Steelcase (United States)

Drug-induced cardiotoxicity represents one of the most common causes of attrition of drug candidates in preclinical and clinical development. For this reason, the evaluation of cardiac toxicity is essential during drug development and regulatory review. In the present study, drug-induced postmarket adverse event combinations from the FDA Adverse Event Reporting System were extracted for 2002 drugs using 243 cardiac toxicity-related preferred terms (PTs). These PTs were combined into 12 groups based on their clinical relevance to serve as training sets. The optimal classification scheme was determined using a combination of data sources that included drug labeling information, published literature, clinical study data, and postmarket surveillance data. Two commercial QSAR platforms were used to construct 12 models, including general cardiac toxicity, cardiac ischemia, heart failure, cardiac valve disease, myocardial disease, pericardial disease, structural heart disease, cardiac arrhythmia, Torsades de Pointes, long QT syndrome, atrial fibrillation and ventricular arrhythmia, and cardiac arrest. The cross-validated performance for the new models reached a sensitivity of up to 80% and negative predictivity of up to 80%. These new models covering a wide range of cardiac endpoints will provide fast, reliable, and comprehensive predictions of potential cardiotoxic compounds in drug discovery and regulatory safety assessment.

Background:Ibrutinib has showed to improve Progression Free Survival (PFS) and Overall Survival (OS) in patients with Chronic Lymphocytic Leukemia (CLL) maintaining a good tolerability profile. Moreover a good tolerability profile was showed in previously published data.Aims:Within the Rete Ematologica Pugliese (REP) seven hematologic centers verified the safety and the efficacy of Ibrutinib as a single agent treatment. Response rate, PFS and OS have been evaluated in all treated patients and in poor cytogenetic risk groups.Methods:One hundred twenty‐two patients from seven hematologic centers of REP were enrolled in the study. Ibrutinib was administred as salvage therapy across different lines as reported: 2nd line n = 75 (61%) (BR n = 48, FCR n = 24, other n = 3); 3rd line n = 35 (28,7%); 4th line n = 12 (8,2%). All patients received Ibrutinib 420 mg once daily until progression or unacceptable toxicity. PFS, OS and Overall Response Rate (ORR) were calculated. Kaplan Meier method was used to estimate PFS/OS and differences in survival times between groups were assessed with a log‐rank test.Results:Patients have a median age of 65 years (range: 28‐84), 50% of them had more than 65 yrs. Cytogenetic FISH was performed in 66% of patients (n = 80). No abnormalities were found in 31% of patients (n = 25): while del17p, del13q, del11q and trisomy12 were found in n = 33, n = 13, n = 3 and n = 6 of patients, respectively. Unmutated and mutated IgVH status was performed in 73 patients (60%); of these, 46(63%) patients had unmutated and 27 (37%) had mutated IgVH.Overall, ORR was achieved in 94 patients (77%) (complete response [CR] was reached in 10%) of patients). In the subgroup having a del17p ORR was achieved in 21 (61%) patients. Median of follow up time is 17 months (range 1‐45). The estimated PFS at 30 months was 66,7% from the entire study population. Patients with del17p displayed a median PFS of 39 months while it was not reached in patients having no history of cytogenetic abnormalities (Figure 2). Median OS was not reached from all treated patients and the estimated OS at 30 months was 72.7%, while no difference in terms of OS was found when patients with and without del17p were compared (81.7% vs 90.2%), (overall logrank p = 0.807) (Figure 4).Out of all treated patients, 47% of them showed the following adverse events (AEs) with grade ≥3: neutropenia (16%), hypertension (12%), atrial fibrillation (3%), anemia (3%), diarrhea (2%).Summary/Conclusion:In REP real‐world experience, treatment for R/R CLL patients with Ibrutinib as a single agent demonstred to be effective across negative and positive cytogenetic groups and to be well tolerated. AES did not result in treatment interruptions in the most of cases. In fact, over a median follow up of 17 months, 80% of patients remain on Ibrutinib‐treatment. Clearly, these results will require longer follow up time to be further confirmed.image

With the common goal of producing higher quality systems at lower costs,model-driven engineering (MDE) is becoming an integral part of all areas and disciplines related to Software Engineering. Far from the initial role of (UML) models as mere sketches of the structure of software systems, models have become primary artefacts in most software engineering activities, ranging from specification and design to analysis and synthesis of applications, including also deployment, testing, and maintenance of software systems. In addition to models, MDE elements such as domain-specific languages, model transformations, and metamodelling are now part of any MDE practitioner’s toolkit, indispensable for leveraging the potential advantages that MDE brings to the software industry. Although significant advances have happened around MDE during the past 10years, the ever-increasing complexity and cost of developing new kinds of applications, together with the stronger requirements on the systems being developed, impose new challenges on the discipline as well as open areas for dedicated research. With the goal of advancing in the field ofMDE, the “European Conference on Modelling: Foundations and Applications” (ECMFA) started in 2005, first as the “European Conference on Model Driven Architecture—Foundations and Applications” (EC-MDA) and since 2010 using its current name and acronym. ECMFA has become the premier Euro-

Isoniazid preventive therapy is effective in reducing the risk of tuberculosis (TB) in persons living with HIV (PLWH); however, screening must exclude TB disease before initiating therapy. Symptom screening alone may be insufficient to exclude TB disease in PLWH because some PLWH with TB disease have no symptoms. The addition of chest radiography (CXR) may improve disease detection. The objective of the present analysis was to compare the costs and effects of the addition of CXR to the symptom screening process against the costs and effects of symptom screening alone. Using data from Botswana, a decision analytic model was used to compare a "Symptom only" policy against a "Symptom+CXR" policy. The outcomes of interest were cost, death, and isoniazid- and multidrug-resistant TB in a hypothetical cohort of 10,000 PLWH. The Symptom+CXR policy prevented 16 isoniazid- and 0.3 multidrug-resistant TB cases; however, because of attrition from the screening process, there were 98 excess cases of TB, 15 excess deaths, and an additional cost of U.S. $127,100. The Symptom+CXR policy reduced deaths only if attrition was close to zero; however, to eliminate attrition the cost would be U.S. $2.8 million per death averted. These findings did not change in best- and worst-case scenario analyses. In Botswana, a policy with symptom screening only preceding isoniazid-preventive therapy initiation prevents more TB and TB-related deaths, and uses fewer resources, than a policy that uses both CXR and symptom screening.