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Contains fulltext : 286832.pdf (Publisher’s version ) (Open Access) BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [

Objective: To compare and validate the calculated LDL values from Friedewald and Anandaraja formulas with directly measured values in the Indian population. Material and Methods: The study was conducted on randomly selected 102 individuals of 16 to 88 years of age during December 2019. The direct LDL values were measured using selective solubilization assay, and Friedewald and Anandaraja formulas were used to calculate LDL for comparison. The correlations between direct and calculated methods were assessed using the linear regression method. Receiver operating characteristic analysis with nonparametric distribution was used to compare the sensitivity and specificity of the three methods. Results: The average LDL of direct method, 107.3 mg/dL, Friedewald formula, 89.7 mg/dL, and Anandaraja was 99.0 mg/dL. The relation between direct and calculated values assessed by linear regression showed 97% and 87% of correlation with Friedewald and Anandaraja, respectively. The ROC analysis inferred that direct (AUC 0.74; 95% CI 0.64-0.83) and Friedewald (AUC 0.71; 95% CI 0.61-0.81) methods had shown about 70% efficiency in predicting true positive and true negative dyslipidemia cases. In our dataset, the Anandaraja formula could not well differentiate positives from negative cases of dyslipidemia with merely 60% AUC. Conclusion: The underpredicted values from the Friedewald formula were associated with deranged cholesterol and HDL values, not triglycerides. Anandaraja formula overpredicted by 10 to 30 mg/dL when triglycerides were 140 mg/dL.

Chronic inflammatory diseases such as psoriasis is associated with high systemic inflammation and elevated sub-clinical coronary disease. High-sensitivity troponin T (hs-cTnT) is a marker of acute myocardial ischemia and indicates myocardial injury. Previously, the presence of high-risk coronary

Eumycetoma due to Madurella mycetomatis is of worldwide occurrence. It usually presents with signs of tumefaction, sinuses and grains which are the hallmarks in diagnosis of the disease. The present case was an eight year old boy admitted with moderate swelling of the forearm with a discharging sinus. The swelling had developed over a four month period. He gave history of trauma one year back to the site. He also had fever for two months. Imaging studies showed large cystic lesions in the bone. On surgical exploration it was observed that a large mass of compacted black grains (5cm X4cm) was filling the space between the radius and ulna bones. A mycological examination of the black grains revealed fungal hyphae and culture showed growth of Madurella mycetomatis. An extensive surgical debridement and voriconazole treatment for 6 weeks relieved the clinical symptoms but there was little radiological improvement. This case represents a rare presentation of mycetoma with a rapid progression of the disease over a few months, not commonly seen with eumycotic agents. The young age of the patient and the site were unusual findings. The external signs were mild and disproportionate to the extensively destructive disease seen underneath. These findings highlight the importance of an early diagnosis to prevent the devastation caused by this relentless infection which may be especially challenging in cases like this which present with unusual features.

Rationale: Costimulatory molecules, including the CD40–CD154 and CD80/86–CD28 dyads, play a prominent role in regulating inflammation in the adaptive immune response. Studies from our group and others suggest a potentially important role for these costimulatory cascades in innate immunity as well. Objectives: To determine the role of CD80/86 alone and in combination with CD40 in lethal polymicrobial sepsis in mice and humans. Methods: The murine cecal ligation and puncture (CLP) model was used to determine the role of CD80/86 alone and in combination with CD40 using wild-type mice, CD80/86−/− mice, and novel CD40/80/86−/− mice. Expression of cell-bound and soluble costimulatory molecules was assessed in humans via ELISA and flow cytometry. Measurements and Main Results: Lethal CLP was associated with up-regulation of CD40 and CD80/86 and their respective ligands CD28 and CD154 on innate effector cells. Blockade or deletion of CD80/86 attenuated mortality and inflammatory cytokine production during CLP. CD40/80/86−/− mice exhibited further reductions in mortality, lung injury, and inflammatory cytokine production compared with CD80/86−/− mice. Finally, humans with sepsis had increased monocyte expression of CD40 and CD80 compared with healthy control subjects; with higher levels in subjects requiring vasopressor support. Levels of soluble CD28 and CD154 were significantly higher in patients who died compared with those who lived. Conclusions: These data demonstrate a central role for CD40 and CD80/86 in the innate immune response and suggest that combined inhibition of CD40 and CD80/86 may improve mortality in sepsis. Expression of costimulatory molecules may serve as biomarkers for outcome in septic patients.

Axon pathfinding and target recognition are highly dynamic and tightly regulated cellular processes. One of the mechanisms involved in regulating protein activity levels during axonal and synaptic development is protein ubiquitination. We describe here the isolation of several Caenorhabditis elegans mutants, termed eno (ectopic/erratic neurite outgrowth) mutants, that display defects in axon outgrowth of specific neuron classes. One retrieved mutant is characterized by abnormal termination of axon outgrowth in a subset of several distinct neuron classes, including ventral nerve cord motor neurons, head motor neurons, and mechanosensory neurons. This mutant is allelic to lin-23, which codes for an F-box-containing component of an SCF E3 ubiquitin ligase complex that was previously shown to negatively regulate postembryonic cell divisions. We demonstrate that LIN-23 is a broadly expressed cytoplasmically localized protein that is required autonomously in neurons to affect axon outgrowth. Our newly isolated allele of lin-23, a point mutation in the C-terminal tail of the protein, displays axonal outgrowth defects similar to those observed in null alleles of this gene, but does not display defects in cell cycle regulation. We have thus defined separable activities of LIN-23 in two distinct processes, cell cycle control and axon patterning. We propose that LIN-23 targets distinct substrates for ubiquitination within each process.

