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Emerging non-volatile memory yields, alongside many advantages, technical shortcomings, such as reduced cell lifetime. Although many wear-leveling approaches exist to extend the lifetime of such memories, usually a trade-off for the granularity of wear-leveling has to be made. Due to iterative write schemes (repeatedly sense and write), wear-out of memory in certain systems is directly dependent on the written bit value and thus can be highly imbalanced, requiring dedicated bit-wise wear-leveling. Such a bit-wise wear-leveling so far has only be proposed together with a special hardware support. However, if no dedicated hardware solutions are available, especially for commercial off-the-shelf systems with non-volatile memories, a software solution can be crucial for the system lifetime. In this work, we propose entirely software-based bit-wise wearleveling, where the position of bits within CPU words in main memory is rotated on a regular basis. We leverage the LLVM intermediate representation to adjust load and store operations of the application with a custom compiler pass. Experimental evaluation shows that the lifetime by applying local rotation within the CPU word can be extended by a factor of up to 21×. We also show that our method can incorporate with coarser-grained wear-leveling, e.g. on block granularity and assist achievement of higher lifetime improvements.

Contains fulltext : 287607.pdf (Publisher’s version ) (Open Access) BACKGROUND: Acute anterior uveitis (AAU) affects up to 40% of patients with axial spondyloarthritis (axSpA). An effective treatment for patients with axSpA that reduces the risk of AAU flares while also targeting axial symptoms is therefore highly desirable. Tumor necrosis factor inhibitors (TNFis) have been shown effective for treatment of axSpA and AAU occurrence, with guidelines conditionally recommending treating patients with axSpA and associated AAU with TNFi monoclonal antibodies. To date, most available data on the impact of TNFis on AAU in axSpA are from observational, open-label studies without parallel comparator arms. However, there is a growing body of evidence describing the impact of the TNFi certolizumab pegol (CZP) on the incidence of axSpA-associated AAU. OBJECTIVE: Our objective was to collate data pertaining to the impact of CZP in axSpA-associated AAU in patients across the full axSpA spectrum. METHODS: Data were obtained from four industry-supported phase 3 and 4 clinical trials (C-VIEW, C-axSpAnd, C-OPTIMISE, and RAPID-axSpA). To supplement these data, a targeted literature review was performed through searches of MEDLINE, Embase, and reference lists. RESULTS: Available data from 1467 patients from the C-VIEW, C-axSpAnd, C-OPTIMISE, and RAPID-axSpA trials show CZP to be effective in AAU in patients across the full axSpA spectrum, reducing AAU flares when compared with placebo or pretreatment period. No differences in AAU outcomes were reported when stratified by axSpA subgroup age or sex. The targeted literature review identified six further studies of CZP in spondyloarthritis-associated AAU, only one of which was specific to axSpA. CONCLUSION: CZP was effective in reducing AAU incidence in clinical trials with patients with axSpA. The targeted literature review, however, highlighted that there remains a paucity of data beyond these trials. Data from comparative studies would further enhance the body of evidence on the effects of CZP in patients with axSpA who develop AAU.

Background52-week results from C-axSpAnd demonstrated the safety and efficacy of certolizumab pegol (CZP) in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) and objective signs of inflammation (sacroiliitis on MRI and/or elevated C-reactive protein levels). Long-term safety and clinical outcomes, including MRI assessments, are evaluated up to 3 years for CZP-treated patients with nr-axSpA.MethodsC-axSpAnd was a phase 3 study comprising a 1-year double-blind, placebo-controlled period and 2-year open-label safety follow-up extension (SFE). At baseline, 317 patients were randomised 1:1 to placebo or CZP 200 mg every 2 weeks. Patients completing the double-blind phase who enrolled into the SFE received open-label CZP for an additional 104 weeks. Long-term safety and clinical outcomes are reported to Week 156. Continuous outcomes are presented as observed case (OC) and dichotomous outcomes as OC and with non-responder imputation.Results243/317 (76.7%) patients entered the SFE, during which 149 (61.3%) experienced ≥1 treatment-emergent adverse event (TEAE); 15 (3.3/100 patient-years) experienced serious TEAEs. Continuous outcome scores (including Ankylosing Spondylitis Disease Activity Score [ASDAS]: 1.8; Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]: 2.7) at Week 52 were maintained at Week 156 (ASDAS: 1.8; BASDAI: 2.6) for the initial CZP-randomised group. Mean SPARCC MRI sacroiliac joint inflammation scores for these patients decreased at Week 52 (baseline: 7.6; Week 52: 1.7), remaining low at Week 156 (2.4).ConclusionsCZP treatment was well tolerated up to 3 years, with no new safety signals versus previous reports. Clinical outcomes achieved after 1 year were sustained to 3 years.Trial registration numberNCT02552212.

The massive number of Internet-of-Things (IoT) devices generates a hard-to-manage volume of data. Cloud-centric processing approaches for the IoT data suffer from high and unpredictable network latency, which causes poor experience in real-time IoT applications, such as healthcare. To address this issue, in edge computing, the data inference starts from the data source (i.e., the IoT devices). However, the constrained computational capabilities of the IoT device and the power-hungry data transmission demand a tradeoff between onboard processing and computation offloading. Hence, the IoT information inference requires efficient and lightweight techniques that are tailored for this tradeoff and respect the constrained resources on IoT devices, such as wearables. This article presents a hierarchical classification approach that decomposes the problem into three classifiers in two hierarchy layers. In the first layer, a lightweight classifier executes directly on the IoT device and decides whether to offload the computation to the gateway or to perform it onboard. The second layer comprises a lightweight classifier on the IoT device (can only distinguish a subset of classes) and a complex classifier on the gateway (to distinguish the remaining classes). The experimental results (using a real-world data set for human activity recognition and implemented on a wearable IoT device) show higher accuracy (92% on average) than a nonhierarchical classifier (87% on average). The execution time and power measurements on the IoT device show $3\times $ energy saving for the classification.

Objectives The efficacy and safety of certolizumab pegol (CZP), an Fc-free, PEGylated anti-TNF, in axial spondyloarthritis (axSpA) has been established in clinical trial settings. We report CZP effectiveness and safety in European clinical practice in patients with axSpA, including radiographic (r-) and non-radiographic (nr-) axSpA. Methods CIMAX (NCT02354105), a European non-interventional multicentre prospective study, observed CZP treatment response and safety over 12 months in a real-world axSpA cohort. The primary outcome was change from baseline in BASDAI to week 52, with additional outcomes pertaining to effectiveness and safety. Patients who received ≥1 dose CZP were followed up for adverse events, and those with baseline and ≥1 post-baseline BASDAI assessment were included in effectiveness analyses. Results A total of 672 patients (r-axSpA: 469; nr-axSpA: 201; unconfirmed diagnosis: 2) from 101 sites received ≥1 dose of CZP, of whom 564 (r-axSpA: 384; nr-axSpA: 179; unconfirmed: 1) were included in the effectiveness analyses. The mean baseline BASDAI was 6.1 in the overall axSpA population and r-axSpA and nr-axSpA subpopulations. At week 52, the mean (s.d.) change in BASDAI was −2.9 (2.3; n = 439); for r-axSpA and nr-axSpA, it was −2.9 (2.2; n = 301) and −2.8 (2.4; n = 137), respectively (P Conclusion Improvements observed in signs and symptoms of axSpA following one year of CZP treatment in real-world clinical practice were similar to those from previous randomized clinical trials, with no new safety concerns.

In the emerging paradigm of edge computing (EC) for Internet of Things (IoT), data processing is pushed to the edge of the IoT network (e.g., gateways and embedded IoT devices). IoT devices must support multiple operation modes in order to adapt to varying runtime situations, like preserving energy at low battery, while still maintaining some crucial functionality, etc. Adapting the optimal operation mode is a challenge for edge devices given the limited resources at the edge of the network (both bandwidth and processing power of the shared gateway), various constraints (e.g., battery lifetime), etc. This paper proposes a fast and low-overhead scheme to determine and adapt the operation mode of edge devices at runtime and orchestrate devices in a way that the efficiency of IoT devices is optimized with respect to the gateway’s resource constraints. The proposed scheme breaks the optimization problem into several smaller ones (i.e., subproblems) whose solutions are aggregated to find the final solution. We present a novel memoization technique that determines the solution to a range of subproblems based on subproblems that are already solved. In addition, we present a novel pruning technique that reduces the search space and consequently reduces both memory and execution time overhead. The experimental results show up to 50% reduction in memory overhead and $14 \times $ reduction in execution time overhead compared to the state-of-the-art solution which is a major step toward efficient EC for IoT.

