoscopy. The statistical analysis was carried out using SPSS software, including descriptive and analytical statistics. Results: Dermoscopic patterns of nail lesions in both groups differed from those seen in psoriasis vulgaris (PV). Trachyonychia was the most common dermoscopic pattern among NPPP patients. Nail bed pustules were found in 75% of the PPP patients, and they were the most common dermoscopic finding identifying PPP nail lesions. In comparison to the NPPP group, patients with PPP had a higher frequency of psoriatic arthritis (PsA) and higher PP and NP severity scores. In the PPP group, all patients with PsA had pustules. Conclusions: NP has a heterogeneous presentation and various clinical manifestations in NPPP, PPP, and PV. The differences in dermoscopic patterns of nail lesions among NPPP, PPP, and PV reflect the diseases' distinct characteristics. A thorough dermoscopic examination of the nails may reveal information about both the underlying pathophysiological pathways and the overall course of psoriasis.

BackgroundThe association between education and atherosclerotic cardiovascular disease (ASCVD) has been well described for decades. Nevertheless, most cardiovascular risk models, including SCORE2, still do not take educational status into account even if this factor is easily assessed and costs nothing to acquire. Using carotid plaques as a proxy for ASCVD, we analysed educational status as associated with carotid plaque development, to determine if the relationship remains, how it relates to traditional risk factors and, how it impacts the European cardiovascular risk model, SCORE2. Our study also provides further data on plaque development in a well-characterised population nearly equally weighted by gender.Methods9,083 subjects (51% female, 49% male) from the Paracelsus 10,000 cohort, underwent a carotid doppler duplex as part of thorough screening for subclinical ASCVD. Well over 90% of carotid doppler duplex examinations were performed by the same experienced clinician. Subjects were then classified by educational status using the Generalized International Standard Classification of Education. Plaque absence or presence was dichotomised and variables analysed using regression modelling to examine educational status relative to cardiovascular risk factors and with respect to the SCORE2 model.ResultsUsing medium educational status as a reference, subjects in our cohort with low educational status had higher odds, while subjects with high educational status had lower odds for carotid plaques compared to subjects with medium education (aOR 1.76 95%CI 1.50–2.06; and 0.0.63 95%CI 0.57–0.70, respectively). Even after adjusting for common risk factors including metabolic syndrome and SCORE2, the relationship was maintained. Furthermore, when comparing the potential predictive power of SCORE2 alone and plus educational status using the Akaike information criterion, we showed a ‘better fit’ when educational status was added.ConclusionsMeasuring educational status is cost-free and easy for clinicians to obtain. We believe cardiovascular risk prediction models such as SCORE2 may more accurately reflect individual risk if educational status is also taken into account. Additionally, we believe clinicians need to understand and appropriately address educational status as a risk factor, to better quantify individual risk and take appropriate measures to reduce risk so that the association may finally be broken.

BackgroundArtificial intelligence (AI) has increasingly been applied to computed tomography angiography (CTA) images to aid in the assessment of atherosclerotic plaque. Our aim was to explore the diagnostic accuracy of AI-assisted CTA for plaque diagnosis and classification through a systematic review and meta-analysis.MethodsA systematic literature review was performed by searching PubMed, EMBASE, and the Cochrane Library according to PRISMA guidelines. Original studies evaluating the diagnostic accuracy of radiomics, machine-learning, or deep-learning techniques applied to CTA images for detecting stenosis, calcification, or plaque vulnerability were included. The quality and risk of bias of the included studies were evaluated using the QUADAS-2 tool. The meta-analysis was conducted using STATA software (version 17.0) to pool sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC) to determine the overall diagnostic performance.ResultsA total of 11 studies comprising 1,484 patients were included. There was low risk of bias and substantial heterogeneity. The overall pooled AUROC for atherosclerotic plaque assessment was 0.96 [95% confidence interval (CI) 0.94–0.97] across 21 trials. Of these, for ≥50% stenosis detection, the AUROC was 0.95 (95% CI 0.93–0.96) in five studies. For identifying ≥70% stenosis, the AUROC was 0.96 (95% CI 0.94–0.97) in six studies. For calcium detection, the AUROC was 0.92 (95% CI 0.90–0.94) in six studies.ConclusionOur meta-analysis demonstrates that AI-assisted CTA has high diagnostic accuracy for detecting stenosis and characterizing plaque composition, with optimal performance in detecting ≥70% stenosis.Systematic Review Registrationhttps://www.crd.york.ac.uk/, PROSPERO, identifier (CRD42023431410).

