Virtual Prototyping for validation of functional architectures

International audienceThis paper will present a new approach how to use virtual prototyping to validate functional architectures. The approach points out how functional architecture can be set up and tested in order to get highly validated data before making final architectural/design decisions. The introduction will speak about the current facts, the constrains and the tendencies to create a common and understandable picture in which the proposed solution may be implemented. Then we will give a description and definition of MiLMiL / SiLSiL / HiL, rapid prototyping and virtual prototyping to avoid confusion. The main part will discuss functional and logical architecture, the mapping of both as well a the variants that have to be considered. It will be shown how validation by virtual prototyping can help to define and proof architectural decision. Finally we will give a short outlook on how to migrate from virtual prototyping systems via rapid prototyping via fullpass and bypass to HiL applications. The conclusion summarizes the advantages compared to the current situation

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Searches for Neutrinos from Gamma-Ray Bursts using the IceCube Neutrino Observatory

Gamma-ray bursts (GRBs) are considered as promising sources of ultra-high-energy cosmic rays (UHECRs) due to their large power output. Observing a neutrino flux from GRBs would offer evidence that GRBs are hadronic accelerators of UHECRs. Previous IceCube analyses, which primarily focused on neutrinos arriving in temporal coincidence with the prompt gamma rays, found no significant neutrino excess. The four analyses presented in this paper extend the region of interest to 14 days before and after the prompt phase, including generic extended time windows and targeted precursor searches. GRBs were selected between May 2011 and October 2018 to align with the data set of candidate muon-neutrino events observed by IceCube. No evidence of correlation between neutrino events and GRBs was found in these analyses. Limits are set to constrain the contribution of the cosmic GRB population to the diffuse astrophysical neutrino flux observed by IceCube. Prompt neutrino emission from GRBs is limited to $\lesssim$1% of the observed diffuse neutrino flux, and emission on timescales up to $10^4$ s is constrained to 24% of the total diffuse flux

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

FLAMSA reduced-intensity conditioning is equally effective in AML patients with primary induction failure as well as in first or second complete remission

Reduced-intensity conditioning regimens have demonstrated lower toxicity but increased relapse rates in the context of allogeneic hematopoietic stem cell transplantation (aSCT) for patients with acute myelogenous leukemia (AML). The FLAMSA- reduced-intensity conditioning (RIC) regimen, combining a cytoreductive and a transplant-conditioning part, has been described to be efficacious in patients with refractory disease. We retrospectively analyzed clinical data of 130 patients with AML after aSCT following FLAMSA RIC at our center. The median follow-up was 37 (10-125) months. The 4-yr overall and disease-free survival rates of the whole cohort were 45% and 40%. Cumulative incidence of relapse was 29%, 35%, and 40% at 1, 2, and 4yr. There were no significant differences regarding overall and disease-free survival for patients transplanted in CR1, CR2, or primary induction failure (PIF). Patients with refractory disease after salvage therapy had significantly lower disease-free and overall survival (OS). Disease-free and OS rates were also significantly decreased in patients with 10% or more BLASTS at transplant. non-relapse mortality was 15%, 19%, and 20% at 1, 2, and 4yr and similar in all cohorts. These data underscore the potency of the FLAMSA RIC regimen for patients with AML especially with PIF. The decision for re-induction therapy prior to aSCT in relapsed patients has to be weighed against the potential toxicity of this approach and might be influenced by the amount of leukemic BLASTS present. Only randomised trials will answer this important question

Relative incidence of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome in clinically suspected cases of thrombotic microangiopathy

Background. Data are lacking on the relative incidence of thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC) and atypical HUS (aHUS) in patients presenting with thrombotic microangiopathies (TMAs). Methods. This was a prospective, cross-sectional, multicentre and non-interventional epidemiological study. Patients fulfilling criteria for TMAs (platelet consumption, microangiopathic haemolytic anaemia and organ dysfunction) were included in the study. The primary objective was to assess the relative incidence of TTP, STEC-HUS, aHUS and 'other' physician-defined diagnoses. The secondary objective was to develop an algorithm to predict a severe deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (<= 10%) using routine laboratory parameters. A post hoc classification using the recent Kidney Disease: Improving Global Outcomes diagnostic criteria was then undertaken to further classify patient groups. Results. aHUS was diagnosed with a relative incidence of 61%, whereas TTP, STEC-HUS and 'other' were diagnosed in 13, 6 and 20% of patients, respectively. In the post hoc analysis, 27% of patients with a TMA were classified as 'primary aHUS' and 53% as 'secondary aHUS'. Multivariate analysis revealed that severe deficiency in ADAMTS13 activity (<= 10%) was unlikely to underlie TMA if platelet and serum creatinine were above threshold values of 30 x 10(9)/L and 1.8 mg/dL, respectively (negative predictive value of 92.3 and 98.1, respectively, if one or both values were above the threshold). Conclusions. In this study, aHUS was the most common single diagnosis among patients presenting with a TMA. In the absence of an ADAMTS13 activity result, platelet count and serum creatinine may aid in the differential diagnosis