In-memory wear-leveling has become an important research field for emerging non-volatile main memories over the past years. Many approaches in the literature perform wear-leveling by making use of special hardware. Since most non-volatile memories only wear out from write accesses, the proposed approaches in the literature also usually try to spread write accesses widely over the entire memory space. Some non-volatile memories, however, also wear out from read accesses, because every read causes a consecutive write access. Software-based solutions only operate from the application or kernel level, where read and write accesses are realized with different instructions and semantics. Therefore different mechanisms are required to handle reads and writes on the software level. First, we design a method to approximate read and write accesses to the memory to allow aging aware coarse-grained wear-leveling in the absence of special hardware, providing the age information. Second, we provide specific solutions to resolve access hot-spots within the compiled program code (text segment) and on the application stack. In our evaluation, we estimate the cell age by counting the total amount of accesses per cell. The results show that employing all our methods improves the memory lifetime by up to a factor of 955×.

Objective Tumor necrosis factor inhibitors (TNFi) are an effective treatment for non-radiographic axial spondyloarthritis (nr-axSpA). To be eligible, however, many authorities require patients with nr-axSpA to show active sacroiliitis on magnetic resonance imaging (MRI) and/or an elevated C-reactive protein (CRP) level, possibly resulting in a perception that patients with nr-axSpA without both factors have only low responses to TNFi treatment. We evaluated clinical responses to certolizumab pegol (CZP) in patients with nr-axSpA stratified by baseline MRI/CRP status. Methods C-axSpAnd was a phase 3, multicenter study on CZP in adult patients with active nr-axSpA and objective signs of inflammation. This analysis assessed efficacy of CZP over the 52-week randomized, double-blind, placebo-controlled period in patients stratified into subgroups based on the presence of active sacroiliitis on MRI and CRP level at baseline. Results CZP-treated patients across all MRI/CRP subgroups achieved clinical responses greater than placebo. Across outcome measures, CZP-treated MRI+/CRP+ patients demonstrated the greatest clinical responses, but substantial improvements were also observed in CZP-treated MRI+/CRP- and MRI-/CRP+ patients. Ankylosing Spondylitis Disease Activity Score Major Improvement response rates at week 52 among CZP-treated patients (75.6% MRI+/CRP+; 47.5% MRI-/CRP+; and 29.7% MRI+/CRP-) were higher than rates in placebo groups (range: 3.9%-12.5%). Assessment of SpondyloArthritis international Society 40% response, Bath Ankylosing Spondylitis Disease Activity Index, and Bath Ankylosing Spondyloarthritis Functional Index had similar response patterns, although differences between the CZP-treated MRI/CRP subgroups were smaller. Clinical responses among CZP-treated patients were also observed in additional subgroups, including those with low Spondyloarthritis Research Consortium of Canada MRI sacroiliac joint inflammation scores and those with normal baseline CRP levels. Conclusion Our findings indicate that CZP treatment benefits patients with nr-axSpA across MRI+/CRP+, MRI-/CRP+, and MRI+/CRP- subgroups.

Background Identification of predictive clinical factors of long-term treatment response may contribute to improved management of non-radiographic axSpA (nr-axSpA) patients. This analysis aims to identify whether any baseline characteristics or Week 12 clinical outcomes in nr-axSpA patients with elevated C-reactive protein (CRP) and/or sacroiliitis on magnetic resonance imaging (MRI) enrolled in the C-axSpAnd study are predictive of achieving clinical response after 1 year of certolizumab pegol (CZP). Methods C-axSpAnd (NCT02552212) was a phase 3, multicentre study, including a 52-Week double-blind, placebo-controlled period. Enrolled patients were randomised to CZP 200 mg Q2W or placebo. Predictors of Week 12 (CZP group only) and Week 52 clinical response were identified using a multivariate stepwise logistic regression analysis. Response variables included Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI), Assessment of SpondyloArthritis International Society 40% response (ASAS40), Bath Ankylosing Spondylitis Disease Activity Index 50% response (BASDAI50) and ASDAS inactive disease (ASDAS-ID). Predictive factors assessed included demographic and baseline characteristics and clinical outcomes at Week 12. A p-value p ≥0.1 for backward elimination. Missing data or values collected after switching to open-label treatment were accounted for using non-responder imputation. Sensitivity analyses accounted for patients with changes in non-biologic background medication. Results Of 317 enrolled patients, 159 and 158 were randomised to CZP and placebo, respectively. Younger age and male sex were identified as predictors of Week 12 response across all assessed efficacy outcomes in CZP-treated patients. Consistent predictors of Week 52 response, measured by ASDAS-MI, ASAS40 and BASDAI50, included human leukocyte antigen (HLA)-B27 positivity and sacroiliitis on MRI at baseline. MRI positivity was also predictive of achieving ASDAS-ID at Week 52. Sensitivity analyses were generally consistent with the primary analysis. In placebo-treated patients, no meaningful predictors of Week 52 response were identified. Conclusions In this 52-Week, placebo-controlled study in nr-axSpA patients with elevated CRP and/or active sacroiliitis on MRI at baseline, MRI sacroiliitis and HLA-B27 positivity, but not elevated CRP or responses at Week 12, were predictive of long-term clinical response to CZP. Findings may support rheumatologists to identify patients suitable for TNFi treatment. Trial registration ClinicalTrials.gov, NCT02552212. Registered on 15 September 2015

With the numerous Internet of Things (IoT) devices, the cloud-centric data processing fails to meet the requirement of all IoT applications. The limited computation and communication capacity of the cloud necessitate the edge computing, i.e., starting the IoT data processing at the edge and transforming the connected devices to intelligent devices . Machine learning (ML) the key means for information inference, should extend to the cloud-to-things continuum too. This paper reviews the role of ML in IoT from the cloud down to embedded devices. Different usages of ML for application data processing and management tasks are studied. The state-of-the-art usages of ML in IoT are categorized according to their application domain, input data type, exploited ML techniques, and where they belong in the cloud-to-things continuum. The challenges and research trends toward efficient ML on the IoT edge are discussed. Moreover, the publications on the “ML in IoT” are retrieved and analyzed systematically using ML classification techniques. Then, the growing topics and application domains are identified.

The massive increase of IoT devices and their collected data raises the question of how to analyze all that data. Edge computing provides a suitable compromise, but the question remains: How much processing should be done locally vs. offloaded to other devices? The diverse application requirements and limited resources at the edge extend the challenges. We propose Oops , an optimization framework to adapt the resource management at runtime distributedly. It orchestrates the IoT devices and adapts their operation mode with respect to their constraints and the gateway’s limited shared resources. Oops reduces runtime overhead significantly while increasing user utility compared to state-of-the-art.

Author(s): Deodhar, Atul; Gensler, Lianne S; Kay, Jonathan; Maksymowych, Walter P; Haroon, Nigil; Landewe, Robert; Rudwaleit, Martin; Hall, Stephen; Bauer, Lars; Hoepken, Bengt; de Peyrecave, Natasha; Kilgallen, Brian; van der Heijde, Desiree | Abstract: ObjectiveThe natural history of nonradiographic axial spondyloarthritis (SpA) is incompletely characterized, and there are concerns that nonsteroidal antiinflammatory drugs provide inadequate disease control in patients with active disease. This study was undertaken to investigate the effects of certolizumab pegol (CZP), an anti-tumor necrosis factor treatment, in patients with nonradiographic axial SpA with objective signs of inflammation.MethodsIn this ongoing parallel-group double-blind study, adults with active disease were recruited from 80 centers in Australia, Europe, North America, and Taiwan, and were randomized 1:1 to receive placebo or CZP (400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks) in addition to nonbiologic background medication (NBBM). Switching to open-label CZP (or other biologic) or making background medication changes was permitted at any point during the trial, although changes before week 12 were discouraged. The primary end point was the proportion of patients achieving major improvement (MI) (i.e., a ≥2.0-point decrease in the score from baseline or achievement of the lowest possible score [0.6]) in the Ankylosing Spondylitis Disease Activity Score (ASDAS) at week 52.ResultsA total of 317 patients were randomized to receive placebo plus NBBM (n = 158) or CZP plus NBBM (n = 159). ASDAS-MI at week 52 was achieved in 47.2% (75 of 159) of CZP plus NBBM patients, which was significantly greater (P l 0.0001) than the 7.0% (11 of 158) of placebo plus NBBM patients in whom ASDAS-MI was achieved. Of the placebo plus NBBM patients, 60.8% (96 of 158) switched to open-label treatment before week 52 compared to 12.6% (20 of 159) of the CZP plus NBBM patients.ConclusionAdding CZP to background medication is superior to adding placebo in patients with active nonradiographic axial SpA. These results indicate that remission in nonradiographic axial SpA treated without biologics occurs infrequently, demonstrating the need for treatment beyond nonbiologic therapy.