Purpose: To describe a pilot study on the use of single-session, high-dose-rate, Food and Drug Administration–cleared, yttrium-90 (Y90) plaque brachytherapy for iris and iridociliary melanoma. Design: A single-center, clinical case series. Participants: Six consecutive patients were included in this study. Each was diagnosed with an iris or iridociliary melanoma based on clinical examination with or without biopsy. Methods: Each tumor was staged according to the American Joint Committee on Cancer criteria and received Y90 eye plaque brachytherapy. The main variables were tumor size, patient age, sex, and method of diagnosis (clinical or biopsy). Surgical techniques, treatment durations, and ocular side effects were recorded. Local control was defined as a lack of tumor growth or regression determined by clinical examinations, including slit-lamp and gonio photography, as well as high-frequency ultrasound measurements. Toxicity parameters included acute and short-term corneal/scleral change, anterior segment inflammation, and cataract progression. Main Outcome Measures: Local and systemic cancer control, tumor regression, visual acuity, as well as radiation-related normal tissue toxicity. Results: High-dose-rate Y90 plaque brachytherapy was used to treat small (American Joint Committee on Cancer cT1) category melanomas. Single-surgery high-dose-rate irradiations were performed under anesthesia. Because of short treatment durations, high-dose-rate Y90 did not require the additional procedures used for low-dose-rate plaque (e.g., sutures, amniotic membrane epicorneal buffering, Gunderson flaps, and second surgeries for plaque removal). Only conjunctival recession was used to avoid normal tissue irradiation. High-dose-rate Y90 treatment durations averaged 8.8 minutes (median, 7.9; range, 5.8–12.9). High-dose-rate Y90 brachytherapy was associated with no periorbital, corneal (Descemet folds), or conjunctival edema. There was no acute or short-term anterior uveitis, secondary cataract, scleropathy, radiation retinopathy, maculopathy, or optic neuropathy. The follow-up was a mean of 16.0 (range 12–24) months. Evidence of local control included a lack of expansion of tumor borders (n = 6, 100%), darkening with or without atrophy of the tumor surface (n = 5/6, 83%), and a mean 24.5% reduction in ultrasonographically measured tumor thickness. There were no cases of metastatic disease. Conclusions: High-dose-rate Y90 brachytherapy allowed for single-surgery, minimally invasive, outpatient irradiation of iris and iridociliary melanomas. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Vascular endothelial protein tyrosine phosphatase (VE-PTP) influences endothelial barrier function by regulating the activation of tyrosine kinase receptor Tie2. We determined whether this action is linked to the development of atherosclerosis by examining the influence of arterial shear stress on VE-PTP, Tie2 activation, plasma leakage, and atherogenesis. We found that exposure to high average shear stress led to downstream polarization and endocytosis of VE-PTP accompanied by Tie2 activation at cell junctions. In aortic regions with disturbed flow, VE-PTP was not redistributed away from Tie2. Endothelial cells exposed to high shear stress had greater Tie2 activation and less macromolecular permeability than regions with disturbed flow. Deleting endothelial VE-PTP in VE-PTPiECKO mice increased Tie2 activation and reduced plasma leakage in atheroprone regions. ApoE-/- mice bred with VE-PTPiECKO mice had less plasma leakage and fewer atheromas on a high-fat diet. Pharmacologic inhibition of VE-PTP by AKB-9785 had similar anti-atherogenic effects. Together, the findings identify VE-PTP as a novel target for suppression of atherosclerosis.

Coronary computed tomographic angiography (CCTA) is becoming the first-line investigation for establishing the presence of coronary artery disease and, with fractional flow reserve (FFRCT), its haemodynamic significance. In patients without significant epicardial obstruction, its role is either to rule out atherosclerosis or to detect subclinical plaque that should be monitored for plaque progression/regression following prevention therapy and provide risk classification. Ischaemic non-obstructive coronary arteries are also expected to be assessed by non-invasive imaging, including CCTA. In patients with significant epicardial obstruction, CCTA can assist in planning revascularisation by determining the disease complexity, vessel size, lesion length and tissue composition of the atherosclerotic plaque, as well as the best fluoroscopic viewing angle; it may also help in selecting adjunctive percutaneous devices (e.g., rotational atherectomy) and in determining the best landing zone for stents or bypass grafts.

In neurodegenerative diseases, proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations in situ. Here, we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid-binding dyes to identify six distinct different conformational strains in vitro, as well as amyloid-β (Aβ) deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in Aβ and tau deposits from Down syndrome, sporadic and familial Alzheimer's disease human brain slices. EMBER has in situ identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick's disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains.

BACKGROUND: Quantitative plaque assessment based on 3D magnetic resonance (MR) vessel wall imaging (VWI) has been shown to provide valuable numerical markers of the burden and risk of intracranial atherosclerotic disease (ICAD). However, plaque quantification is currently time-consuming and observer-dependent due to the demand for heavy manual effort. A VWI-dedicated automated processing pipeline (VWI-APP) is desirable. PURPOSE: To develop and evaluate a VWI-APP for end-to-end quantitative analysis of intracranial atherosclerotic plaque. METHODS: We retrospectively enrolled 91 subjects with ICAD (80 for pipeline development, 10 for an end-to-end pipeline evaluation, and 1 for demonstrating longitudinal plaque assessment) who had undergone VWI and MR angiography. In an end-to-end evaluation, diameter stenosis (DS), normalized wall index (NWI), remodeling ratio (RR), plaque wall contrast ratio (CR), and total plaque volume (TPV) were quantified at each culprit lesion using the developed VWI-APP and a computer-aided manual approach by a neuroradiologist, respectively. The time consumed in each quantification approach was recorded. Two-sided paired t-tests and intraclass correlation coefficient (ICC) were used to determine the difference and agreement in each plaque metric between VWI-APP and manual quantification approaches. RESULTS: There was no significant difference between VWI-APP and manual quantification in each plaque metric. The ICC was 0.890, 0.813, 0.827, 0.891, and 0.991 for DS, NWI, RR, CR, and TPV, respectively, suggesting good to excellent accuracy of the pipeline method in plaque quantification. Quantitative analysis of each culprit lesion on average took 675.7 s using the manual approach but shortened to 238.3 s with the aid of VWI-APP. CONCLUSIONS: VWI-APP is an accurate and efficient approach to intracranial atherosclerotic plaque quantification. Further clinical assessment of this automated tool is warranted to establish its utility in the risk assessment of ICAD lesions.

