Wolters Kluwer N.V. is a global information services and publishing company. The company provides products and services for professionals in the health, tax, accounting, corporate, financial services, legal and regulatory sectors. Wolters Kluwer has annual revenues of €3.4 billion, employs approximately 18,000 people worldwide and maintains operations across Europe, North America, Asia Pacific and Latin America. Wolters Kluwer is headquartered in Alphen aan den Rijn, Netherlands. Its shares are quoted on the Euronext Amsterdam and are included in the AEX index and Euronext 100 index. The CEO and Chairman of the Executive Board is Nancy McKinstry.Wolters Kluwer formed under its present name in 1987 when Kluwer Publishers merged with Wolters Samson as a defensive move against an attempted hostile takeover of Kluwer Publishers by Elsevier. In 2003 Wolters Kluwer sold Kluwer Academic Publishers to two private equity funds who shortly after merged with BertelsmannSpringer to form Springer Science+Business Media. Wolters Kluwer Education, was sold to Bridgepoint Capital for 700 million euros in March 2007, who renamed it Infinitas Learning. Wikipedia.

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Agency: European Commission | Branch: H2020 | Program: RIA | Phase: MG-6.1-2014 | Award Amount: 18.11M | Year: 2015

NEXTRUST objective is to increase efficiency and sustainability in logistics by developing interconnected trusted collaborative networks along the entire supply chain. These trusted networks, built horizontally and vertically, will fully integrate shippers, LSPs and intermodal operators as equal partners. To reach a high level of sustainability, we will not only bundle freight volumes, but shift them off the road to intermodal rail and waterway. NEXTRUST will build these trusted networks ideally bottom up, with like-minded partners, adding multiple layers of transport flows that have been de-coupled and then re-connected more effectively along the supply chain. We will develop C-ITS cloud based smart visibility software to support the re-engineering of the networks, improving real-time utilization of transport assets. NEXTRUST will focus on research activities that create stickiness for collaboration in the market, validated through pilot cases in live conditions. The action engages major shippers as partners (Beiersdorf, Borealis, Colruyt, Delhaize, KC, Mondelez, Panasonic, Philips, Unilever) owning freight volumes well over 1.000.000 annual truck movements across Europe, plus SME shippers and LSPs with a track record in ICT innovation. The pilot cases cover the entire scope of the call and cover a broad cross section of entire supply chain (from raw material to end-consumers) for multiple industries. The creation and validation of trusted collaborative networks will be market oriented and implemented at an accelerated rate for high impact. We expect our pilot cases to reduce deliveries by 20%-40% and with modal shift to reduce GHG emissions by 40%-70%. Load factors will increase by 50%-60% given our emphasis on back-load/modal shift initiatives. NEXTRUST will achieve a high impact with improved asset utilization and logistics cost efficiency, creating a sustainable, competitive arena for European logistics that will be an inspirational example for the market.

Carter N.J.,Wolters Kluwer
Drugs | Year: 2011

Pirfenidone is an orally administered pyridine that has orphan designation for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in the EU.Pirfenidone 2403mgday for 72 weeks administered to patients with IPF was associated with a significantly lower mean decline in the percent predicted forced vital capacity than placebo (primary endpoint) according to data from one of two randomized, double-blind, multinational trials (studies 004 and 006 also known as the CAPACITY trials), and data from a pooled analysis of both trials.In another randomized, double-blind, multicentre Japanese trial, the adjusted mean in the change in vital capacity from baseline to week 52 was significantly lower in patients with IPF who received pirfenidone 1800mgday (considered to be comparable to the 2403mgday dose in studies 004 and 006 on a weight-normalized basis) than in those who received placebo (primary endpoint).Pirfenidone had an acceptable tolerability profile in clinical trials, with most adverse events being mild to moderate in severity. © 2011 Adis Data Information BV. All rights reserved.