Introduction L’identification de facteurs cliniques predictifs de la reponse au traitement a long terme dans la spondyloarthrite axiale non radiographique (nr-axSpA) pourrait contribuer a une amelioration de la prise en charge des patients. Nous voulons savoir si des caracteristiques demographiques ou cliniques des patients atteints de nr-axSpA dans l’etude C-axSpAnd sont predictives de l’obtention d’une reponse clinique apres 1 an de traitement par le certolizumab pegol (CZP). Patients et methodes C-axSpAnd ( NCT02552212 ) est une etude multicentrique interventionnelle de phase III, comprenant une periode en double aveugle controlee versus placebo de 52 semaines. Un modele de regression logistique multivariee par etape a ete utilise pour identifier les facteurs predictifs de la reponse. Variables d’efficacite a la Semaine 52 chez les patients randomises pour recevoir le CZP 200 mg toutes les 2 semaines : primaire, reponse ASDAS-amelioration majeure (ASDAS-MI) et secondaire, reponse ASAS40. Les facteurs predictifs utilises dans le modele incluaient les caracteristiques demographiques et cliniques a l’inclusion ainsi que les resultats cliniques a la Semaine 12. Une valeur de p ≤ 0,05 etait necessaire pour la selection directe ; p = 0,1 pour l’elimination en amont. Pour les donnees manquantes ou les valeurs recueillies apres le passage dans l’extension en ouvert, l’imputation des non-repondeurs a ete utilisee. Une analyse de sensibilite a ete conduite pour les patients ayant modifie leur traitement de fond non biologique au cours de la periode controlee versus placebo de 52 semaines. Resultats 159/317 patients ont ete randomises pour recevoir CZP 200 mg toutes les deux semaines et 158/317 pour recevoir le placebo. Les facteurs predictifs identifies pour la reponse ASDAS-MI a la Semaine 52 chez les patients traites par CZP incluaient la presence d’une sacro-iliite a l’IRM (IRM + ) couplee a la positivite a l’antigene leucocytaire humain (HLA)-B27 (HLA + ), un score BASDAI plus eleve a l’inclusion et une amelioration de l’ASDAS plus importante a la Semaine 12. Concernant la reponse ASAS40, IRM+/HLA–B27+ a egalement ete identifie comme un facteur predictif de la reponse a la Semaine 52, tout comme un BASMI plus faible a l’inclusion et des ameliorations du PtGADA et du ASQoL plus importantes a la Semaine 12. L’analyse de sensibilite a identifie les memes facteurs predictifs pour les reponses ASDAS-MI et ASAS40, a l’exception de la variation du PtGADA par rapport a l’inclusion, facteur predictif de la reponse ASAS40. L’analyse de sensibilite a egalement identifie l’obtention de la reponse ASAS40 a la Semaine 12 comme facteur predictif de la reponse ASAS40 a la Semaine 52. Chez les patients du groupe placebo, aucun facteur predictif significatif de la reponse a la Semaine 52 n’a ete identifie. Conclusion La presence d’une sacro-iliite a l’IRM et la positivite de l’HLA-B27 ont ete identifiees comme facteurs predictifs de la reponse a la Semaine 52 (ASDAS-MI et ASAS40) chez les patients atteints de nr–axSpA traites par CZP.

Row-Hammering is a challenge for computing systems that use DRAM. It can cause bit flips in a DRAM row by accessing its neighboring rows. Several mitigation techniques on memory controller level were already suggested. The techniques are in two categories: The first category uses static probabilities, which leads to a performance penalty due to a high number of extra row activations. The second category is based on so-called Tabled Counters, which have large hardware requirements and are mostly infeasible to implement. We introduce a novel Row-Hammer mitigation technique that uses time-varying probabilities combined with a relatively small history table. Our technique reduces the number of extra row activations compared to static probabilistic techniques and it demands less storage than Tabled Counters techniques. Compared to state of the art, our technique offers a good compromise that has 9× - 27× reduced storage requirement than Tabled Counters and 6× - 12× fewer activations than probabilistic techniques.

Introduction: Acute anterior uveitis (AAU), affecting up to 40% of patients with axial spondyloarthritis (axSpA), risks permanent visual deficits if not adequately treated. We report 2-year results from C-VIEW, the first study to prospectively investigate certolizumab pegol (CZP) on AAU in patients with active axSpA at high risk of recurrent AAU. Patients and methods: C-VIEW (NCT03020992) was a 104-week (96 weeks plus 8-week safety follow-up), open-label, multicenter study. Eligible patients had active axSpA, human leukocyte antigen-B27 (HLA-B27) positivity and a history of recurrent AAU (⩾2 AAU flares in total; ⩾1 in the year prior to baseline). Patients received CZP 400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks to week 96. The primary efficacy endpoint was the AAU flare event rate during 96 weeks’ CZP versus 2 years pre-baseline. Results: Of 115 enrolled patients, 89 initiated CZP (male: 63%; radiographic/non-radiographic axSpA: 85%/15%; mean disease duration: 9.1 years); 83 completed week 96. There was a significant 82% reduction in AAU flare event rate during CZP versus pre-baseline [rate ratio (95% confidence interval): 0.18 (0.12–0.28), p Conclusion: CZP treatment significantly reduced AAU flare event rate in patients with axSpA and a history of AAU, indicating CZP is a suitable treatment option for patients at risk of recurrent AAU. Trial Registration ClinicalTrials.gov: NCT03020992, URL: https://clinicaltrials.gov/ct2/show/NCT03020992 [Media: see text]

Runtime/reconfigurable architectures based on Field-Programmable Gate Arrays (FPGAs) are a promising augment to conventional processor architectures such as Central Processing Units (CPUs) and Graphic Processing Units (GPUs). Since the reconfigurable parts are typically manufactured in the latest technology, they may suffer from aging and environmentally induced dependability threats. In this chapter, strategic online test methods for dependable runtime-reconfigurable architectures as well as cross-layer optimizations for high reliability and lifetime are developed. Firstly, two orthogonal online tests are proposed that ensure reliable configuration of the reconfigurable fabric and aid fault detection. Secondly, a novel design method called module diversification is presented that enables self-repair of the system in case of faults caused by degradation effects as well as single-event upsets in the configuration. Thirdly, a novel stress-aware placement method is proposed that aims for slowing down system degradation by aging effects. The combined methods ensure reliable operation across architectural and gate level and allow to prolong the lifetime of dependable runtime-reconfigurable architectures.

Background:Acute anterior uveitis (AAU) is the most common extra-articular manifestation in axial spondyloarthritis (axSpA), affecting up to 40% of patients and causing significant burden.1 Previous studies have shown that tumour necrosis factor inhibitors (TNFi) can reduce the incidence of AAU flares in patients with radiographic axSpA (ankylosing spondylitis),2-4 but few have focused on patients across the full axSpA spectrum.1Objectives:To report 2-year outcomes from the phase 4, open-label C-VIEW study (NCT03020992), which investigated the impact of certolizumab pegol (CZP) treatment on AAU in patients with active axSpA and a recent history of AAU.Methods:C-VIEW prospectively investigated patients with active axSpA who were HLA-B27 positive and had recurrent AAU, with a history of ≥1 AAU flare in the year prior to baseline (additional study criteria and study design are described elsewhere5). The primary efficacy variable was the incidence of AAU flares during 96 weeks of CZP treatment versus the 2-year pre-baseline period. AAU incidence was evaluated using Poisson regression adjusted for duration of time in each period, with period (pre- and post-baseline) and axSpA disease duration as covariates. Secondary efficacy variables were Assessment of SpondyloArthritis international Society 20%/40% (ASAS20/40) response rates, as well as mean Ankylosing Spondylitis Disease Activity Score (ASDAS) and mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) to Week 96.Results:Of 115 enrolled patients, 89 initiated CZP treatment; 83 completed Week 96. The primary analysis revealed an 82% reduction in the incidence of AAU flares during CZP treatment compared with pre-baseline (Figure 1A; rate ratio [95% CI]: 0.18 [0.12, 0.28], p5Conclusion:These data support the use of CZP for the treatment of patients with axSpA and a history of recurrent AAU. During 96 weeks’ CZP treatment, there was a significant reduction of 82% in the AAU flare rate compared to pre-baseline. There were also substantial improvements in patients’ axSpA disease activity.References:[1]Martin TM. Curr Opin Rheumatol 2002;14:337–41.[2]van der Heijde D. Rheumatology (Oxford) 2017;56:1498–509.[3]van Bentum RE. J Rheumatol 2019;46:153–9.[4]van Denderen JC. J Rheumatol 2014;41:1843–8.[5]van der Horst-Bruinsma I. RMD Open 2020;6:e001161.Table 1.Changes in axSpA disease activity to Week 96Disease activity measureWeek 0(n=89)Week 48(n=86)Week 96(n=82)ASAS responder rates, n (%)ASAS20N/A65 (75.6)62 (75.6)ASAS40N/A46 (53.5)48 (58.5)ASDAS, mean (SD)3.5 (1.0)2.0 (0.9)1.9 (1.0)BASDAI, mean (SD)6.5 (1.5)3.3 (2.1)3.0 (2.1)Observed data are shown. Patients received CZP 400 mg at Weeks 0/2/4, then 200 mg Q2W through 96 weeks. ASAS20/40: Assessment of SpondyloArthritis international Society 20%/40%; ASDAS: Ankylosing Spondylitis Disease Activity Score; axSpA: axial spondyloarthritis; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; CZP: certolizumab pegol; Q2W: every 2 weeks; SD: standard deviation.Acknowledgements:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Irene van der Horst-Bruinsma Speakers bureau: AbbVie, BMS, MSD, Pfizer, UCB Pharma, Consultant of: AbbVie, Eli Lilly, MSD, Novartis, UCB Pharma, Grant/research support from: AbbVie, MSD, Pfizer, Rianne van Bentum: None declared, Frank Verbraak Speakers bureau: Bayer, IDxDR, Novartis, UMC, Consultant of: Bayer, Novartis, Grant/research support from: Bayer, Thomas Rath Speakers bureau: AbbVie, BMS, Chugai, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma, Consultant of: AbbVie, BMS, Chugai, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma, Bengt Hoepken Shareholder of: UBC Pharma, Employee of: UCB Pharma, Oscar Irvin-Sellers Shareholder of: UCB Pharma, Employee of: UCB Pharma, Thomas Kumke Shareholder of: UCB Pharma, Employee of: UCB Pharma, Lars Bauer Shareholder of: UCB Pharma, Employee of: UCB Pharma, Martin Rudwaleit Speakers bureau: AbbVie, Eli Lilly, Novartis, UCB Pharma, Consultant of: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, UCB Pharma