BackgroundImaging factors, specifically baseline plaque features on high-resolution magnetic resonance vessel wall imaging (HR-VWI) that could be associated with in-stent restenosis (ISR), are still unknown. We aimed to investigate the presenting clinical and plaque features on HR-VWI associated with ISR.MethodsSixty-four patients with intracranial stent placement for intracranial atherosclerotic stenosis who had pre- and post-contrast T1-weighted HR-VWI on 3.0T prior to stenting were included in this analysis. Student's t-test, Mann-Whitney U test, χ2 test, or the Cochran-Mantel-Haenszel (CMH) test were used to compare clinical and baseline HR-VWI characteristics of the patients between the ISR and non-ISR groups. Univariable and multivariable logistic analysis were used to test the clinical and imaging factors associated with ISR.ResultsAmong the 64 patients, 9 patients (14.06%) developed ISR during the 2-year follow-up period. Plaque burden (median 0.89 vs 0.92, P=0.04), minimum lumen area (0.009 cm2 vs 0.006 cm2, P=0.04), plaque eccentricity (55.6% vs 89.1%, P＜0.01), enhancement ratio (1.36 vs 0.84, P＜0.01), and enhancement involvement (type 2 represents ≥50% cross-sectional wall involvement; 100% vs 63.6%, P=0.03) all significantly differed between patients with and without ISR. Multivariable analysis revealed that lower frequency of plaque eccentricity (OR 0.18, 95% CI 0.04 to 0.96, P=0.04) and higher enhancement ratio (OR 3.57, 95% CI 1.02 to 12.48, P=0.04) were independently associated with ISR.ConclusionsPreliminary findings showed that ISR was independently associated with plaque concentricity and higher enhancement ratios on pre-stenting HR-VWI for patients with symptomatic intracranial atherosclerotic stenosis.

Abstract In 2018, SGS Belgium NV developed RSV-NICA (Respiratory Syncytial Virus-Nasobronchial Infective Challenge Agent), an RSV type A challenge agent for use in RSV Controlled Human Infection Model (CHIM) studies. It is widely recognized that the stability of RSV can be influenced by a variety of environmental parameters, such as temperature and pH. Consequently, our objective was to evaluate the stability of the viral titer of RSV-NICA following five years of controlled storage and to determine the uniformity of the viral titers across different vials of a GMP-qualified batch of RSV-NICA. In addition, we examined the capacity of RSV-NICA to infect human primary airway epithelial cells (MucilAir™), the principal target cells of RSV, and evaluated the influence of single and recurrent freeze–thaw cycles on the infectious viral titer of the challenge agent. The aliquoted RSV-NICA virus stock was subjected to standard virological and molecular methods to gather data on the titer and consistency of the viral titer contained within 24 representative vials of the stock. Our findings illustrate that over a span of five years of cryo-storage, the infectious viral titer in 75% of the tested vials exhibited a comparable average infectious viral titer (4.75 ± 0.06 vs 4.99 ± 0.11; p-value = 0.14). A considerable reduction down to an undetectable level of infectious virus was observed in the remaining vials. RSV-NICA demonstrated its capacity to effectively infect differentiated human airway epithelial cells, with active virus replication detected in these cells through increasing RSV genome copy number over time. Virus tropism for ciliated cells was suggested by the inhibition of cilia beating coupled with an increase in viral RNA titers. No discernable impact on membrane barrier function of the epithelial lung tissues nor cytotoxicity was detected. Pooling of vials with infectious titers > 4.0 log10 TCID50/ml and freeze-thawing of these combined vials showed no deterioration of the infectious titer. Furthermore, pooling and re-aliquoting of vials spanning the entire range of viral titers (including vials with undetectable infectious virus) along with subjecting the vials to three repeated freeze–thaw cycles did not result in a decrease of the infectious titers in the tested vials. Taken together, our findings indicate that long-term cryo-storage of vials containing RSV-NICA challenge agent may influence the infectious viral titer of the virus, leading to a decrease in the homogeneity of this titer throughout the challenge stock. However, our study also demonstrates that when heterogeneity of the infectious titer of an RSV stock is observed, rounds of pooling, re-aliquoting and subsequent re-titration serve as an effective method not only to restore the homogeneity of the infectious titer of an RSV-A stock, but also to optimize patient-safety, scientific and operational aspects of viral inoculation of study participants during at least the period of one RSV CHIM trial. RSV-NICA is a stable, suitable CHIM challenge agent that can be utilized in efficacy trials for RSV vaccines and antiviral entities.

The stainless-steel crown (SSC) is a durable restoration and has several indications for use in primary teeth such as following a pulpotomy/pulpectomy, fractured teeth, teeth with developmental defects, or large multi-surface caries lesions where amalgam is likely to fail. Due to its durability and a lifespan like the primary tooth, it could well be the gold standard in restorative care. SSCs protect the crown from fracture, reduce the possibility for leakage, and ensure a biological seal. However, the placement of the SSC should follow a meticulous technique. There are some clinical situations where the SSC may fail, leading to plaque accumulation and gingivitis. This could be secondary to improper crimping of crown margins, which lead to poorly adapted SSC. In some clinical situations, ledge formation under the crown or failure to clean excess cement can contact the gingiva and cause gingival inflammation. This study was carried out on 41 children between the ages of 4 and 10 in Al Qassim region to study the effects of SSCs on gingiva and oral hygiene. The study also aims to establish the correlation between SSC adaptation and post-insertion inflammation. The plaque and gingival index were recorded at 3 months’ post SSC insertion. Clinical examination was undertaken, and gingival index (Loe and Silness 1967) and plaque index (Silness and Loe 1967) were used to record gingival health and plaque accumulation, respectively. The result for post-inflammation and SSC adaptation showed that there was no statistically significant difference in post-insertion inflammation and crown adaptation (P value = 0.216). The result for pre-operative inflammation and post-operative inflammation shows that there is no significant difference in post-inflammation and adaptation (P value = 0.47). We found that oral hygiene care had a heightening effect and oral hygiene maintenance plays a key role in preventing gingival inflammation irrespective of the SSC adaptation over short periods of time (3 months).

