Cloud Capacity Spectrum Method: Accounting for record-to-record variability in fragility analysis using nonlinear static procedures

This paper investigates a number of computational issues related to the use of nonlinear static procedures in fragility analysis of structures. Such approaches can be used to complement nonlinear dynamic procedures, reducing the computational and modelling effort. Specifically, this study assesses the performance of the Capacity Spectrum Method (CSM) with real (i.e. recorded) ground motions (as opposed to code-based conventional spectra) to explicitly account for record-to-record variability in fragility analysis. The study focuses on single-degree-of-freedom systems, providing a basis for future multi-degree-of-freedom system applications. A case-study database of 2160 inelastic oscillators is defined through parametric backbones with different elastic periods, (yield) base shear coefficients, values of the ductility capacity, hardening ratios, residual strength values and hysteresis rules. These case studies are analysed using 100 real ground motions. An efficient algorithm to perform the CSM with real spectra is proposed, combined with a cloud-based approach (Cloud-CSM) to derive fragility relationships. Simple criteria to solve the issue of multiple CSM solutions (i.e. two or more points on the backbone satisfying the CSM procedure) are proposed and tested. It is demonstrated that the performance point selection can be carried out based on a particularly efficient intensity measure detected via optimal intensity measure analysis. The effectiveness of the proposed Cloud-CSM in fragility analysis is discussed through extensive comparisons with nonlinear time-history analyses, the code-based N2 method, and a simple method involving an intensity measure as a direct proxy for the performance displacement. The Cloud-CSM provides errors lower than ±20% in predicting the median of the fragility curves in most of the analysed cases and outperforms the other considered methodologies in calculating the fragility dispersion

The GPIIIA PlA2 polymorphism is associated with an increased risk of cardiovascular adverse events

<p>Abstract</p> <p>Background</p> <p>The clinical impact of PlA2 polymorphism has been investigated in several diseases, but the definition of its specific role on thrombotic cardiovascular complications has been challenging. We aimed to explore the effect of PlA2 polymorphism on outcome in patients with atherosclerosis.</p> <p>Methods</p> <p>We studied 400 consecutive patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention. A replication study was conducted in 74 hypertensive patients with cerebrovascular events while a group of 100 healthy subjects was included as control population. PlA genotype was determined by PCR-RFLP on genomic DNA from peripheral blood cells. Major adverse cardiac events (MACE), were considered as end points, and recorded at a mean follow up of 24 ± 4.3 months.</p> <p>Results</p> <p>The frequencies of PlA2 polymorphism was similar between groups and genotype distribution was in Hardy-Weinberg equilibrium. In patients with CAD, the presence of PlA2 allele was associated with higher incidence of cardiac death (13.1% vs. 1.5%, p = 0.0001), myocardial infarction (10.7% vs. 2.6%, p = 0.004) and needs of new revascularization (34.8% vs. 17.7%, p = 0.010). Accordingly, the Kaplan-Meier analysis for event free survival in patients harboring the PlA2 allele showed worse long-term outcome for these patients (p = 0.015). Cox regression analysis identified the presence of PlA2 as an independent predictor of cardiac death (OR: 9.594, 95% CI: 2.6 to 35.3, p = 0.002) and overall MACE (OR: 1.829, 95% CI: 1.054 to 3.176, p = 0.032). In the replication study, the PlA2 polymorphism increased the risk of stroke (OR: 4.1, 95% CI: 1.63-12.4, p = 0.02) over TIA and was identified as an independent risk factor for stroke (B:-1.39; Wald: 7.15; p = 0.001).</p> <p>Conclusions</p> <p>Our study demonstrates that in patients with severe atherosclerosis the presence of PlA2 allele is associated with thrombotic cardiovascular complications.</p

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

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Nobori biolimus-eluting stent vs. permanent polymer drug-eluting stents in patients undergoing percutaneous coronary intervention

Permanent polymer coatings on drug-eluting stents (DES) surface have been identified as triggers of adverse events following percutaneous coronary intervention (PCI). However, efficacy and safety data for the Nobori biolimus-eluting stent (BES), a biodegradable polymer DES, are limited, so the aim of this study was to evaluate clinical outcomes associated with the Nobori BES compared with permanent polymer DES in patients undergoing PCI

Early stent thrombosis with bivalirudin in patients undergoing percutaneous coronary intervention: A meta-analysis of randomised clinical trials

Although bivalirudin has been shown to reduce bleeding events in patients undergoing percutaneous coronary intervention, residual concerns remain about a possible higher risk of early (within 30 days) stent thrombosis (ST). Therefore, we performed a meta-analysis of randomised trials reporting ST events with bivalirudin compared to other antithrombotic therapies (heparins ± glycoprotein IIb/IIIa inhibitors). A systematic literature search of electronic resources was performed through May, 2014. The primary endpoint was definite early ST, according to Academic Research Consortium criteria. Secondary endpoints included: all-cause death, myocardial infarction and major bleeding. A total of 11 trials, including 16,415 patients, were accrued. Compared to other regimens, bivalirudin significantly increased the risk of early ST (odds ratio [OR]=1.80; 95% confidence interval [CI], 1.28-2.52; p=0.0007) and reduced the risk of major bleeding (OR [95%CI]=0.64 [0.51-0.82], p=0.0003), with a comparable risk ofmortality or myocardial infarction. The higher risk of early ST was mainly attributable to acute (OR [95% CI] =4.33 [2.33-8.05], p &lt; 0.001) than subacute (OR [95% CI] =0.89 [0.53-1.50], p =0.67) ST events (p for interaction &lt; 0.001). Non-fatal myocardial infarction was the most common presentation (83%) of early ST events, while death occurred infrequently (about 5%). In conclusion, in patients undergoing PCI, bivalirudin compared to heparins is associated with a higher risk of early ST, which is mainly related to more frequent acute events. Further studies are required to evaluate alternative strategies to mitigate this risk, without hampering the benefits derived from the reduction in bleeding events with bivalirudin