Background:C-OPTIMISE was a phase 3b clinical trial investigating certolizumab pegol (CZP) maintenance dose continuation, reduction or withdrawal following achievement of sustained remission in patients with axial spondyloarthritis (axSpA). During the C-OPTIMISE maintenance period, the majority of patients randomised to CZP, either the full or reduced maintenance dose, did not experience disease flares. Conversely, in those who had CZP withdrawn, only a minority of patients remained flare-free.1Objectives:This post-hoc analysis evaluates disease activity and clinical markers of inflammation in patients who did not experience a disease flare following randomisation to CZP full maintenance dose, CZP reduced maintenance dose or placebo (PBO) during the maintenance period (Weeks 48–96) of C-OPTIMISE.Methods:C-OPTIMISE (NCT02505542) was a multicentre, double-blind, parallel-group, randomised phase 3b study with a 48-week open-label run-in period.1 Adult patients with early (3.5 at any visit. We report ASDAS, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and C-reactive protein (CRP) and fecal calprotectin levels during Weeks 48–96 in CZP- and PBO-randomised patients who did not experience a flare (i.e. completed Week 96 on randomised treatment). Missing data were imputed using last observation carried forward.Results:Of 313 patients entering the maintenance period at Week 48, 197 (62.9%) completed Week 96 on randomised treatment without experiencing a flare; of these, 89 (85.6%) and 84 (80.0%) patients were in the CZP 200 mg Q2W and CZP 200 mg Q4W arm, respectively, with only 24 (23.1%) patients randomised to PBO not experiencing a flare. Baseline characteristics of these patients are shown in the Table 1. During Weeks 48–96, disease activity (ASDAS, BASDAI) and CRP levels were comparable between the CZP full and reduced maintenance dose group, and lower in both CZP arms than in PBO (Figure 1 A–C). From Week 60 up to Week 96, PBO patients who did not flare had consistently higher mean ASDAS, BASDAI and CRP levels compared with CZP-randomised patients (Figure 1 A–C). Similarly, there was a greater increase in fecal calprotectin levels between Weeks 48 and 96 in the PBO arm compared with both CZP arms (Figure 1 D).Table 1.Baseline (Week 0) characteristics of patients who did not experience flares during the C-OPTIMISE maintenance periodPlacebo (n=24)CZP 200 mg Q4W (n=84)CZP 200 mg Q2W (n=89)Age (years), mean (SD)29.8 (7.4)32.9 (6.7)32.4 (7.2)Male, n (%)19 (79.2)69 (82.1)69 (77.5)Time since diagnosis (years)Mean (SD)2.0 (1.8)2.0 (1.7)2.5 (1.6)Median1.21.22.7Symptom duration (years)Mean (SD)2.7 (1.7)3.4 (1.9)3.9 (2.9)Median2.83.53.9ASDAS, mean (SD)3.4 (0.8)3.7 (0.8)3.7 (0.7)BASDAI, mean (SD)6.3 (1.1)6.6 (1.5)6.4 (1.4)CRP (mg/L), geometric mean6.287.887.35Fecal calprotectin (µg/g), mean (SD)71.8 (111.4)87.1 (110.5)81.0 (120.0)SD: standard deviation.Conclusion:Despite not meeting the threshold for a flare, consistently higher disease activity and increases in serologic and inflammatory biomarkers were observed in PBO-randomised patients who did not experience a flare during the C-OPTIMISE study compared to those who remained on CZP. These findings confirm that patients with axSpA who achieve sustained remission benefit from continued CZP treatment, either with the full or reduced maintenance dose, over treatment withdrawal.References:[1]Landewé R. Ann Rheum Dis 2020;79:920–8.Acknowledgements:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Lianne S. Gensler Consultant of: AbbVie, Eli Lilly, Gilead, GSK, Novartis, Pfizer, UCB Pharma, Grant/research support from: Pfizer, Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, Novartis, Merck, Pfizer, UCB Pharma, Paid instructor for: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, Novartis, Merck, Pfizer, UCB Pharma, Consultant of: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, Novartis, Merck, Pfizer, UCB Pharma, Grant/research support from: AbbVie, Merck, Novartis, Lars Bauer Shareholder of: UCB Pharma, Employee of: UCB Pharma, Bengt Hoepken Shareholder of: UCB Pharma, Employee of: UCB Pharma, Thomas Kumke Shareholder of: UCB Pharma, Employee of: UCB Pharma, Mindy Kim Shareholder of: UCB Pharma, Employee of: UCB Pharma, Robert B.M. Landewé Speakers bureau: Abbott, Amgen, BMS, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth, Consultant of: Abbott, Ablynx, Amgen, AstraZeneca, BMS, Centocor, GSK, Merck, Novartis, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth, Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth

Introduction Achievement of remission is a key treatment goal for patients with axial spondyloarthritis (axSpA). C-OPTIMISE assessed achievement of sustained clinical remission in patients with axSpA, including radiographic (r) and non-radiographic (nr) axSpA, during certolizumab pegol (CZP) treatment, and subsequent maintenance of remission following CZP dose continuation, dose reduction or withdrawal. Here, we report outcomes from the first 48 weeks (induction period) of C-OPTIMISE, during which patients received open-label CZP. Methods C-OPTIMISE (NCT02505542) was a two-part, multicenter, phase 3b study in adult patients with early axSpA (r-/nr-axSpA), including a 48-week open-label induction period followed by a 48-week maintenance period. Patients with active adult-onset axSpA

BackgroundAcute anterior uveitis (AAU) is the most common extra-articular manifestation in patients with axial spondyloarthritis (axSpA). C-VIEW investigates the impact of the Fc-free TNF inhibitor certolizumab pegol (CZP) on AAU flares in patients with active axSpA at high risk of recurrent AAU.MethodsC-VIEW (NCT03020992) is a 96-week ongoing, multicentre, open-label, phase 4 study. Included patients had an axSpA diagnosis, a history of recurrent AAU (≥2 AAU flares, ≥1 flare in the year prior to study entry), HLA-B27 positivity, active disease, and failure of ≥2 non-steroidal anti-inflammatory drugs. Patients received CZP 400 mg at Weeks 0/2/4, then 200 mg every 2 weeks up to 96 weeks. This 48-week pre-planned interim analysis compares AAU flare incidence in the 48 weeks before and after initiation of CZP treatment, using Poisson regression to account for possible within-patient correlations.ResultsIn total, 89 patients were included (male: 63%; radiographic/non-radiographic axSpA: 85%/15%; mean axSpA disease duration: 8.6 years). During 48 weeks’ CZP treatment, 13 (15%) patients experienced 15 AAU flares, representing an 87% reduction in AAU incidence rate (146.6 per 100 patient-years (PY) in the 48 weeks pre-baseline to 18.7 per 100 PY during CZP treatment). Poisson regression analysis showed that the incidence rate of AAU per patient reduced from 1.5 to 0.2 (pConclusionsThere was a significant reduction in the AAU flare rate during 48 weeks of CZP treatment, indicating that CZP is a suitable treatment option for patients with active axSpA and a history of recurrent AAU.