Abstract Background Periodontitis is the most common oral disease in dogs, and its progression and severity are influenced by risk factors, such as age and body size. Recent studies have assessed the canine oral microbiota in relation to different stages of periodontitis and niches within the oral cavity. However, knowledge of the bacterial composition at different ages and body sizes, especially in puppies, is limited. This study aimed to characterize the oral microbiota in the healthy gingiva of small breed puppies using next-generation sequencing. Additionally, we assessed the impact of dental care practices and the presence of retained deciduous teeth on the oral microbiota. Results In this study, plaque samples were collected from the gingival margin of 20 small breed puppies (age, 6.9 ± 0.6 months). The plaque samples were subjected to next-generation sequencing targeting the V3-V4 region of the 16 S rRNA. The microbiota of the plaque samples was composed mostly of gram-negative bacteria, primarily Proteobacteria (54.12%), Bacteroidetes (28.79%), and Fusobacteria (5.11%). Moraxella sp. COT-017, Capnocytophaga cynodegmi COT-254, and Bergeyella zoohelcum COT-186 were abundant in the oral cavity of the puppies. In contrast, Neisseria animaloris were not detected. The high abundance of Pasteurellaceae suggests that this genus is characteristic of the oral microbiota in puppies. Dental care practices and the presence of retained deciduous teeth showed no effects on the oral microbiota. Conclusions In this study, many bacterial species previously reported to be detected in the normal oral cavity of adult dogs were also detected in 6–8-month-old small breed dogs. On the other hand, some bacterial species were not detected at all, while others were detected in high abundance. These data indicate that the oral microbiota of 6–8-month-old small breed dogs is in the process of maturating in to the adult microbiota and may also have characteristics of the small dog oral microbiota.

Abstract Objective This study aimed to examine the clinical and multimodal ultrasonic characteristics differences between carotid web (CW) and CW with plaque as well as the potential risk factors for stroke caused by CW. Methods We retrospectively enrolled patients diagnosed with CW by CTA or high-resolution MRI (HRMRI) and simultaneously underwent contrast enhanced ultrasound (CEUS) and superb microvascular imaging examinations from January 2015 to October 2022. The CW angle was measured using computer-aided software. The variations between CW and CW with plaque were evaluated, and univariable and multivariable logistic regressions were utilized to identify possible risk predictors for stroke caused by CW. Results Two hundred ninety-nine patients with an average age of 60.85 (± 8.77) years were included. Sex, age, history of smoking, alcohol, hypertension, diabetes mellitus, homocysteine level, and treatment, as well as web length and thickness, luminal stenosis, location wall, number, CW angle, and CEUS enhancement, were quite different among CW and CW with plaque patients (p

Background Orthodontic appliances hinder proper oral hygiene, leading to plaque retention and biofilm formation which can cause dental diseases. This study investigates the initial impact of orthodontic treatment with fixed appliances versus clear aligners on microbial profiles and gingival/plaque indices.Methods Nine patients were included in this small-scale prospective longitudinal pilot study – five in treatment with fixed appliances and four with clear aligners. Plaque biofilm samples were collected subgingivally, supragingivally and from clear aligner trays, and gingival and plaque indices were recorded at six timepoints over 3 months. DNA was extracted and next-generation 16S rRNA sequencing of the V4 region was performed.Results Fixed appliance patients showed higher plaque and gingival index scores early on (p ≤ 0.05) and higher levels of oral pathogens (p ≤ 0.05). Microbiological analysis revealed distinct microbial communities on clear aligner trays, with health- and disease-associated microbes present at significantly different levels (p ≤ 0.05) compared to intraoral plaque samples.Conclusions Patients undergoing orthodontic therapy with fixed appliances had higher levels of plaque retention and oral pathogens. Clear aligner patients’ had microbial profiles with more oral health-associated species and lower gingival/plaque indices. However, the biofilm on clear aligner trays requires further study, and the small sample size limits the conclusiveness of all findings.Implications Dentists may consider clear aligners as an alternative to fixed appliances, with potential benefits in plaque accumulation and oral microbial composition. All patients undergoing orthodontic therapy should practice good oral hygiene to prevent plaque retention and reduce oral pathogen colonization.

