Reduction of Vascular Inflammation, LDL-C, or Both for the Protection from Cardiovascular Events?

Background: Low density lipoprotein cholesterol (LDL-C) and low grade arterial inflammation are key pathogenic factors for atherosclerosis and its manifestation, cardiovascular disease (CVD). Objective: In this narrative review we assessed if decreasing LDL-C levels or inflammation or both is more effective in reducing CVD events. Results: In the Scandinavian Simvastatin Survival Study (4S), all statin trials of the 90s’ and the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) the benefit came from the LDL-C reduction. In the GREak and Atorvastatin Coronary heart disease Evaluation (GREACE), the Treating to New Targets (TNT), and the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trials both mechanisms in combination produced significant benefits. In the Atorvastatin for Reduction of MYocardial Damage during Angioplasty (ARMYDA) trials and the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) with a human antibody targeting IL-1β with no lipid lowering effect, the reduction in arterial inflammation played the only beneficial role because there was no change in lipids levels. Conclusion: Both LDL-C and inflammation reduction are beneficial to the reduction of CVD risk. However, canakinumab is a very expensive drug that only induced a 15% reduction in CVD events, thus drastically reducing the possibility for it to be used in clinical practice. Besides, canakinumab is associated with increased infections, some fatal. A potent statin with anti-inflammatory effects is probably the best choice for the majority of those needing hypolipidaemic drug therapy

Impact of Orthodontic Forces on Plasma Levels of Markers of Bone Turnover and Inflammation in a Rat Model of Buccal Expansion.

Plasma levels of protein analytes might be markers to predict and monitor the kinetics of bone and tissue remodeling, including maximization of orthodontic treatment stability. They could help predict/prevent and/or diagnose possible adverse effects such as bone dehiscences, gingival recession, or root resorption. The objective of this study was to measure plasma levels of markers of bone turnover and inflammation during orthodontic force application in a rat model of orthodontic expansion. Two different orthodontic forces for bilateral buccal expansion of the maxillary arches around second and third molars were applied in 10 rats equally distributed in low-force (LF) or conventional force (CF) groups. Four rats served as the control group. Blood samples were collected at days 0, 1, 2, 3, 6, 13, 21, and 58. Longitudinal concentrations of osteoprotegerin (OPG), soluble receptor activator of nuclear factor kappaB ligand (sRANKL), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor α (TNF), and parathyroid hormone (PTH) were determined in blood samples by a multiplex immunoassay. CF and LF resulted in a significantly maxillary skeletal expansion while the CF group demonstrated significantly higher expansion than the LF group in the long term. Bone turnover demonstrated a two-phase response. During the "early phase" (up to 6 days of force application), LF resulted in more sRANKL expression and increased sRANKL/OPG ratio than the CF and control animals. There was a parallel increase in PTH levels in the early phase in response to LF. During the "late phase" (6-58 days), the markers of bone turnover were stable in both groups. IL-4, IL-6, and IL-10 levels did not significantly change the test groups throughout the study. These results suggest that maxillary expansion in response to different orthodontic forces follows different phases of bone turnover that may be force specific

Cognitively-inspired Agent-based Service Composition for Mobile & Pervasive Computing

Automatic service composition in mobile and pervasive computing faces many challenges due to the complex and highly dynamic nature of the environment. Common approaches consider service composition as a decision problem whose solution is usually addressed from optimization perspectives which are not feasible in practice due to the intractability of the problem, limited computational resources of smart devices, service host's mobility, and time constraints to tailor composition plans. Thus, our main contribution is the development of a cognitively-inspired agent-based service composition model focused on bounded rationality rather than optimality, which allows the system to compensate for limited resources by selectively filtering out continuous streams of data. Our approach exhibits features such as distributedness, modularity, emergent global functionality, and robustness, which endow it with capabilities to perform decentralized service composition by orchestrating manifold service providers and conflicting goals from multiple users. The evaluation of our approach shows promising results when compared against state-of-the-art service composition models.Comment: This paper will appear on AIMS'19 (International Conference on Artificial Intelligence and Mobile Services) on June 2

Advanced trauma life support course for medical students. A new era?