Just like every ecosystem, the computing one is subject to permanent evolution. In this paper we identify three major challenges resulting from this evolution. Those challenges stem from the hardware and application layer likewise. For one, we entered the era of many- * hardware architectures, which poses new requirements to upper layers. And with the proliferation of the computing continuum (e.g., cloud-, fog- and edge-computing), applications become more demanding and dynamic: The system needs to be able to satisfy application-intrinsic requirements and counter application-extrinsic uncertainties. As part of our contribution we present the current and ongoing research topics of our system-software stack for future many-* architectures. We further present the various mechanisms and concepts we employ within our system-software and describe how the system-software collaborates with other layers to tackle those challenges. Those concepts include a fundamentally different execution model and control-flow abstraction, allowing for massive micro-parallelism to efficiently utilize the hardware. Since the system-software research is performed as part of a collaborative research centre, we are able to approach the challenges on all layers of the technology stack and verify our solutions on an FPGA-based prototype platform. This allows us to design mechanisms in collaboration with every layer of the technology stack, that, when put together, cooperate across layer boundaries.

Several emerging technologies for byte-addressable non-volatile memory (NVM) have been considered to replace DRAM as the main memory in computer systems during the last years. The disadvantage of a lower write endurance, compared to DRAM, of NVM technologies like Phase-Change Memory (PCM) or Ferroelectric RAM (FeRAM) has been addressed in the literature. As a solution, in-memory wear-leveling techniques have been proposed, which aim to balance the wear-level over all memory cells to achieve an increased memory lifetime. Generally, to apply such advanced aging-aware wear-leveling techniques proposed in the literature, additional special hardware is introduced into the memory system to provide the necessary information about the cell age and thus enable aging-aware wear-leveling decisions. This paper proposes software-only aging-aware wear-leveling based on common CPU features and does not rely on any additional hardware support from the memory subsystem. Specifically, we exploit the memory management unit (MMU), performance counters, and interrupts to approximate the memory write counts as an aging indicator. Although the software-only approach may lead to slightly worse wear-leveling, it is applicable on commonly available hardware. We achieve page-level coarse-grained wear-leveling by approximating the current cell age through statistical sampling and performing physical memory remapping through the MMU. This method results in non-uniform memory usage patterns within a memory page. Hence, we further propose a fine-grained wear-leveling in the stack region of C / C++ compiled software. By applying both wear-leveling techniques, we achieve up to $78.43\%$ of the ideal memory lifetime, which is a lifetime improvement of more than a factor of $900$ compared to the lifetime without any wear-leveling.

Background Certolizumab pegol (CZP) treatment has demonstrated improvements in multiple manifestations of non-radiographic axial spondyloarthritis (nr-axSpA), including patient-reported outcomes (PROs). Here, we report PROs for nr-axSpA patients treated with CZP or placebo in CaxSpAnd - the first 52-week placebo-controlled study to investigate the efficacy of an anti-TNF agent in patients with active nr-axSpA and objective signs of inflammation. Methods C-axSpAnd (NCT02552212) is a 3-year, phase 3, multicenter study including a 52-week double-blind, placebo-controlled period (completed); patients who had an inadequate response to ≥ 2 non-steroidal anti-inflammatory drugs were randomized 1:1 to placebo or CZP (400mg at Weeks 0/2/4, then 200mg every 2 weeks). Clinical PROs included: Sleep Problems Index scores I (6 items) and II (9 items) from the Medical Outcomes Study Sleep Scale (assesses sleep disturbance, adequacy, somnolence, quantity, snoring, and awakening short of breath or with a headache), nocturnal spinal pain (numerical rating scale [NRS]), fatigue (BASDAI Q1), and morning stiffness (average of BASDAI Q5 + 6). Post-hoc analyses of minimal clinically important differences (MCID [≥1-point improvement]) for fatigue and nocturnal spinal pain were conducted. Variables were analyzed using an ANCOVA model including baseline score as a covariate and fixed effects for treatment group, region and MRI/CRP classification. P-values were nominal. Missing values following discontinuation of double-blind treatment were imputed using last observation carried forward. Results 317 patients with nr-axSpA were randomised to CZP (n = 159) or placebo (n = 158); 125 (79%) and 54 (34%) patients, respectively, completed Week 52. CZP-treated patients showed greater improvements (indicated by higher scores) in Sleep Problems Index II scores vs placebo-treated patients at Week 12 (mean change from baseline: 4.8 [CZP] vs 2.2 [placebo]; p < 0.001). Improvements were also seen in other clinical PROs (Table). By Week 12, greater proportions of patients treated with CZP vs placebo experienced at least MCID response in fatigue (85.4% vs 57.6%, respectively) and nocturnal spinal pain (82.8% vs 58.9%, respectively); results were sustained through Week 52. Conclusion CZP-treated nr-axSpA patients showed substantial improvements in sleep quality and other clinical outcomes important to patients; future analyses of these data will explore associations between sleep quality and other clinical PROs. Disclosures R. Sengupta: Other; R.S. has received speaker fees, support for conference attendance and grants from Abbvie, Biogen, Celgene, Novartis, Pfizer and UCB Pharma. L. Gensler: Grants/research support; AbbVie, Amgen, Novartis, UCB Pharma; consulting fees from Galapagos, Eli Lilly and Janssen. J. Kay: Consultancies; AbbVie, Boehringer Ingelheim, Celltrion Healthcare, Horizon Therapeutics, Merck Sharp & Dohme, MorphoSys, Novartis, Pfizer, Samsung Bioepis, Sandoz and UCB Pharma. Grants/research support; Gilead Sciences, Novartis AG, Pfizer and UCB Pharma. W. Maksymowych: Other; Consultant and/or speaker fees and/or grants from AbbVie, Amgen, Eli Lilly, Janssen, Merck, Pfizer, Synarc, Sanofi and UCB Pharma. N. Haroon: Consultancies; Abbvie, Amgen, Eli Lilly, Janssen, Novartis and UCB Pharma. L. Bauer: Other; Employee of UCB Pharma. B. Hoepken: Other; Employee of UCB Pharma. N. de Peyrecave: Other; Employee of UCB Pharma. T. Kumke: Other; Employee of UCB Pharma. A. Deodhar: Consultancies; AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Glaxo Smith and Klein, Janssen, Novartis, Pfizer and UCB. Grants/research support; BMS, Eli Lilly, Glaxo Smith & Kline, Janssen, Novartis, Pfizer and UCB.