Purpose: Patients with conjunctival squamous cell carcinoma that present with persisting disease or recurrence following topical chemotherapy and/or surgery especially when invading the sclera are challenging to treat. Herein, we describe the use of high-dose-rate (HDR), FDA-cleared, yttrium-90 (90Y) plaque brachytherapy for such lesions. Observation: Three cases of invasive conjunctival squamous cell carcinoma that had exhibited a poor response or recurrence following topical chemotherapy and/or surgery are described. As treatment, HDR 90Y beta-radiation was applied to the tumor and margins for a single, continuous duration. In contrast to low-dose-rate (LDR) plaque, HDR 90Y brachytherapy did not require episcleral sutures, amniotic membrane buffering of the cornea, a Gunderson flap, outpatient dwell time, or second surgery. Radiation safety was improved by eliminating LDR-implant related post-operative radiation exposure to health care personnel, the community, family, and pets. Follow-up examination at one month revealed complete tumor resolution in all patients. At last follow-up (8, 11 and 18 months) all patients remained clinically tumor-free as confirmed by slit-lamp biomicroscopy, anterior segment optical coherence tomography, and high-frequency ultrasound imaging. There were no acute complications (e.g., corneal edema, iridocyclitis, scleropathy, keratopathy or cataract). Conclusion and Importance: 90Y brachytherapy demonstrated efficacy as a single-surgery, minimally invasive, outpatient irradiation for squamous carcinoma of the ocular surface. While short-term results were promising, long-term follow-up monitoring for side-effects and recurrence are essential.

BackgroundAmong people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein.MethodsREPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score.ResultsThe primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055).ConclusionsAmong US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015).

BACKGROUND: Alzheimers disease (AD) cases are often characterized by the pathological accumulation of α-synuclein (α-syn) in addition to amyloid-β (Aβ) and tau hallmarks. The role of α-syn has been extensively studied in synucleinopathy disorders, but less so in AD. Recent studies have shown that α-syn may also play a role in AD and its downregulation may be protective against the toxic effects of Aβ accumulation. OBJECTIVE: We hypothesized that selectively knocking down α-syn via RNA interference improves the neuropathological and biochemical findings in AD mice. METHODS: Here we used amyloid precursor protein transgenic (APP-Tg) mice to model AD and explore pathologic and behavioral phenotypes with knockdown of α-syn using RNA interference. We selectively reduced α-syn levels by stereotaxic bilateral injection of either LV-shRNA α-syn or LV-shRNA-luc (control) into the hippocampus of AD mice. RESULTS: We found that downregulation of α-syn results in significant reduction in the number of Aβ plaques. In addition, mice treated with LV-shRNA α-syn had amelioration of abnormal microglial activation (Iba1) and astrocytosis (GFAP) phenotypes in AD mice. CONCLUSION: Our data suggests a novel link between Aβ and α-syn pathology as well as a new therapeutic angle for targeting AD.

AIMS: Residual cardiovascular risk persists despite statin therapy. In REDUCE-IT, icosapent ethyl (IPE) reduced total events, but the mechanisms of benefit are not fully understood. EVAPORATE evaluated the effects of IPE on plaque characteristics by coronary computed tomography angiography (CCTA). Given the conclusion that the IPE-treated patients demonstrate that plaque burden decreases has already been published in the primary study analysis, we aimed to demonstrate whether the use of an analytic technique defined and validated in histological terms could extend the primary study in terms of whether such changes could be reliably seen in less time on drug, at the individual (rather than only at the cohort) level, or both, as neither of these were established by the primary study result. METHODS AND RESULTS: EVAPORATE randomized the patients to IPE 4 g/day or placebo. Plaque morphology, including lipid-rich necrotic core (LRNC), fibrous cap thickness, and intraplaque hemorrhage (IPH), was assessed using the ElucidVivo® (Elucid Bioimaging Inc.) on CCTA. The changes in plaque morphology between the treatment groups were analyzed. A neural network to predict treatment assignment was used to infer patient representation that encodes significant morphological changes. Fifty-five patients completed the 18-month visit in EVAPORATE with interpretable images at each of the three time points. The decrease of LRNC between the patients on IPE vs. placebo at 9 months (reduction of 2 mm3 vs. an increase of 41 mm3, p = 0.008), widening at 18 months (6 mm3 vs. 58 mm3 increase, p = 0.015) were observed. While not statistically significant on a univariable basis, reductions in wall thickness and increases in cap thickness motivated multivariable modeling on an individual patient basis. The per-patient response assessment was possible using a multivariable model of lipid-rich phenotype at the 9-month follow-up, p

Precise, scalable, and quantitative evaluation of whole slide images is crucial in neuropathology. We release a deep learning model for rapid object detection and precise information on the identification, locality, and counts of cored plaques and cerebral amyloid angiopathy (CAA). We trained this object detector using a repurposed image-tile dataset without any human-drawn bounding boxes. We evaluated the detector on a new manually-annotated dataset of whole slide images (WSIs) from three institutions, four staining procedures, and four human experts. The detector matched the cohort of neuropathology experts, achieving 0.64 (model) vs. 0.64 (cohort) average precision (AP) for cored plaques and 0.75 vs. 0.51 AP for CAAs at a 0.5 IOU threshold. It provided count and locality predictions that approximately correlated with gold-standard human CERAD-like WSI scoring (p = 0.07 ± 0.10). The openly-available model can quickly score WSIs in minutes without a GPU on a standard workstation.