Melatonin is associated with reverse remodeling after cardiac resynchronization therapy in patients with heart failure and ventricular dyssynchrony

Background Cardiac resynchronization therapy (CRT) is an effective treatment for left ventricular reverse remodeling (LVRR) in patients with congestive heart failure (HF) and ventricular dyssynchrony. Melatonin is a secretory product of the pineal gland with highly beneficial effects from any tissues including the heart. Herein, we investigated whether the response to CRT is associated with levels of melatonin before CRT implantation in patients with HF and ventricular dyssynchrony. Methods Diurnal melatonin levels were performed in serum from 93 patients with HF and ventricular dyssynchrony before CRT implantation. Moreover, we calculated the MADIT-CRT score. Evaluation of patients at 1-year follow-up included an echocardiographic study since the patients were categorized as responders if they presented both a reduction in left ventricular end-systolic volume index > 10% and an increase in left ventricular ejection fraction > 10%. Results At 1-year, 34 patients (36.5%) were considered responders to CRT according to the predefined criteria. The diurnal melatonin levels were significantly lower in the non-responder group (9.9 ± 2.84 vs 14.7 ± 2.32 pg/mL). After adjustment by multivariate analysis, diurnal serum melatonin levels (P < 0.001) and diabetes mellitus (P = 0.03) were predictors of LVRR. On Cox regression analysis, diurnal serum melatonin levels (P < 0.001) and left atrial volume < 40 mL/m2 (P = 0.04) remained independent predictors of the adverse clinical events. The area under of curve for the prediction LVRR of melatonin (0.91, 95%CI 0.85–0.97; P < 0.001) was significantly higher compared to MADIT-CRT score (0.69, 95%CI 0.58–0.80; P = 0.002). Conclusion Diurnal levels of melatonin before CRT implantation are associated with LVRR at 12 month follow-up

Biological Rhythm and Chronotype: New Perspectives in Health

The circadian rhythm plays a fundamental role in regulating biological functions, including sleep–wake preference, body temperature, hormonal secretion, food intake, and cognitive and physical performance. Alterations in circadian rhythm can lead to chronic disease and impaired sleep. The circadian rhythmicity in human beings is represented by a complex phenotype. Indeed, over a 24-h period, a person’s preferred time to be more active or to sleep can be expressed in the concept of morningness–eveningness. Three chronotypes are distinguished: Morning, Neither, and Evening-types. Interindividual differences in chronotypes need to be considered to reduce the negative effects of circadian disruptions on health. In the present review, we examine the bi-directional influences of the rest–activity circadian rhythm and sleep–wake cycle in chronic pathologies and disorders. We analyze the concept and the main characteristics of the three chronotypes

Meta-analysis of randomized trials comparing the effectiveness of different strategies for the treatment of drug-eluting stent restenosis

The investigators performed a network meta-analysis of randomized trials comparing the effectiveness of currently available strategies for the treatment of drug-eluting stent (DES) restenosis. Despite the widespread use of DES in patients who undergo percutaneous coronary intervention, the optimal treatment for DES restenosis remains poorly defined. A systematic search of electronic resources was performed. The primary end point was diameter stenosis at follow-up angiography. Seven trials were included, enrolling a total of 1,586 patients with 1,728 restenotic lesions. The following treatment options were found: balloon angioplasty (BA) in 343 patients (19.3%), iopromide-based paclitaxel-eluting balloons (PEB) in 343 (21.6%), sirolimus-eluting stents in 441 (27.8%), paclitaxel-eluting stents in 462 (29.1%), and everolimus-eluting stents in 34 (2.2%). Compared with BA, PEB (-17.74%, 95% credible interval [CI] -25.17% to -11.31%), everolimus-eluting stents (-14.93%, 95% CI -33.47% to 1.16%), paclitaxel-eluting stents (-15.3%, 95% CI -22.96% to -8.35%), and sirolimus-eluting stents (-11.08%, 95% CI -17.89% to -3.4%) had similar reductions in diameter stenosis at follow-up angiography. PEB (85%) and everolimus-eluting stents (68%) had the greatest probabilities for being the best treatment option. Furthermore, PEB were the best treatment in terms of late luminal loss (85%) and binary restenosis (85%). BA had the lowest efficacy with respect to all study end points. In conclusion, in patients with DES restenosis, repeat DES implantation and iopromide-based PEB are valid alternatives. However, PEB had greater angiographic efficacy and therefore should be considered the new benchmark comparator in the treatment of DES restenosis. The use of BA should be discouraged in patients with DES restenosis