Lyseng-Williamson K.A.,Wolters Kluwer
Drugs | Year: 2011

Levetiracetam (Keppra®, E Keppra®) is an established second-generation antiepileptic drug (AED). Worldwide, levetiracetam is most commonly approved as adjunctive treatment of partial onset seizures with or without secondary generalization; other approved indications include monotherapy treatment of partial onset seizures with or without secondary generalization, and adjunctive treatment of myoclonic seizures associated with juvenile myoclonic epilepsy and primary generalized tonic-clonic (GTC) seizures associated with idiopathic generalized epilepsy.Levetiracetam has a novel structure and unique mechanisms of action. Unlike other AEDs, the mechanisms of action of levetiracetam appear to involve neuronal binding to synaptic vesicle protein 2A, inhibiting calcium release from intraneuronal stores, opposing the activity of negative modulators of GABA- and glycin-gated currents and inhibiting excessive synchronized activity between neurons. In addition, levetiracetam inhibits N-type calcium channels. Levetiracetam is associated with rapid and complete absorption, high oral bioavailability, minimal metabolism that consists of hydrolysis of the acetamide group, and primarily renal elimination. It lacks cytochrome P450 isoenzyme-inducing potential and is not associated with clinically significant pharmacokinetic interactions with other drugs, including other AEDs.The efficacy of oral immediate-release levetiracetam in controlling seizures has been established in numerous randomized, double-blind, controlled, multicentre trials in patients with epilepsy. Adjunctive levetiracetam reduced the frequency of seizures in paediatric and adult patients with refractory partial onset seizures to a significantly greater extent than placebo. Monotherapy with levetiracetam was noninferior to that with carbamazepine controlled release in controlling seizures in patients with newly diagnosed partial onset seizures. Levetiracetam also provided seizure control relative to placebo as adjunctive therapy in patients with idiopathic generalized epilepsy with myoclonic seizures or GTC seizures. In addition, patients receiving oral levetiracetam showed improvements in measures of health-related quality of life relative to those receiving placebo.Although treatment-emergent adverse events were commonly reported in the clinical trials of levetiracetam, the overall proportion of patients who experienced at least one treatment-emergent adverse event was broadly similar in the levetiracetam and placebo treatment groups, with most events being mild to moderate in severity. Levetiracetam is not associated with cognitive impairment or drug-induced weight gain, but has been associated with behavioural adverse effects in some patients. © 2011 Adis Data Information BV. All rights reserved.

Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR).Everolimus (starting dosage 3.0 mg/m2) was associated with a significant reduction in the volume of the largest subependymal giant cell astrocytoma (SEGA) in 28 patients aged ≥3 years with tuberous sclerosis complex (TSC) in a phase II trial (C2485). At 6 months, 32% of patients treated with everolimus had a ≥50% reduction in the volume of their largest SEGA lesion (assessed via an independent central radiology review); 75% had a ≥30% reduction. No patients developed new lesions. During the extension phase of this trial (median duration 34 months), the reduction in SEGA volume was maintained, with no everolimus recipient requiring surgery or other therapy for SEGA or hydrocephalus.In a phase III trial (EXIST-1) in 117 patients with SEGA associated with TSC, 35% of everolimus recipients (starting dosage 4.5 mg/m2) versus none of the placebo recipients (p<0.0001) had an overall response (a reduction in the sum of all target SEGA volumes of ≥50% relative to baseline, nonworsening of non-target SEGA lesions, no new SEGA lesions, and no newworsening hydrocephalus). Everolimus was generally well tolerated in patients with SEGA associated with TSC; most drug-related adverse reactions were mild to moderate in severity.

Supraventricular tachyarrhythmia (including atrial fibrillation), hypertension and tachycardia in the perioperative setting, and acute ischaemic heart disease are generally agreed to require rapid attention and treatment. Prolonged tachyarrhythmia or hypertension can result in significant morbidity, such as cerebrovascular events, myocardial infarction and other end-organ damage. This article reviews the clinical efficacy and tolerability of intravenous infusions of esmolol for the short-term treatment of tachyarrhythmias and the short-term control of tachycardia and hypertension, and provides an overview of the pharmacological properties of the drug.Esmolol, a cardioselective β-blocker, has been proven effective in the control of elevated haemodynamic parameters in patients with supraventricular tachyarrhythmia, hypertension and tachycardia in the perioperative setting, and acute ischaemic heart disease, as well as being associated with a reduced risk of some clinical sequelae to increased haemodynamic parameters. Esmolol is, moreover, generally well tolerated; while it is associated with an increased risk of hypotension, this is rapidly reversible.Definitive conclusions on the efficacy of esmolol are difficult to reach, as most trials investigating esmolol have limitations such as small patient populations, and few studies investigate the same parameters. Ideally, several further studies would be beneficial; however, as esmolol is a well established, older drug, these are less likely to occur.Despite this, esmolol, as a fast-acting, rapidly reversible, easily titratable β-blocker, is an established option for the short-term treatment of tachyarrhythmias and the short-term control of tachycardia and hypertension. © 2012 Adis Data Information BV. All rights reserved.