The predictive ability of coronary heart disease (CHD) and ischemic stroke (IS) polygenic risk scores (PRS) have been evaluated individually, but whether they predict the combined outcome of atherosclerotic cardiovascular disease (ASCVD) remains insufficiently researched. It is also unclear whether associations of the CHD and IS PRS with ASCVD are independent of subclinical atherosclerosis measures. 7,286 White and 2,016 Black participants from the population-based Atherosclerosis Risk in Communities study who were free of cardiovascular disease and type 2 diabetes at baseline were included. We computed previously validated CHD and IS PRS consisting of 1,745,179 and 3,225,583 genetic variants, respectively. Cox proportional hazards models were used to test the association between each PRS and ASCVD, adjusting for traditional risk factors, ankle-brachial index, carotid intima media thickness, and carotid plaque. The hazard ratios (HR) for the CHD and IS PRS were significant with HR of 1.50 (95% CI: 1.36-1.66) and 1.31 (95% CI: 1.18-1.45) respectively for the risk of incident ASCVD per standard deviation increase in CHD and IS PRS among White participants after adjusting for traditional risk factors. The HR for the CHD PRS was not significant with an HR of 0.95 (95% CI: 0.79-1.13) for the risk of incident ASCVD in Black participants. The HR for the IS PRS was significant with an HR of 1.26 (95%CI: 1.05-1.51) for the risk of incident ASCVD in Black participants. The association of the CHD and IS PRS with ASCVD was not attenuated in White participants after adjustment for ankle-brachial index, carotid intima media thickness, and carotid plaque. The CHD and IS PRS do not cross-predict well, and predict better the outcome for which they were created than the composite ASCVD outcome. Thus, the use of the composite outcome of ASCVD may not be ideal for genetic risk prediction.

Despite the increasing demographic diversity of the United States' aging population, there remain significant gaps in post-mortem research investigating the ethnoracial heterogeneity in the neuropathological landscape of Alzheimer Disease (AD). Most autopsy-based studies have focused on cohorts of non-Hispanic White decedents (NHWD), with few studies including Hispanic decedents (HD). We aimed to characterize the neuropathologic landscape of AD in NHWD (n = 185) and HD (n = 92) evaluated in research programs across three institutions: University of California San Diego, University of California Davis, and Columbia University. Only persons with a neuropathologic diagnosis of intermediate/high AD determined by NIA Reagan and/or NIA-AA criteria were included. A frequency-balanced random sample without replacement was drawn from the NHWD group using a 2:1 age and sex matching scheme with HD. Four brain areas were evaluated: posterior hippocampus, frontal, temporal, and parietal cortices. Sections were stained with antibodies against Aβ (4G8) and phosphorylated tau (AT8). We compared the distribution and semi-quantitative densities for neurofibrillary tangles (NFTs), neuropil threads, core, diffuse, and neuritic plaques. All evaluations were conducted by an expert blinded to demographics and group status. Wilcoxon's two-sample test revealed higher levels of neuritic plaques in the frontal cortex (p = 0.02) and neuropil threads (p = 0.02) in HD, and higher levels of cored plaques in the temporal cortex in NHWD (p = 0.02). Results from ordinal logistic regression controlling for age, sex, and site of origin were similar. In other evaluated brain regions, semi-quantitative scores of plaques, tangles, and threads did not differ statistically between groups. Our results demonstrate HD may be disproportionately burdened by AD-related pathologies in select anatomic regions, particularly tau deposits. Further research is warranted to understand the contributions of demographic, genetic, and environmental factors to heterogeneous pathological presentations.

Purpose of reviewThe omega-3 fatty acids (n3-FAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have recently undergone testing for their ability to reduce residual cardiovascular (CV) risk among statin-treated subjects. The outcome trials have yielded highly inconsistent results, perhaps attributable to variations in dosage, formulation, and composition. In particular, CV trials using icosapent ethyl (IPE), a highly purified ethyl ester of EPA, reproducibly reduced CV events and progression of atherosclerosis compared with mixed EPA/DHA treatments. This review summarizes the mechanistic evidence for differences among n3-FAs on the development and manifestations of atherothrombotic disease.Recent findingsLarge randomized clinical trials with n3-FAs have produced discordant outcomes despite similar patient profiles, doses, and triglyceride (TG)-lowering effects. A large, randomized trial with IPE, a prescription EPA only formulation, showed robust reduction in CV events in statin treated patients in a manner proportional to achieved blood EPA concentrations. Multiple trials using mixed EPA/DHA formulations have not shown such benefits, despite similar TG lowering. These inconsistencies have inspired investigations into mechanistic differences among n3-FAs, as EPA and DHA have distinct membrane interactions, metabolic products, effects on cholesterol efflux, antioxidant properties, and tissue distribution. EPA maintains normal membrane cholesterol distribution, enhances endothelial function, and in combination with statins improves features implicated in plaque stability and reduces lipid content of plaques. Insights into reductions in residual CV risk have emerged from clinical trials using different formulations of n3-FAs. Among high-risk patients on contemporary care, mixed n3-FA formulations showed no reduction in CV events. The distinct benefits of IPE in multiple trials may arise from pleiotropic actions that correlate with on-treatment EPA levels beyond TG-lowering. These effects include altered platelet function, inflammation, cholesterol distribution, and endothelial dysfunction. Elucidating such mechanisms of vascular protection for EPA may lead to new interventions for atherosclerosis, a disease that continues to expand worldwide.