Background Certolizumab pegol (CZP) treatment has been shown to significantly improve work and household productivity and social participation compared to placebo in active non-radiographic axial spondyloarthritis (nr-axSpA) patients up to 24 weeks. Here, we report the impact of CZP in combination with non-biologic background medication (NBBM) on signs and symptoms of nr-axSpA compared to placebo+NBBM. Methods C-axSpAnd (NCT02552212) is a 3-year, phase 3, multicentre study including a 52-week double-blind, placebo-controlled period (completed). Patients had active nr-axSpA, objective signs of inflammation (OSI; elevated CRP and/or positive MRI of the sacroiliac joint), previous inadequate response to ≥ 2 NSAIDs and were randomised 1:1 to CZP (400 mg at Weeks 0/2/4, then 200 mg every 2 weeks) or placebo. The validated arthritis-specific Work Productivity Survey (WPS) assessed the impact of nr-axSpA on work and household productivity and social participation. Missing data were imputed using last observation carried forward (LOCF) post hoc in the Full Analysis Set (randomised patients who received ≥1 dose of CZP). Results 317 patients were randomised (CZP: 159; placebo: 158). Mean age at baseline was 37.3 years and 51.4% of patients were female. At baseline, most patients were employed (CZP: 124 [77.8%]; placebo: 123 [78.0%]) and reported a mean 3.7 (CZP) and 3.5 (placebo) workdays missed per month due to disease (Table 1). By Week 12, work absenteeism substantially improved in the CZP group compared with placebo (0.9 vs 2.1 days missed per month, LOCF), with further improvements at Week 52 (0.3 vs 2.0 days missed per month, LOCF). Between Week 12 and Week 52, most placebo patients (104, 65.8%) switched to open-label CZP, impacting Week 52 imputed outcomes. Despite this, similar patterns of improvement following CZP treatment were seen for absenteeism, workdays with impaired productivity, household days with missed/reduced productivity and social participation between imputed and observed case data (Table 1). Improvements were similar between male and female patients (data not shown). Conclusion CZP treatment resulted in improvements in work and household productivity and social participation for nr-axSpA patients as early as Week 12 compared to background medication only, with benefits maintained to Week 52. Disclosures K. Gaffney: Other; Research Grants/Consultancy Fees from Abbvie, Biogen, Celgene, Gilead, Izana, Janssen, Lilly, Novartis, Pfizer, UCB Pharma. A. Deodhar: Consultancies; AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Glaxo Smith and Klein, Janssen, Novartis, Pfizer and UCB. Grants/research support; BMS, Eli Lilly, Glaxo Smith & Kline, Janssen, Novartis, Pfizer and UCB. L. Gensler: Consultancies; Galapagos, Eli Lilly and Janssen. Grants/research support; AbbVie, Amgen, Novartis, UCB Pharma. J. Kay: Consultancies; AbbVie, Boehringer Ingelheim, Celltrion Healthcare, Horizon Therapeutics, Merck Sharp & Dohme, MorphoSys, Novartis, Pfizer, Samsung Bioepis, Sandoz and UCB Pharma. Grants/research support; Gilead Sciences, Novartis AG, Pfizer and UCB Pharma. W. Maksymowych: Other; Consultant and/or speaker fees and/or grants from AbbVie, Amgen, Eli Lilly, Janssen, Merck, Pfizer, Synarc, Sanofi and UCB Pharma. N. Haroon: Consultancies; Abbvie, Amgen, Eli Lilly, Janssen, Novartis and UCB Pharma. R. Landewé: Consultancies; Abbott, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Centocor, GlaxoSmithKline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth. Member of speakers’ bureau; Abbott, Amgen, Bristol Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth. Grants/research support; Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth. M. Rudwaleit: Consultancies; Abbott, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Roche, UCB Pharma. S. Hall: Other; Consulting fees/ research grants from AbbVie, Eli Lilly, Novartis, and UCB Pharma. L. Bauer: Other; Employee of UCB Pharma. B. Hoepken: Other; Employee of UCB Pharma. N. de Peyrecave: Other; Employee of UCB Pharma. T. Kumke: Other; Employee of UCB Pharma. D. van der Heijde: Consultancies; AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB. Other; Director of Imaging Rheumatology BV.

Rotigotine transdermal patch is approved for the treatment of early and advanced idiopathic Parkinson’s disease (PD) and moderate-to-severe idiopathic restless legs syndrome (RLS). A cold chain manufacturing and distribution process was temporarily implemented in 2008, as this reduced the crystal formation reported within patches stored at room temperature. In order to overcome the crystallization issue and meet EMA and FDA requirements, a new room temperature stable formulation was developed. The three studies reported here were conducted to determine whether the new room temperature stable patch demonstrated similar bioavailability and adhesiveness to the original and intermediate patches. Data are reported from three cross-over studies that compared the original, cold chain and room temperature stable patch. Two open-label bioequivalence studies investigated the 2 mg/24 h dosage in healthy individuals (SP951, n = 52 [Clinicaltrials.gov: NCT00881894]; SP0987, n = 50 [NCT01059903]) and a double-blind patch adhesiveness study investigated the 8 mg/24 h dosage in patients with PD (SP1066, n = 56 [NCT01338896]). Plasma concentration–time curves and geometric means for pharmacokinetic parameters were similar for the cold chain vs. original patch in SP951 (AUC(0–tz): 2.68 vs. 2.71 ng/mL*h; point estimate: 0.99 [90% confidence interval (CI): 0.91, 1.07]) (Cmax: 0.131 vs. 0.136 ng/mL; 0.96 [0.89, 1.04]) and for the room temperature stable vs. cold chain patch in SP0987 (AUC(0–tz): 4.51 vs. 4.87 ng/mL*h; 0.90 [0.84, 0.97]) (Cmax: 0.23 vs. 0.23 ng/mL; 0.95 [0.88, 1.02]). In both studies, 90% CIs for ratios of AUC(0–tz) and Cmax were within the bioequivalence acceptance range (0.8–1.25). In SP1066, overall median adhesiveness scores were similar for cold chain (0.5 [range: 0–4]) and room temperature stable (0 [0–4]) formulations. These results demonstrated bioequivalence and indicated similar adhesiveness of the approved room temperature stable rotigotine patch with the original and cold chain patches. Potential limitations include the enrolment of healthy volunteers in the bioequivalence studies, as these individuals were likely to be younger than the general PD or RLS population.

With the widespread use of IoT applications and the increasing trend in the number of connected smart devices, the concept of routing has become very challenging. In this regard, the IPv6 Routing Protocol for Low-power and Lossy Networks (PRL) was standardized to be adopted in IoT networks. Nevertheless, while mobile IoT domains have gained significant popularity in recent years, since RPL was fundamentally designed for stationary IoT applications, it could not well adjust with the dynamic fluctuations in mobile applications. While there have been a number of studies on tuning RPL for mobile IoT applications, but still there is a high demand for more efforts to reach a standard version of this protocol for such applications. Accordingly, in this survey, we try to conduct a precise and comprehensive experimental study on the impact of various mobility models on the performance of a mobility-aware RPL to help this process. In this regard, a complete and scrutinized survey of the mobility models has been presented to be able to fairly justify and compare the outcome results. A significant set of evaluations has been conducted via precise IoT simulation tools to monitor and compare the performance of the network and its IoT devices in mobile RPL-based IoT applications under the presence of different mobility models from different perspectives including power consumption, reliability, latency, and control packet overhead. This will pave the way for researchers in both academia and industry to be able to compare the impact of various mobility models on the functionality of RPL, and consequently to design and implement application-specific and even a standard version of this protocol, which is capable of being employed in mobile IoT applications.

BackgroundThe best strategy for maintaining clinical remission in patients with axial spondyloarthritis (axSpA) has not been defined. C-OPTIMISE compared dose continuation, reduction and withdrawal of the tumour necrosis factor inhibitor certolizumab pegol (CZP) following achievement of sustained remission in patients with early axSpA.MethodsC-OPTIMISE was a two-part, multicentre phase 3b study in adults with early active axSpA (radiographic or non-radiographic). During the 48-week open-label induction period, patients received CZP 200 mg every 2 weeks (Q2W). At Week 48, patients in sustained remission (Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.5 at any time point) during the double-blind period.ResultsAt Week 48, 43.9% (323/736) patients achieved sustained remission, of whom 313 were randomised to CZP full maintenance dose, CZP reduced maintenance dose or placebo. During Weeks 48 to 96, 83.7% (87/104), 79.0% (83/105) and 20.2% (21/104) of patients receiving the full maintenance dose, reduced maintenance dose or placebo, respectively, were flare-free (pConclusionsPatients with early axSpA who achieve sustained remission at 48 weeks can reduce their CZP maintenance dose; however, treatment should not be completely discontinued due to the high risk of flare following CZP withdrawal.Trial registration numberNCT02505542, ClinicalTrials.gov.

Time-critical systems need to be analyzable for timing guarantees. There is an increasing demand for predictable performance that modern processor architectures fail to provide since they focus on average-case performance only. Recent work has demonstrated that runtime reconfiguration of hardware accelerators via an FPGA is a viable way to achieve high performance for optimized worst-case execution time (WCET) guarantees. Since execution of the worst-case path is highly improbable, configuring accelerators for this path costs reconfigurable area that could better be used to accelerate more probable paths. This work presents the first approach that comprises (1) an online average-case execution time (ACET) optimization while (2) maintaining the optimized WCET guarantee utilizing reconfigurable accelerators. We achieve this by a new design-time technique which determines the runtime slack bounds that allow speculative reconfiguration of accelerators that benefit the ACET. Combined with an online slack monitoring approach that introduces negligible overheads by using a performance counter, we show a runtime reduction of up to 10.4% for a complex and real-world application on top of an already-optimized WCET guarantee.