The anticholinergic agent tiotropium bromide (Spiriva®) is a long-acting bronchodilator that is indicated for the treatment of chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of tiotropium bromide inhalation powder, administered using the HandiHaler® device, in patients with COPD, as well as reviewing its pharmacological properties and the results of pharmacoeconomic analyses. Shorter-term placebo-controlled trials in patients with COPD demonstrated significantly higher trough forced expiratory volume in 1 second (FEV1) responses with tiotropium bromide than with placebo, confirming it has a duration of action of ≥24 hours and is suitable for once-daily administration. Lung function improved to a greater extent with tiotropium bromide than with ipratropium bromide or, in most instances, salmeterol. Indacaterol was shown to be noninferior to tiotropium bromide in terms of the trough FEV1 response. The large, 4-year UPLIFT® trial did not show a significant reduction in the annual rate of decline in FEV1 with tiotropium bromide versus placebo in patients with COPD, although subgroup analyses demonstrated a significantly lower rate of decline with tiotropium bromide than with placebo in some patient groups (e.g. patients with moderate COPD, patients aged ≥50 years, patients not receiving maintenance therapy at baseline). Tiotropium bromide prevented exacerbations in patients with COPD, with a significantly lower exacerbation rate and a significantly longer time to first exacerbation seen with tiotropium bromide than with placebo or salmeterol. Exacerbation rates did not significantly differ between patients receiving tiotropium bromide and those receiving salmeterolfluticasone propionate. Tiotropium bromide also had beneficial effects on health-related quality of life (HR-QOL) and other endpoints, such as dyspnoea and rescue medication use. Combination therapy with tiotropium bromide plus formoterol with or without budesonide improved lung function to a significantly greater extent than tiotropium bromide alone in patients with COPD. In addition, exacerbation rates were lower and HR-QOL was improved with tiotropium bromide plus budesonideformoterol versus tiotropium bromide alone. Although the addition of salmeterolfluticasone propionate to tiotropium bromide did not reduce the COPD exacerbation rate, it did improve lung function and HR-QOL. Tiotropium bromide inhalation powder is generally well tolerated in patients with COPD, with anticholinergic adverse events (e.g. dry mouth, constipation, gastrointestinal obstruction, dysuria) among the most commonly reported adverse events. The UPLIFT® trial showed no significant difference between tiotropium bromide and placebo recipients in the risk of stroke, and the risk of serious cardiac adverse events (including congestive heart failure and myocardial infarction) was significantly lower with tiotropium bromide than with placebo. The absence of a detrimental effect on cardiovascular outcomes was supported by the results of a meta-analysis and pooled analyses. In addition, on-treatment mortality was lower with tiotropium bromide than with placebo in the UPLIFT® trial. Pooled analyses showed significantly lower cardiovascular mortality with tiotropium bromide than with placebo, with a meta-analysis demonstrating no significant difference between patients receiving tiotropium bromide and controls in cardiovascular mortality. Results of modelled pharmacoeconomic analyses conducted from a healthcare payer perspective in several developed countries suggest that tiotropium bromide is a cost-effective option in patients with COPD.In conclusion, tiotropium bromide inhalation powder is a useful option for the maintenance treatment of patients with COPD. © 2012 Adis Data Information BV. All rights reserved.