Radioiodinated imaging agents for Aβ amyloid plaque imaging in Alzheimer’s disease (AD) patients have not been actively pursued. Our previous studies employed the “diaza” derivatives [11C]TAZA and [18F]flotaza in order to develop successful positron emission tomography (PET) imaging agents for Aβ plaques. There is a need for radioiodinated imaging agents for Aβ plaques for single photon emission computed tomography (SPECT) and PET imaging. We report our findings on the preparation of [124/125I]IAZA, a “diaza” analog of [11C]TAZA and [18F]flotaza, and the evaluation of binding to Aβ plaques in the postmortem human AD brain. The binding affinity of IAZA for Aβ plaques was Ki = 10.9 nM with weak binding affinity for neurofibrillary tangles (Ki = 3.71 μM). Both [125I]IAZA and [124I]IAZA were produced in >25% radiochemical yield and >90% radiochemical purity. In vitro binding of [125I]IAZA and [124I]IAZA in postmortem human AD brains was higher in gray matter containing Aβ plaques compared to white matter (ratio of gray to white matter was >7). Anti-Aβ immunostaining strongly correlated with [124/125I]IAZA in postmortem AD human brains. The binding of [124/125I]IAZA in postmortem human AD brains was displaced by the known Aβ plaque imaging agents. Thus, radiolabeled [124/123I]IAZA may potentially be a useful PET or SPECT radioligand for Aβ plaques in brain imaging studies.

BackgroundThe TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current Trem2 R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2R47H NSS (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products.MethodsTrem2R47H NSS mice were treated with the demyelinating agent cuprizone, or crossed with the 5xFAD mouse model of amyloidosis, to explore the impact of the TREM2 R47H variant on inflammatory responses to demyelination, plaque development, and the brain's response to plaques.ResultsTrem2R47H NSS mice display an appropriate inflammatory response to cuprizone challenge, and do not recapitulate the null allele in terms of impeded inflammatory responses to demyelination. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in Trem2R47H NSS mice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygous Trem2R47H NSS (5xFAD/Trem2R47H NSS) mice have reduced size and number of microglia that display impaired interaction with plaques compared to microglia in age-matched 5xFAD hemizygous controls. This is associated with a suppressed inflammatory response but increased dystrophic neurites and axonal damage as measured by plasma neurofilament light chain (NfL) level. Homozygosity for Trem2R47H NSS suppressed LTP deficits and loss of presynaptic puncta caused by the 5xFAD transgene array in 4-month-old mice. At a more advanced (12-month-old) disease stage 5xFAD/Trem2R47H NSS mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Twelve-month old Trem2R47H NSS mice also display LTP deficits and postsynaptic loss.ConclusionsThe Trem2R47H NSS mouse is a valuable model that can be used to investigate age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function including its effects on plaque development, microglial-plaque interaction, production of a unique interferon signature and associated tissue damage.

BackgroundGenetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain.MethodsWe engineered a novel App knock-in mouse model (AppSAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous AppSAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays.ResultsLeveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The AppSAA knock-in mouse model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged.DiscussionOur findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology.

BackgroundThe complement system is part of the innate immune system that clears pathogens and cellular debris. In the healthy brain, complement influences neurodevelopment and neurogenesis, synaptic pruning, clearance of neuronal blebs, recruitment of phagocytes, and protects from pathogens. However, excessive downstream complement activation that leads to generation of C5a, and C5a engagement with its receptor C5aR1, instigates a feed-forward loop of inflammation, injury, and neuronal death, making C5aR1 a potential therapeutic target for neuroinflammatory disorders. C5aR1 ablation in the Arctic (Arc) model of Alzheimer's disease protects against cognitive decline and neuronal injury without altering amyloid plaque accumulation.MethodsTo elucidate the effects of C5a-C5aR1 signaling on AD pathology, we crossed Arc mice with a C5a-overexpressing mouse (ArcC5a+) and tested hippocampal memory. RNA-seq was performed on hippocampus and cortex from Arc, ArcC5aR1KO, and ArcC5a+ mice at 2.7-10 months and age-matched controls to assess mechanisms involved in each system. Immunohistochemistry was used to probe for protein markers of microglia and astrocytes activation states.ResultsArcC5a+ mice had accelerated cognitive decline compared to Arc. Deletion of C5ar1 delayed or prevented the expression of some, but not all, AD-associated genes in the hippocampus and a subset of pan-reactive and A1 reactive astrocyte genes, indicating a separation between genes induced by amyloid plaques alone and those influenced by C5a-C5aR1 signaling. Biological processes associated with AD and AD mouse models, including inflammatory signaling, microglial cell activation, and astrocyte migration, were delayed in the ArcC5aR1KO hippocampus. Interestingly, C5a overexpression also delayed the increase of some AD-, complement-, and astrocyte-associated genes, suggesting the possible involvement of neuroprotective C5aR2. However, these pathways were enhanced in older ArcC5a+ mice compared to Arc. Immunohistochemistry confirmed that C5a-C5aR1 modulation in Arc mice delayed the increase in CD11c-positive microglia, while not affecting other pan-reactive microglial or astrocyte markers.ConclusionC5a-C5aR1 signaling in AD largely exerts its effects by enhancing microglial activation pathways that accelerate disease progression. While C5a may have neuroprotective effects via C5aR2, engagement of C5a with C5aR1 is detrimental in AD models. These data support specific pharmacological inhibition of C5aR1 as a potential therapeutic strategy to treat AD.