To improve computing performance in real-time applications, modern embedded platforms comprise hardware accelerators that speed up the task’s most compute-intensive parts. A recent trend in the design of real-time embedded systems is to integrate field-programmable gate arrays (FPGA) that are reconfigured with different accelerators at runtime, to cope with dynamic workloads that are subject to timing constraints. One of the major limitations when dealing with partial FPGA reconfiguration in real-time systems is that the reconfiguration port can only perform one reconfiguration at a time: if a high-priority task issues a reconfiguration request while the reconfiguration port is already occupied by a lower-priority task, the high-priority task has to wait until the current reconfiguration is completed (a phenomenon known as priority inversion ), unless the current reconfiguration is aborted (introducing unbounded delays in low-priority tasks, a phenomenon known as starvation ). This article shows how priority inversion and starvation can be solved by making the reconfiguration process preemptive —that is, allowing it to be interrupted at any time and resumed at a later time without restarting it from scratch. Such a feature is crucial for the design of runtime reconfigurable real-time systems but not yet available in today’s platforms. Furthermore, the trade-off of achieving a guaranteed bound on the reconfiguration delay for low-priority tasks and the maximum delay induced for high-priority tasks when preempting an ongoing reconfiguration has been identified and analyzed. Experimental results on the Xilinx Zynq-7000 platform show that the proposed implementation of preemptive reconfiguration introduces a low runtime overhead, thus effectively solving priority inversion and starvation.

The Internet-of-Things (IoT) envisions an infrastructure of ubiquitous networked smart devices offering advanced monitoring and control services. The current art in IoT architectures utilizes gateways to enable application-specific connectivity to IoT devices. In typical configurations, IoT gateways are shared among several IoT edge devices. Given the limited available bandwidth and processing capabilities of an IoT gateway, the service quality (SQ) of connected IoT edge devices must be adjusted over time not only to fulfill the needs of individual IoT device users but also to tolerate the SQ needs of the other IoT edge devices sharing the same gateway. However, having multiple gateways introduces an interdependent problem, the binding, i.e., which IoT device shall connect to which gateway. In this article, we jointly address the binding and allocation problems of IoT edge devices in a multigateway system under the constraints of available bandwidth, processing power, and battery lifetime. We propose a distributed trade-based mechanism in which after an initial setup, gateways negotiate and trade the IoT edge devices to increase the overall SQ. We evaluate the efficiency of the proposed approach with a case study and through extensive experimentation over different IoT system configurations regarding the number and type of the employed IoT edge devices. Experiments show that our solution improves the overall SQ by up to 56% compared to an unsupervised system. Our solution also achieves up to 24.6% improvement on overall SQ compared to the state-of-the-art SQ management scheme, while they both meet the battery lifetime constraints of the IoT devices.

ObjectivesTo report 4-year imaging outcomes in the RAPID-axSpA (NCT01087762) study of patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA), treated with certolizumab pegol (CZP).MethodsThis phase III, randomised trial was placebo-controlled and double-blind to week 24, dose-blind to week 48 and open-label to week 204. Patients fulfilling the Assessment of Spondyloarthritis International Society (ASAS) axSpA criteria with active disease were stratified (AS/nr-axSpA) according to the modified New York (mNY) criteria at randomisation. Spinal radiographs were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). MRI inflammation used the Spondyloarthritis Research Consortium of Canada (SPARCC) score for sacroiliac joints (SIJ) and the Berlin spinal score (remission defined as SPARCC ResultsMRI improvements from baseline (BL) to week 12 were maintained to week 204 (SPARCC BL: AS=8.5, nr-axSpA=7.5; SPARCC week 204: AS=1.3, nr-axSpA=2.4; Berlin BL: AS=7.4, nr-axSpA=4.4; Berlin week 204: AS=2.6, nr-axSpA=1.9). 66.7% of patients with AS and 69.6% of patients with nr-axSpA with BL SPARCC scores ≥2, and 65.4% of patients with AS and 57.3% of patients with nr-axSpA with BL Berlin score >2, achieved remission at week 204. Mean mSASSS change in AS from BL to week 204 was 0.98 (95% CI 0.34, 1.63); 0.67 (95% CI 0.21,1.13) from BL to week 96; and 0.31 (95% CI 0.02,0.60) from week 96 to week 204. Corresponding nr-axSpA changes were 0.06 (95% CI −0.17,0.28), –0.01 (95% CI −0.19,0.17) and 0.07 (95% CI −0.07,0.20). 4.5% of patients with nr-axSpA fulfilled the mNY criteria at week 204, while 4.3% of patients with AS no longer did so.ConclusionsIn patients with CZP-treated axSpA, rapid decreases in spinal and SIJ MRI inflammation were maintained to week 204. Overall, 4-year spinal progression was low, with less progression during years 2–4 than 0–2. Radiographic SIJ grading changes demonstrated limited progression.Trial registration numberNCT01087762; Post-results.

Introduction Les etudes anterieures ont montre que l’arret des inhibiteurs du facteur de necrose tumorale (anti-TNF) chez les patients atteints de spondyloarthrite axiale (axSpA) ayant obtenu une remission persistante conduit souvent a une rechute [1] . Toutefois, aucune etude n’a formellement teste les strategies de reduction de la dose de l’anti-TNF dans une large population axSpA ni evalue le risque de rechute apres une reduction de la dose ou l’arret du traitement par l’anti-TNF. L’etude C-OPTIMISE a evalue le pourcentage de patients sans poussee apres soit la poursuite du traitement par l’anti-TNF, soit la reduction de la dose ou l’arret du traitement chez des adultes atteints d’axSpA precoce traites par certolizumab pegol (CZP). Nous analysons ici si les reponses apres reduction de la dose ont ete comparables chez les patients stratifies en fonction de la sous-population d’axSpA, du genre et de l’âge. Patients et methodes C-OPTIMISE (NCT02505542) etait une etude de phase IIIb, multicentrique, en 2 parties, conduite chez des adultes atteints d’axSpA active precoce (stratifies selon que l’axSpA etait radiographique [r] ou non-radiographique [nr]). Les patients ont recu CZP 200 mg toutes les 2 semaines (Q2S; dose de charge 400 mg aux semaines 0, 2 et 4) pendant la periode d’induction en ouvert. A la semaine 48, les patients en remission persistante (score d’activite de la spondylarthrite [ASDAS] 3,5 a n’importe quel temps d’evaluation) au cours des semaines 48 a 96. Resultats Au cours de la periode d’induction de 48 semaines, 43,9 % des patients (323/736) ont atteint un etat de remission persistante et 313 patients ont ete inclus dans la periode d’entretien de 48 semaines (r/nr-axSpA: 168/145 patients; hommes/femmes: 247/66 patients; âge ≤ 32/ > 32 ans: 165/148 patients). Au cours de la periode d’entretien, les reponses chez les patients r-axSpA et nr-axSpA ont ete comparables entre les trois bras randomises; 83,9 % des patients r-axSpA et 83,3 % des patients nr-axSpA recevant la dose d’entretien complete de CZP n’ont pas eu de poussee et, dans le bras traite par la dose d’entretien reduite, 82,1 % des patients r-axSpA et 75,5 % des patients nr-axSpA n’ont pas eu de poussee. Dans le groupe PBO, ces pourcentages ont diminue respectivement de 17,9 % et 22,9 %. Des reponses similaires ont ete observees chez les patients stratifies en fonction du genre ou de l’âge, des pourcentages substantiellement plus eleves de patients randomises pour recevoir la dose d’entretien complete ou reduite de CZP restant indemnes de poussee versus PBO dans tous les sous-groupes ( Fig. 1 ). Conclusion Les resultats de C-OPTIMISE indiquent qu’une dose d’entretien reduite convient pour les patients atteints d’axSpA qui obtiennent une remission persistante apres 1 an de traitement par CZP, quelle que soit la sous-population d’axSpA, le genre ou l’âge. L’arret complet du traitement n’est pas recommande en raison du risque eleve de poussee.

