The current landscape of imaging recommendations in cardiovascular clinical guidelines: toward an imaging-guided precision medicine

The purpose of this article is to provide an overview on the role of CT scan and MRI according to selected guidelines by the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA). ESC and ACC/AHA guidelines were systematically reviewed for recommendations to CT and MRI use in specific cardiovascular (CV) clinical categories. All recommendations were collected in a dataset, including the class of recommendation, the level of evidence (LOE), the specific imaging technique, the clinical purpose of the recommendation and the recommending Society. Among the 43 included guidelines (ESC: n = 18, ACC/AHA: n = 25), 26 (60.4%) contained recommendations for CT scan or MRI (146 recommendations: 62 for CT and 84 for MRI). Class of recommendation IIa (32.9%) was the most represented, followed by I (28.1%), IIb (24%) and III (11.9%). MRI recommendations more frequently being of higher class (I: 36.9%, IIa: 29.8%, IIb: 21.4%, III: 11.9%) as compared to CT (I: 16.1%, IIa: 37.1%, IIb: 27.4%, III: 19.4%). Most of recommendation (55.5%) were based on expert opinion (LOE C). The use of cardiac CT and cardiac MR in the risk assessment, diagnosis, therapeutic and procedural planning is in continuous development, driven by an increasing need to evolve toward an imaging-guided precision medicine, combined with cost-effectiveness and healthcare sustainability. These developments must be accompanied by an increased availability of high-performance scanners in healthcare facilities and should emphasize the need of increasing the number of radiologists fully trained in cardiac imaging

Role of toll-like receptors in actuating stem/progenitor cell repair mechanisms: Different functions in different cells

Toll-like receptors (TLRs) represent one of the bridges that regulate the cross-talk between the innate and adaptive immune systems. TLRs interact with molecules shared and preserved by the pathogens of origin but also with endogenous molecules (damage/danger-associated molecular patterns (DAMPs)) that derive from injured tissues. This is probably why TLRs have been found to be expressed on several kinds of stem/progenitor cells (SCs). In these cells, the role of TLRs in the regulation of the basal motility, proliferation, differentiation processes, self-renewal, and immunomodulation has been demonstrated. In this review, we analyze the many different functions that the TLRs assume in SCs, pointing out that they can have different effects, depending on the background and on the kind of ligands that they recognize. Moreover, we discuss the TLR involvement in the response of SC to specific tissue damage and in the reparative processes, as well as how the identification of molecules mediating the differential function of TLR signaling could be decisive for the development of new therapeutic strategies. Considering the available studies on TLRs in SCs, here we address the importance of TLRs in sensing an injury by stem/progenitor cells and in determining their behavior and reparative activity, which is dependent on the conditions. Therefore, it could be conceivable that SCs employed in therapy could be potentially exposed to TLR ligands, which might modulate their therapeutic potential in vivo. In this context, to modulate SC proliferation, survival, migration, and differentiation in the pathological environment, we need to better understand the mechanisms of action of TLRs on SCs and learn how to control these receptors and their downstream pathways in a precise way. In this manner, in the future, cell therapy could be improved and made safer

An economic evaluation for the use of decompressive craniectomy in the treatment of refractory traumatic intracranial hypertension

Objectives : The management of intracranial hypertension is a primary concern following traumatic brain injury. Data from recent randomized controlled trials have indicated that decompressive craniectomy results in some improved clinical outcomes compared to medical treatment for patients with refractory intracranial hypertension post-traumatic brain injury (TBI). This economic evaluation aims to assess the cost-effectiveness of decompressive craniectomy as a last-tier intervention for refractory intracranial hypertension from the perspective of the National Health Service (NHS). Methods: A Markov model was used to present the results from an international, multicentre, parallel-group, superiority, randomized trial. A cost-utility analysis was then carried out over a 1-year time horizon, measuring benefits in quality adjusted life years (QALYs) and costs in pound sterling. Results: The cost-utility analysis produced an incremental cost-effectiveness ratio (ICER) of £96,155.67 per QALY. This means that for every additional QALY gained by treating patients with decompressive craniectomy, a cost of £96,155.67 is incurred to the NHS. Conclusions: The ICER calculated is above the National Institute for Health and Care Excellence (NICE) threshold of £30,000 per QALY. This indicates that decompressive craniectomy is not a cost-effective first treatment option for refractory intracranial hypertension and maximum medical management is preferable initially