Background: Small dense LDL particle (sdLDL-p) is now recognized as an important predictor of ACS events. CCTA-derived coronary plaque burden is a reliable marker of subclinical atherosclerosis. The systemic inflammatory state in Psoriasis (PSO) is associated with high CVD risk and lipoprotein

Background: Visceral adipose tissue (VAT) has been linked to increased cardiovascular (CV) risk. Furthermore, there is limited data on how anthropometric measures and known markers of cardiometabolic disease (CMD) relate to the presence of VAT. Therefore, the aim of this study was to define how CMD biomarkers relate to directly-quantified volume-based measures of VAT using computed tomography (CT) scan measurements in a well-phenotyped sample of patients from an ongoing cohort study of inflammation and CMD. Methods and Results: We evaluated the relationship between directly measured VAT, anthropometric measures [body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR)] and CMD biomarkers [lipoproteins, lipoprotein particle size, high sensitivity C-reactive protein (hsCRP), insulin resistance markers] in a longitudinal study of CV risk predictors in chronic inflammation (NCT: NCT01778569). Patients underwent blood testing and CT to measure the sum of visceral adipose tissue between the diaphragm and the inferior border of the urinary bladder (slice 50-150 SumVAT) during a single baseline visit in 2012-2013 (N=42), resulting in a validated, volume-based measurement of VAT. Linear regression modeling was used to understand the relationship between VAT, anthropometric measures and CMD biomarkers. Those with higher levels of visceral adiposity were more likely to be male (p=0.05) and have higher BMI. Adjusting for age, sex, race, physical activity, smoking, and CV risk factors, HDL, hsCRP, insulin, and HOMA-IR were independent predictors of 50-150 SumVAT (Table). Conclusions: Markers of lipid metabolism, inflammation, and insulin resistance serve as independent predictors of visceral adiposity and may be useful surrogates to estimate VAT when volume-based CT measures are not possible. Therefore, these biomarkers may be used to evaluate cardio-metabolic risk in areas with limited access to imaging for defining visceral adiposity, particularly community-based settings.

Lupus (SLE) patients are fifty times more likely to experience a cardiovascular event compared to age- and sex-matched controls. High levels of oxidized HDL (oxHDL) in SLE patients may contribute to this association. Under normal conditions, unoxidized HDL induces an anti-inflammatory response within macrophages (MØ). We addressed whether lupus oxHDL modifies this response and putative mechanisms associated with enhanced inflammation. Methods: Affymetrix gene expression analysis was performed on control MØs exposed to control or lupus HDL before an LPS challenge. Confirmation at the mRNA and protein level was performed. Signaling pathways involved in gene induction abnormalities were explored using molecular approaches. Results: MØs exposed to SLE HDL up-regulate IL-6, IL-12B and TNF-α at the mRNA and protein levels, compared to MØs exposed to healthy HDL. SLE HDL showed impaired induction of ATF3 mRNA and nuclear translocation. ATF3 activity was restored when the oxHDL binding protein LOX-1 receptor was inhibited with blocking antibodies. SLE HDL also showed a decrease activation of kinases upstream of ATF3 activation. Conclusion: Lupus HDL induces inflammatory responses in macrophages which may promote phenotypic proatherogenic changes and increase cardiovascular risk in this disease. Modifying the HDL proteome in SLE may decrease this risk.

Objective: To investigate whether changes in the cerebral cortex exhibit similar distribution patterns in both disorders of Down's syndrome and Alzheimer's disease, we performed a comparative neuropathologic study of patients with these disorders to further clarify the possible relationships between these dementing conditions. Design: The regional and laminar distribution and density of neurofibrillary tangles and senile plaques were analyzed in the cerebral cortex of a series of 16 patients (aged 6 to 74 years) with Down's syndrome and in 10 elderly individuals with Alzheimer's disease. Results: Quantitative analyses revealed that the time course of neurofibrillary tangle formation in Down's syndrome displays regional patterns comparable with those observed in aging and Alzheimer's disease with layer II of the entorhinal cortex being affected first in Down's syndrome, followed by the hippocampus proper and neocortex. The oldest patients with Down's syndrome had neurofibrillary tangle densities sometimes higher than in patients with Alzheimer's disease. At variance with Alzheimer's disease, amyloid deposition was widespread in all of the cortical areas investigated and was observed much earlier than neurofibrillary tangle formation. Patients with Down's syndrome also frequently had higher senile plaque densities than patients with Alzheimer's dis Conclusions: These results indicate that the development of pathologic changes in patients with Down's syndrome does not parallel that observed in elderly individuals and patients with Alzheimer's disease in all respects. However, the comparable development patterns of neurofibrillary tangle formation suggest that detailed analysis of patients with Down's syndrome may be useful to further our knowledge of the mechanisms underlying the installation of the neuropathologic alterations leading to the demonstrated loss of select neuronal populations in Alzheimer's disease.