Background:Identification of predictive clinical factors of long-term treatment response in non-radiographic axial spondyloarthritis (nr-axSpA) may contribute to improved management of patients with this chronic disease. Certolizumab pegol (CZP) is currently the only FDA-approved tumour necrosis factor inhibitor (TNFi) for treatment of nr-axSpA.1Objectives:To identify whether any demographic or baseline characteristics of nr-axSpA patients from the C-axSpAnd study2 are predictive of achieving a clinical response after 1 year of CZP treatment.Methods:C-axSpAnd (NCT02552212) was a phase 3, interventional multicentre study including a 52-week double-blind, placebo-controlled period. Full study design is reported elsewhere.2 Multivariate stepwise logistic regression analysis was used to identify predictors of response for the primary efficacy variable (Ankylosing Spondylitis Disease Activity Score – major improvement [ASDAS-MI] at Week 52) and the main secondary efficacy variable (Assessment of SpondyloArthritis international Society 40% [ASAS40] at Week 52) in patients randomised to CZP 200 mg every 2 weeks (Q2W). Predictive factors used in the model included demographic and baseline characteristics, and clinical outcomes at Week 12. A p value ≤0.05 was required for forward selection into the model and p=0.1 for backward elimination from the model. Non-responder imputation was used to account for missing data or values collected after switching to open-label treatment. A sensitivity analysis was conducted to account for patients who had changes in their non-biologic background medication during the 52-week placebo-controlled period.Results:A total of 159/317 patients were randomised to CZP 200 mg Q2W and 158/317 to placebo. Predictive factors identified for Week 52 ASDAS-MI in the CZP-treated patients included being positive for both presence of sacroiliitis on MRI (MRI+) and human leukocyte antigen (HLA)-B27 (HLA-B27+), having a higher Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at baseline, and having a larger Week 12 improvement in ASDAS (Figure 1A). For ASAS40 response, MRI+/HLA-B27+ was also identified as a predictor of Week 52 response, along with a lower baseline Bath AS Metrology Index (BASMI) and larger Week 12 improvements in Patient Global Assessment of Disease Activity (PtGADA) and AS Quality of Life (ASQoL; Figure 1B). Sensitivity analysis identified the same predictors for ASDAS-MI and ASAS40, with the exception of change from baseline in PtGADA as a predictor of ASAS40. Sensitivity analysis also identified achievement of Week 12 ASAS40 as a predictor of Week 52 ASAS40. In placebo-treated patients, no meaningful predictors of response at Week 52 were identified.Conclusion:Presence of sacroiliitis on MRI and HLA-B27 positivity were identified as consistent predictors of Week 52 response (ASDAS-MI and ASAS40) in nr-axSpA patients treated with CZP. To our knowledge, this is the first report from an interventional 52-week placebo-controlled study in nr-axSpA to identify objective clinical features, particularly the presence of sacroiliac joint inflammation, as being predictive of response.References:[1]Ashrafi M. Curr Opin Rheumatol 2020;32:321–9.[2]Deodhar A. Arthritis Rheumatol 2019;71:1101–11.Acknowledgements:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Walter P Maksymowych Speakers bureau: AbbVie, Janssen, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, BMS, Boehringer, Eli Lilly, Novartis, Pfizer, UCB Pharma, Grant/research support from: AbbVie, Novartis, Pfizer, Thomas Kumke Shareholder of: UCB Pharma, Employee of: UCB Pharma, Simone Auteri Shareholder of: UCB Pharma, Employee of: UCB Pharma, Bengt Hoepken Shareholder of: UCB Pharma, Employee of: UCB Pharma, Lars Bauer Shareholder of: UCB Pharma, Employee of: UCB Pharma, Martin Rudwaleit Speakers bureau: AbbVie, Eli Lilly, Novartis, UCB Pharma, Consultant of: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, UCB Pharma

Real-time systems have an increasing demand for predictable performance. Only recently novel models and analyses were proposed that make the performance benefits of runtime-reconfigurable architectures accessible for optimized worst-case execution time (WCET) guarantees. However, the implicit assumption in these works is that the process of reconfiguration itself complies with execution time guarantees. The realization of a reconfiguration controller that fulfills these assumptions and that is amenable to WCET guarantees is so far unavailable. In this letter, we detail the challenges of runtime reconfiguration in real-time systems and show that conflicts while accessing a shared main memory during reconfiguration can lead to a slowdown of more than ${21\times }$ in reconfiguration bandwidth. We present concepts that enable runtime reconfiguration under WCET guarantees and release our implementation of these concepts as open source.

Introduction: Dopamine receptor agonists (DAs) are commonly used to treat Parkinson’s disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms (‘dopamine receptor agonist’ OR ‘rotigotine’) AND ‘switch’. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h rotigotine) may be switched overnight.

Runtime reconfigurable architectures based on Field-Programmable Gate Arrays (FPGAs) allow area- and power-efficient acceleration of complex applications. However, being manufactured in latest semiconductor process technologies, FPGAs are increasingly prone to aging effects, which reduce the reliability and lifetime of such systems. Aging mitigation and fault tolerance techniques for the reconfigurable fabric become essential to realize dependable reconfigurable architectures. This article presents an accelerator diversification method that creates multiple configurations for runtime reconfigurable accelerators that are diversified in their usage of Configurable Logic Blocks (CLBs). In particular, it creates a minimal number of configurations such that all single-CLB and some multi-CLB faults can be tolerated. For each fault we ensure that there is at least one configuration that does not use that CLB. Second, a novel runtime accelerator placement algorithm is presented that exploits the diversity in resource usage of these configurations to balance the stress imposed by executions of the accelerators on the reconfigurable fabric. By tracking the stress due to accelerator usage at runtime, the stress is balanced both within a reconfigurable region as well as over all reconfigurable regions of the system. The accelerator placement algorithm also considers faulty CLBs in the regions and selects the appropriate configuration such that the system maintains a high performance in presence of multiple permanent faults. Experimental results demonstrate that our methods deliver up to 3.7 $\times$ higher performance in presence of faults at marginal runtime costs and 1.6 $\times$ higher MTTF than state-of-the-art aging mitigation methods.

Objective The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA. Methods RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported. Results Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported. Conclusion In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96 weeks were sustained through 4 years of treatment, with no new safety signals. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01087762.

Reconfigurable processors with fine-grained runtime-reconfigurable fabrics are used to speed up applications from different domains. Such a reconfigurable fabric allows loading of application-specific accelerators, where multiple accelerators can be combined using a coarse-grained runtime-reconfigurable $\mu $ Program to speed up complex computationally intensive kernels. To allow a large degree of adaptivity in the reconfigurable fabric, as it is required by, e.g., multitasking systems, the $\mu $ Program for a kernel should not be generated at compile time, as it would constrain the adaptivity of the system. To enable flexible and efficient use of the reconfigurable fabric, we propose the necessary algorithms for runtime: 1) accelerator placement (i.e., deciding where on the fabric an accelerator should be reconfigured at runtime); 2) $\mu $ Program generation; and 3) $\mu $ Program caching. Accelerator synthesis and implementation are done at compile time to reduce runtime overhead in generating accelerators. We evaluate the proposed algorithms using different application scenarios and demonstrate the proposed concepts on an field-programmable gate array-based prototype of a reconfigurable processor. In comparison with state-of-the-art reconfigurable processors that generate $\mu $ Programs at compile time, we obtain an average speedup of $1.29\times $ (up to $1.84\times $ ).

Real-time embedded systems need to be analyzable for timing guarantees. Despite significant scientific advances, however, timing analysis lags years behind current microarchitectures with out-of-order scheduling pipelines, several hardware threads, and multiple (shared) cache layers. To satisfy the increasing performance demands, analyzable performance features are required. We propose a novel timing analysis approach to introduce runtime reconfigurable instruction set processors as one way to escape the scarcity of analyzable performance while preserving the flexibility of the system. We introduce extensions to the state-of-the-art Integer linear programming (ILP)-based program path analysis for computing precise worst case time bounds in the presence of the widely used technique to continue processor execution during reconfiguration by emulating not yet reconfigured custom instructions (CIs) in software. We identify and safely bound a timing anomaly of runtime reconfiguration, where executing faster than worst case time during reconfiguration extends the execution time of the whole program. Stalling the processor during reconfiguration (easier to analyze but not state-of-the-art for reconfigurable processors) is not required in our approach. Finally, we show the precision of our analysis on a complex multimedia application with multiple reconfigurable CIs for several hardware parameters and give advice on how to deal with reconfiguration delay under timing guarantees.

The correctness of a real-time system does not depend on the correctness of its calculations alone but also on the non-functional requirement of adhering to deadlines. Guaranteeing these deadlines by static timing analysis, however, is practically infeasible for current microarchitectures with out-of-order scheduling pipelines, several hardware threads, and multiple (shared) cache layers. Novel timing-analyzable features are required to sustain the strongly increasing demand for processing power in real-time systems. Recent advances in timing analysis have shown that runtime-reconfigurable instruction set processors are one way to escape the scarcity of analyzable processing power while preserving the flexibility of the system. When moving calculations from software to hardware by means of reconfigurable custom instructions (CIs)—additional to a considerable speedup—the overestimation of a task’s worst-case execution time (WCET) can be reduced. CIs typically implement functionality that corresponds to several hundred instructions on the central processing unit (CPU) pipeline. While analyzing instructions for worst-case latency may introduce pessimism, the latency of CIs—executed on the reconfigurable fabric—is precisely known. In this work, we introduce the problem of selecting reconfigurable CIs to optimize the WCET of an application. We model this problem as an extension to state-of-the-art integer linear programming (ILP)-based program path analysis. This way, we enable optimization based on accurate WCET estimates with integration of information about global program flow, for example, infeasible paths. We present an optimal solution with effective techniques to prune the search space and a greedy heuristic that performs a maximum number of steps linear in the number of partitions of reconfigurable area available. Finally, we show the effectiveness of optimizing the WCET on a reconfigurable processor by evaluating a complex multimedia application with multiple reconfigurable CIs for several hardware parameters.