Aortic stenting in the growing sheep causes aortic endothelial dysfunction but not hypertension: Clinical implications for coarctation repair

Stent implantation is the treatment of choice for adolescents and adults with aortic coarctation (CoAo). Despite excellent short-term results, 20%-40% of the patients develop arterial hypertension later in life, which was attributed to inappropriate response of the aortic baroreceptors to increased stiffness of the ascending aorta (ASAO), either congenital or induced by CoAo repair. In particular, it has been hypothesized that stent itself may cause or sustain hypertension. Therefore, we aimed to study the hemodynamic and structural impact following stent implantation in the normal aorta of a growing animal

Multicomponent Synthesis of Polyphenols and Their In Vitro Evaluation as Potential \u3b2-Amyloid Aggregation Inhibitors

While plant polyphenols possess a variety of biological properties, exploration of chemical diversity around them is still problematic. Here, an example of application of the Ugi multicomponent reaction to the combinatorial assembly of artificial, yet \u201cnatural-like\u201d, polyphenols is presented. The synthesized compounds represent a second-generation library directed to the inhibition of \u3b2-amyloid protein aggregation. Chiral enantiopure compounds, and polyphenol-\u3b2-lactam hybrids have been prepared too. The biochemical assays have highlighted the importance of the key pharmacophores in these compounds. A lead for inhibition of aggregation of truncated protein A\u3b2pE3-42 was selected

Giant Aneurysm of the Right Atrial Appendage in a 39-Year-Old Woman

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Evidence from Family Studies for Autoimmunity in Arrhythmogenic Right Ventricular Cardiomyopathy: Associations of Circulating Anti-Heart and Anti-Intercalated Disk Autoantibodies with Disease Severity and Family History

Background: Serum anti-heart autoantibodies (AHA) and anti-intercalated disk autoantibodies (AIDA) are autoimmune markers in myocarditis. In arrhythmogenic right ventricular cardiomyopathy (ARVC) myocarditis has been reported. To provide evidence for autoimmunity, we searched for AHA and AIDA in ARVC. Methods: We studied: 42 ARVC probands, 23 male, aged 42, interquartile range (IQR) 33;49, 20 from familial and 22 non-familial pedigrees; 37 clinically affected relatives (AR), 24 male aged 35, IQR 18;46; 96 healthy relatives (HR), 49 male, aged 27, IQR 17;45. Serum AHA and AIDA were tested by indirect immunofluorescence on human myocardium and skeletal muscle in 171 of the 175 ARVC individuals and in controls with: non-inflammatory cardiac disease (NICD) (n=160), ischemic heart failure (IHF) (n=141), normal blood donors (NBD) (n=270). Screening of five desmosomal genes was performed in probands; when a sequence variant was identified, cascade family screening followed, blind to immunological results. Results: AHA frequency was higher (36.8%) in probands, AR (37.8%) and HR (25%) than in NICD (1%), IHF (1%) or NBD (2.5%) (p=0.0001). AIDA frequency was higher in probands (8%, p=0.006), in AR (21.6%, p=0.00001) and in HR (14.6% p=0.00001) than in NICD (3.75%), IHF (2%) or NBD (0.3%). AHA positive status was associated with higher frequency of palpitation (p=0.004), ICD implantation (p=0.021), lower left ventricular ejection fraction (LVEF) (p=0.004), AIDA positive status with both lower RV and LVEF (p=0.027 and p=0.027 respectively). AHA and/or AIDA positive status in the proband and/or at least one of the respective relatives was more common in familial (17/20, 85%) than in sporadic (10/22, 45%) pedigrees (p=0.007). Conclusions: Presence of AHA and AIDA provides evidence of autoimmunity in the majority of familial and in almost half of sporadic ARVC. In probands and in AR these antibodies were associated with disease severity features; longitudinal studies are needed to clarify whether they may predict ARVC development in HR or if they be a result of manifest ARVC

The prognostic value of peripheral blood inflammatory indices early variation in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with nivolumab (Δ-Meet-URO analysis)