Intelligent non-colorimetric indicators for the perishable supply chain by non-wovens with photo-programmed thermal response

Spoiled perishable products, such as food and drugs exposed to inappropriate temperature, cause million illnesses every year. Risks range from intoxication due to pathogen-contaminated edibles, to suboptimal potency of temperature-sensitive vaccines. High-performance and low-cost indicators are needed, based on conformable materials whose properties change continuously and irreversibly depending on the experienced time-temperature profile. However, these systems can be limited by unclear reading, especially for colour-blind people, and are often difficult to be encoded with a tailored response to detect excess temperature over varying temporal profiles. Here we report on optically-programmed, non-colorimetric indicators based on nano-textured non-wovens encoded by their cross-linking degree. This combination allows a desired time-temperature response to be achieved, to address different perishable products. The devices operate by visual contrast with ambient light, which is explained by backscattering calculations for the complex fibrous material. Optical nanomaterials with photo-encoded thermal properties might establish new design rules for intelligent labels

De novo mutations in regulatory elements in neurodevelopmental disorders

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordWe previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.Health Innovation Challenge FundWellcome TrustUK Department of HealthWellcome Trust Sanger Institut

Electrospun ZnO/Poly(Vinylidene fluoride-trifluoroethylene) scaffolds for lung tissue engineering

Due to the morbidity and lethality of pulmonary diseases, new biomaterials and scaffolds are needed to support the regeneration of lung tissues, while ideally providing protective effects against inflammation and microbial aggression. In this study, we investigated the potential of nanocomposites of poly(vinylidene fluoride-co-trifluoroethylene) [P(VDF-TrFE)] incorporating zinc oxide (ZnO), in the form of electrospun fiber meshes for lung tissue engineering. We focused on their anti-inflammatory, antimicrobial, and mechanoelectrical character according to different fiber mesh textures (i.e., collected at 500 and 4000 rpm) and compositions: (0/100) and (20/80) w/w% ZnO/P(VDF-TrFE), plain and composite, respectively. The scaffolds were characterized in terms of morphological, physicochemical, mechanical, and piezoelectric properties, as well as biological response of A549 alveolar epithelial cells in presence of lung-infecting bacteria. By virtue of ZnO, the composite scaffolds showed a strong anti-inflammatory response in A549 cells, as demonstrated by a significant decrease of interleukin (IL) IL-1a, IL-6, and IL-8 expression in 6 h. In all the scaffold types, but remarkably in the aligned composite ones, transforming growth factor b (TGF-b) and the antimicrobial peptide human b defensin-2 (HBD-2) were significantly increased. The ZnO/P(VDF-TrFE) electrospun fiber meshes hindered the biofilm formation by Staphylococcus aureus and Pseudomonas aeruginosa and the cell/scaffold constructs were able to impede S. aureus adhesion and S. aureus and P. aeruginosa invasiveness, independent of the scaffold type. The data obtained suggested that the composite scaffolds showed potential for tunable mechanical properties, in the range of alveolar walls and fibers. Finally, we also showed good piezoelectricity, which is a feature found in elastic and collagen fibers, the main extracellular matrix molecules in lungs. The combination of all these properties makes ZnO/P(VDF-TrFE) fiber meshes promising for lung repair and regeneration

Genetic variants in the NOTCH4 gene influence the clinical features of migraine

BACKGROUND: Recent studies suggested an important role for vascular factors in migraine etiopathogenesis. Notch4 belongs to a family of transmembrane receptors that play an important role in vascular development and maintenance. The aim of this study was to test the hypothesis that polymorphisms of the NOTCH4 gene would modify the occurrence and the clinical features of migraine. FINDINGS: Using a case–control strategy, we genotyped 239 migraine patients and 264 controls for three different non-synonymous polymorphisms (T320A, G835V, R1346P) of the NOTCH4 gene and for the (CTG) n-encoding polyleucine polymorphism in exon 1. Although the analyzed polymorphisms resulted not associated with migraine, the clinical characteristics of our patients were significantly influenced by the different NOTCH4 genotypes. Longer duration of disease and severity of neurovegetative symptoms during headache attacks were associated with the R1346P and G835V polymorphisms, respectively. In female patients, worsening of migraine symptoms at menarche was significantly correlated with T320A polymorphism. CONCLUSIONS: Our study shows that genetic variations within the NOTCH4 gene significantly modify the clinical characteristics of migraine and may have a role in disease pathogenesis