Developing architecture in volatile environments:lessons learned from a biobank IT infrastructure project

Abstract The architecture specifies how the system should be designed and built. Several architecture frameworks exist for implementing the architectural design process. However, shortcomings are identified in current architectural design processes, especially concerning volatile domains like healthcare. We claim that an iterative architectural design process is required, where the technical concerns are separated from the non-technical ones. Furthermore, a strong guiding vision is required. Based on our experiences from a biobank IT infrastructure process, we present a Continuous Renewability architectural design process that is modular, interoperable, controlled and abstracted, thus being capable of handling complex systems with severe uncertainties

Defining an architecture for evolving environments

Abstract The architecture of a system specifies how the system should be designed and built. However, shortcomings are identified in current architecture process frameworks concerning evolving domains like healthcare. We claim that an iterative architecture process is required, where the technical concerns are separated from the non-technical ones. Furthermore, a strong guiding vision is required. Based on our experiences from a biobank IT infrastructure process, we present an architecture process that is modular, interoperable, controlled and abstracted, thus being capable of handling complex systems with large uncertainties

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis

.AbstractBackgroundInterferon beta is used to modify the course of relapsing multiple sclerosis. Despiteinterferon beta therapy, many patients have relapses. Natalizumab, an α4 integrinantagonist, appeared to be safe and effective alone and when added to interferonbeta-1a in preliminary studies.MethodsWe randomly assigned 1171 patients who, despite interferon beta-1a therapy, hadhad at least one relapse during the 12-month period before randomization to receivecontinued interferon beta-1a in combination with 300 mg of natalizumab (589patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks.The primary end points were the rate of clinical relapse at 1 year and the cumulativeprobability of disability progression sustained for 12 weeks, as measured by theExpanded Disability Status Scale, at 2 years.ResultsCombination therapy resulted in a 24 percent reduction in the relative risk of sustaineddisability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61to 0.96; P = 0.02). Kaplan–Meier estimates of the cumulative probability of progressionat two years were 23 percent with combination therapy and 29 percent withinterferon beta-1a alone. Combination therapy was associated with a lower annualizedrate of relapse over a two-year period than was interferon beta-1a alone (0.34vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T2-weighted magneticresonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combinationtherapy were anxiety, pharyngitis, sinus congestion, and peripheral edema.Two cases of progressive multifocal leukoencephalopathy, one of which was fatal,were diagnosed in natalizumab-treated patients.ConclusionsNatalizumab added to interferon beta-1a was significantly more effective than interferonbeta-1a alone in patients with relapsing multiple sclerosis. Additional researchis needed to elucidate the benefits and risks of this combination treatment.(ClinicalTrials.gov number, NCT00030966.

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. Methods: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Findings: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Funding: Bayer and Janssen

The incidence and significance of anti-natalizumab antibodies - Results from AFFIRM and SENTINEL

Objective: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab

Health-related quality of life in multiple sclerosis: Effects of natalizumab

Objective: To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. Methods: HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-la (IFN-\u3b2-1a) plus natalizumab 300mg (n = 589), or IFN-\u3b2-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. Results: Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. Interpretation: HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab. \ua9 2007 American Neurological Association. Published by Wiley-Liss, Inc

Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis

The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS)who had experienced disease activitywhile receiving interferon beta-1a (IFNβ-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNβ-1a 30 μg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNβ-1a remained free of newor enlarging T2- lesions compared with 30% of patients receiving IFNβ-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNβ-1a and increased in those receiving IFNβ-1a alone (–277.5 mm3 versus 525.6 mm3; pb0.001). Compared with IFNβ-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3 mm3 versus 2210.5mm3; pb0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; pb0.001), and a slower rate of brain atrophy during the second year of therapy (–0.31% versus –0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNβ-1a alon