IntroductionTrauma represents a major public health issue and is one of the leading causes of death and disability worldwide. A systematic approach toward dealing with trauma patients was facilitated through the ATLS program, which has become a milestone in trauma care. Our new ATLS course for medical students was set in motion in 2015. Our aim was to make medical students familiar with trauma patients interactively, through a program like ATLS, and here we present the results of this endeavor.MethodsA two-day ATLS-Medical Student (MS) course was offered from November 2015 to July 2018, and analysis was performed retrospectively on the data gathered over a three-month period through online questionnaires. Before graduating, 261 newly qualified medical doctors were interviewed and evaluated as part of the ATLS course.ResultsAfter the course, the vast majority of medical students (251 MSs; 96.16%) felt more capable of managing severely injured patients and 58% of students felt that the medical services they offered were better due to the ATLS training. Regarding the educational fee for the course, 56.7% of the students reported that they felt the fee of 100 euros was fair.DiscussionThe interactive format of the course, which differs from more traditional methods of teaching, has been endorsed by medical students. Though they lack clinical experience, that does not prohibit them from acquiring more specialized or specific knowledge, enabling them to excel. Most of the students improved their skillset either in theoretical knowledge, practical skills, or even in the emotional component of the course, i.e., dealing with treating a severely injured patient. It was decided that the program would be re-evaluated and extended to all Greek Medical Schools.ConclusionThe advantage of providing doctors with trauma training at the beginning of their careers is evident. For that reason, it was decided that the program would be re-evaluated and extended to all Greek Medical Schools

Cytokines and Inflammatory Mediators [30-39]: 30. The LPS Stimulated Production of Interleukin-10 is not Associated with -819C/T and -592C/A Promoter Polymorphisms in Healthy Indian Subjects

Background: Interleukin-10 is a pivotal immunoregulatory cytokine with pleiotropic effects on the immune system. IL-10 promoter polymorphisms have been associated with disease susceptibility and the ability to secrete IL-10 in vitro. We suspected that the association of the widely studied -819C/T and -592C/A polymorphisms with the IL-10 production might vary between ethnic groups. Therefore, we examined the association of -819 C/T and -592 C/A promoter polymorphisms with in vitro LPS stimulated secretion of IL-10 in normal healthy Indian volunteers. Methods: Peripheral blood was collected from 103 healthy volunteers and diluted whole blood cultures were set up with 100 ng/ml of LPS as stimulant: supernatant was collected at 24 h and IL-10 levels were assayed by ELISA. Genotyping was done for -819C/T polymorphism in 101 individuals and -592C/A polymorphism in 68 individuals by polymerase chain reaction followed by RFLP. The differences in IL-10 production between the genotypes were analysed by ANOVA. Results: There were 30, 47 and 24 individuals with the CC, CT and TT genotypes with a minor allele (T) frequency of 47% for the -819C/T polymorphism. The CC and TT genotypes at position -819 were strongly associated with CC and AA genotypes at -592 position suggestive of strong linkage disequilibrium. There was no association between the -819 genotype and the in vitro LPS stimulated IL-10 levels. Conclusions: The -819C/T and the -592 C/A polymorphisms of the IL-10 promoter region are not significantly associated with LPS stimulated IL-10 production healthy Indian subjects. Disclosure statement: All authors have declared no conflicts of interes

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Event reconstruction for KM3NeT/ORCA using convolutional neural networks

The KM3NeT research infrastructure is currently under construction at two locations in the Mediterranean Sea. The KM3NeT/ORCA water-Cherenkov neutrino detector off the French coast will instrument several megatons of seawater with photosensors. Its main objective is the determination of the neutrino mass ordering. This work aims at demonstrating the general applicability of deep convolutional neural networks to neutrino telescopes, using simulated datasets for the KM3NeT/ORCA detector as an example. To this end, the networks are employed to achieve reconstruction and classification tasks that constitute an alternative to the analysis pipeline presented for KM3NeT/ORCA in the KM3NeT Letter of Intent. They are used to infer event reconstruction estimates for the energy, the direction, and the interaction point of incident neutrinos. The spatial distribution of Cherenkov light generated by charged particles induced in neutrino interactions is classified as shower- or track-like, and the main background processes associated with the detection of atmospheric neutrinos are recognized. Performance comparisons to machine-learning classification and maximum-likelihood reconstruction algorithms previously developed for KM3NeT/ORCA are provided. It is shown that this application of deep convolutional neural networks to simulated datasets for a large-volume neutrino telescope yields competitive reconstruction results and performance improvements with respect to classical approaches