Background: Immunotherapy has improved the treatment landscape of mRCC pts and identifying biomarkers for patients’ selection is clinically needed. Inflammatory indices from peripheral blood showed a prognostic value in different tumors and therapies, including immunotherapy. These biomarkers are inexpensive and readily available in clinical practice. We aimed to assess the prognostic role of the dynamic evaluation of these indices in immunotherapy-naïve pretreated mRCC pts. Methods: The Meet-URO 15 multicentric retrospective study enrolled 571 pretreated mRCC pts receiving nivolumab. The Δ-Meet-URO was a secondary analysis on the early variation through the first four cycles of therapy compared with baseline (difference, delta - Δ) of white blood cells, platelets and inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, platelets x NLR), their comparison with baseline values and correlation with treatment response, overall (OS) and progression-free survival (PFS). The baseline and Δ cut-offs were identified by ROC curves for OS. Results: The analysis was performed on 422 mRCC pts (74% of the entire cohort). Patients with ΔNeutrophils < 730 at 2nd, 3rd and 4th cycles were more responders (p < 0.001, p = 0.003 and p < 0.001) with longer mPFS (11 vs 6.1 months, p = 0.033) and mOS (46.9 vs 20.8 months, p = 0.046) compared to ΔNeutrophils ≥ 730. There was a significant interaction between baseline and ΔNeutrophils on PFS (p = 0.047). Pts with baseline neutrophils ≥ 4330/mm3 had longer mPFS when ΔNeutrophils < 730 (p = 0.002), whilst no difference was observed in those pts with baseline neutrophils < 4330/mm3 according to ΔNeutrophils (p = 0.46). Similar non-significant trends were observed in mOS. Patients with ΔNLR < 0.5 at 3rd and 4th cycles were more responders (p = 0.004 and p = 0.001, respectively) with doubled mPFS (12.1 vs 6.4 months, p = 0.007) and mOS (46.9 vs 21.7 months, p = 0.062) compared to ΔNLR ≥ 0.5. No significant interaction between baseline NLR and ΔNLR was observed in PFS and OS, suggesting a similar association between ΔNLR and PFS or OS, regardless of the baseline NLR cut-off of 3.2. The multivariable analyses confirmed all these results. Conclusions: The early assessment of NLR and neutrophils variations during immunotherapy for mRCC pts is a promising, affordable and non-invasive prognostic tool. Prospective and external validation analyses are warranted

Causative classification of river flood events

A wide variety of processes controls the time of occurrence, duration, extent, and severity of river floods. Classifying flood events by their causative processes may assist in enhancing the accuracy of local and regional flood frequency estimates and support the detection and interpretation of any changes in flood occurrence and magnitudes. This paper provides a critical review of existing causative classifications of instrumental and preinstrumental series of flood events, discusses their validity and applications, and identifies opportunities for moving toward more comprehensive approaches. So far no unified definition of causative mechanisms of flood events exists. Existing frameworks for classification of instrumental and preinstrumental series of flood events adopt different perspectives: hydroclimatic (large‐scale circulation patterns and atmospheric state at the time of the event), hydrological (catchment scale precipitation patterns and antecedent catchment state), and hydrograph‐based (indirectly considering generating mechanisms through their effects on hydrograph characteristics). All of these approaches intend to capture the flood generating mechanisms and are useful for characterizing the flood processes at various spatial and temporal scales. However, uncertainty analyses with respect to indicators, classification methods, and data to assess the robustness of the classification are rarely performed which limits the transferability across different geographic regions. It is argued that more rigorous testing is needed. There are opportunities for extending classification methods to include indicators of space–time dynamics of rainfall, antecedent wetness, and routing effects, which will make the classification schemes even more useful for understanding and estimating floods

Missense mutations in Desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro

<p>Abstract</p> <p>Background</p> <p>Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement.</p> <p>We screened 54 ARVC probands for mutations in desmocollin-2 (<it>DSC2</it>), the only desmocollin isoform expressed in cardiac tissue.</p> <p>Methods</p> <p>Mutation screening was performed by denaturing high-performance liquid chromatography and direct sequencing.</p> <p>To evaluate the pathogenic potentials of the <it>DSC2 </it>mutations detected in patients affected with ARVC, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to obtain a fusion protein with green fluorescence protein (GFP); constructs were transfected in neonatal rat cardiomyocytes and in HL-1 cells.</p> <p>Results</p> <p>We identified two heterozygous mutations (c.304G>A (p.E102K) and c.1034T>C (p.I345T)) in two probands and in four family members. The two mutations p.E102K and p.I345T map to the N-terminal region, relevant to adhesive interactions.</p> <p>In vitro functional studies demonstrated that, unlike wild-type DSC2, the two N-terminal mutants are predominantly localised in the cytoplasm.</p> <p>Conclusion</p> <p>The two missense mutations in the N-terminal domain affect the normal localisation of DSC2, thus suggesting the potential pathogenic effect of the reported mutations. Identification of additional DSC2 mutations associated with ARVC may result in increased diagnostic accuracy with implications for genetic counseling.</p

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19