Introduction: The CC chemokine ligand 18 (CCL18) is a chemokine highly expressed in chronic inflammation in humans. Recent observations of elevated CCL18 plasma levels in patients with acute cardiovascular syndromes prompted an investigation into the role of CCL18 in the pathogenesis of human and mouse atherosclerosis. Methods and results: CCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages. Repeated administration of CCL18 in Western-type diet--fed ApoE-/- mice or PCSK9mutoverexpressing wild type (WT) mice led to increased plaque burden, enriched in CD3+ T cells. In subsequent experimental and molecular modeling studies, we identified CCR6 as a functional receptor mediating CCL18 chemotaxis, intracellular Ca2+ flux, and downstream signaling in human Jurkat and mouse T cells. CCL18 failed to induce these effects in vitro in murine spleen T cells with CCR6 deficiency. The ability of CCR6 to act as CCL18 receptor was confirmed in vivo in an inflammation model, where subcutaneous CCL18 injection induced profound focal skin inflammation in WT but not in CCR6-/- mice. This inflammation featured edema and marked infiltration of various leukocyte subsets, including T cells with a Th17 signature, supporting CCR6's role as a Th17 chemotactic receptor. Notably, focal overexpression of CCL18 in plaques was associated with an increased presence of CCR6+ (T) cells. Discussion: Our studies are the first to identify the CCL18/CCR6 axis as a regulator of immune responses in advanced murine and human atherosclerosis. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to extract radiomic features from vertebrobasilar artery calcification (VBAC) on head computed tomography (CT) images and investigate its diagnostic performance to identify culprit lesions responsible for acute cerebral infarctions. Methods: Patients with intracranial atherosclerotic disease who underwent vessel wall MRI (VW-MRI) and head CT examinations from a single center were retrospectively assessed for VBAC visual and textural analyses. Each calcified plaque was classified by the likelihood of having caused an acute cerebral infarction identified on VW-MRI as culprit or non-culprit. A predefined set of texture features extracted from VBAC segmentation was assessed using the minimum redundancy and maximum relevance method. Five key features were selected to integrate as a radiomic model using logistic regression by the Aikaike Information Criteria. The diagnostic value of the radiomic model was calculated for discriminating culprit lesions over VBAC visual assessments. Results: A total of 1,218 radiomic features were extracted from 39 culprit and 50 non-culprit plaques, respectively. In the VBAC visual assessment, culprit plaques demonstrated more observed presence of multiple calcifications, spotty calcification, and intimal predominant calcification than non-culprit lesions (all p < 0.05). In the VBAC texture analysis, 55 (4.5%) of all extracted features were significantly different between culprit and non-culprit plaques (all p < 0.05). The radiomic model incorporating 5 selected features outperformed multiple calcifications [AUC = 0.81 with 95% confidence interval (CI) of 0.72, 0.90 vs. AUC = 0.61 with 95% CI of 0.49, 0.73; p = 0.001], intimal predominant calcification (AUC = 0.67 with 95% CI of 0.58, 0.76; p = 0.04) and spotty calcification (AUC = 0.62 with 95% CI of 0.52, 0.72; p = 0.005) in the identification of culprit lesions. Conclusion: Culprit plaques in the vertebrobasilar artery exhibit distinct calcification radiomic features compared to non-culprit plaques. CT texture analysis of VBAC has potential value in identifying lesions responsible for acute cerebral infarctions, which may be helpful for stroke risk stratification in clinical practice. [ABSTRACT FROM AUTHOR]

In 2018, SGS Belgium NV developed RSV-NICA (Respiratory Syncytial Virus-Nasobronchial Infective Challenge Agent), an RSV type A challenge agent for use in RSV Controlled Human Infection Model (CHIM) studies. It is widely recognized that the stability of RSV can be influenced by a variety of environmental parameters, such as temperature and pH. Consequently, our objective was to evaluate the stability of the viral titer of RSV-NICA following five years of controlled storage and to determine the uniformity of the viral titers across different vials of a GMP-qualified batch of RSV-NICA. In addition, we examined the capacity of RSV-NICA to infect human primary airway epithelial cells (MucilAir™), the principal target cells of RSV, and evaluated the influence of single and recurrent freeze–thaw cycles on the infectious viral titer of the challenge agent. The aliquoted RSV-NICA virus stock was subjected to standard virological and molecular methods to gather data on the titer and consistency of the viral titer contained within 24 representative vials of the stock. Our findings illustrate that over a span of five years of cryo-storage, the infectious viral titer in 75% of the tested vials exhibited a comparable average infectious viral titer (4.75 ± 0.06 vs 4.99 ± 0.11; p-value = 0.14). A considerable reduction down to an undetectable level of infectious virus was observed in the remaining vials. RSV-NICA demonstrated its capacity to effectively infect differentiated human airway epithelial cells, with active virus replication detected in these cells through increasing RSV genome copy number over time. Virus tropism for ciliated cells was suggested by the inhibition of cilia beating coupled with an increase in viral RNA titers. No discernable impact on membrane barrier function of the epithelial lung tissues nor cytotoxicity was detected. Pooling of vials with infectious titers > 4.0 log10 TCID50/ml and freeze-thawing of these combined vials showed no deterioration of the infectious titer. Furthermore, pooling and re-aliquoting of vials spanning the entire range of viral titers (including vials with undetectable infectious virus) along with subjecting the vials to three repeated freeze–thaw cycles did not result in a decrease of the infectious titers in the tested vials. Taken together, our findings indicate that long-term cryo-storage of vials containing RSV-NICA challenge agent may influence the infectious viral titer of the virus, leading to a decrease in the homogeneity of this titer throughout the challenge stock. However, our study also demonstrates that when heterogeneity of the infectious titer of an RSV stock is observed, rounds of pooling, re-aliquoting and subsequent re-titration serve as an effective method not only to restore the homogeneity of the infectious titer of an RSV-A stock, but also to optimize patient-safety, scientific and operational aspects of viral inoculation of study participants during at least the period of one RSV CHIM trial. RSV-NICA is a stable, suitable CHIM challenge agent that can be utilized in efficacy trials for RSV vaccines and antiviral entities. [ABSTRACT FROM AUTHOR]