Plosker G.L.,Wolters Kluwer
CNS Drugs | Year: 2011

Interferon-β-1b has been used as a disease-modifying therapy in multiple sclerosis (MS) for many years. Although its mechanism of action in MS has not been fully elucidated, it appears to involve immunomodulatory effects mediated by interactions with specific receptors.Large, randomized, multicentre, clinical trials of 23.5 years duration have demonstrated the efficacy of interferon-β-1b 250μg subcutaneously every other day in patients with a first clinical event suggestive of MS (i.e. those with clinically isolated syndrome CIS) and in those with relapsing-remitting MS (RRMS). In terms of its efficacy on primary (or co-primary) endpoints, interferon-β-1b significantly reduced the risk of developing clinically definite MS compared with placebo in patients with CIS in the BENEFIT study. In patients with RRMS, interferon-β-1b was associated with a significantly lower annualized relapse rate and a significantly higher proportion of relapse-free patients compared with placebo in a registration trial conducted by the Interferon-β MS Study Group. The INCOMIN trial in patients with RRMS showed a significant advantage of interferon-β-1b over intramuscular interferon-β-1a in terms of the percentage of relapse- and progression-free patients and the proportion of patients without new MRI-documented lesions. Other active-comparator trials in RRMS used a variety of primary (or co-primary) endpoints and showed no significant differences between interferon-β-1b and either subcutaneous glatiramer acetate (BECOME and BEYOND trials) or subcutaneous interferon-β-1a (Danish MS Group trial) for these outcomes.In patients with secondary progressive MS (SPMS), the European Study Group showed that interferon-β-1b significantly increased the time to confirmed disease progression compared with placebo, although there was no significant between-group difference for this primary endpoint in a similar trial conducted by the North American Study Group. The studies allowed inclusion of patients with superimposed relapse, and both trials showed a significant reduction in annualized relapse rate with interferon-β-1b.The most frequently reported adverse events with interferon-β-1b are flu-like symptoms and injection-site reactions, which can usually be managed. The incidence of these adverse events generally declines markedly after the first year of treatment. Lymphopenia is the most frequently reported laboratory abnormality and occurs in the majority of patients. Depression, suicidal ideation and injection-site necrosis were the most serious adverse events reported with interferon-β-1b in clinical trials. Long-term safety data over a 16-year follow-up period showed no unexpected adverse events among patients treated with interferon-β-1b.Thus, interferon-β-1b is a well established, first-line, disease-modifying therapy that has demonstrated efficacy in newly emerging MS, RRMS and SPMS with superimposed relapse in well designed clinical trials, and has a generally manageable tolerability profile, with no unexpected adverse events after many years of follow-up. © 2011 Adis Data Information BV. All rights reserved.

Curran M.P.,Wolters Kluwer
Drugs | Year: 2012

Crizotinib is an inhibitor of receptor tyrosine kinases (including anaplastic lymphoma kinase ALK).Oral crizotinib 250mg twice daily was associated with clinically meaningful response rates in two noncomparative trials (phase I and phase II) in patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC).In the phase I trial (median duration of treatment of 32 weeks) and phase II trial (median duration of treatment of 22 weeks), the objective response rate in crizotinib recipients was 61 and 50, respectively, and the median duration of response was 48.1 and 41.9 weeks, respectively. Responses were rapid, with the majority of patients achieving an objective response within the first 8 weeks of treatment.Crizotinib was generally well tolerated, with most adverse reactions being grade 1 or 2. The most commonly reported treatment-related adverse reactions were vision disorder, gastrointestinal disorders and oedema. © 2012 Adis Data Information BV. All rights reserved.

Systems and methods are disclosed for distributing content pursuant to audit-based processes. Audit content in runtime workpapers may be dynamically constructed in response to industry-driven and response-driven rules using information from one or more of the distributed content libraries. Dynamic updates may also be provided for generated runtime workpapers constructed from the distributed content. The system and method may also provide drilldown functionality for enabling a user to view a source workpaper for a specified data value which has flowed into the generated dynamic workpaper and/or tip functionality to provide a user with additional guidance based on the status and data associated with the generated workpaper.

Agency: European Commission | Branch: H2020 | Program: RIA | Phase: ICT-09-2014 | Award Amount: 4.00M | Year: 2015

The rapid growth of web data creates demand for software engineering methods which can build and maintain applications that extract, process and publish web data. However, converting Big Data sources into high-quality, structured knowledge for use in business processes is usually considered data engineering. ALIGNED will develop models, methods and tools for engineering information systems based on co-evolving software and web data. Tools for model-driven software evolution based on Linked Data sources, runtime data quality analytics, human data curation and process integration will aid more efficient governance, increased agility and higher productivity. The opportunities for web data have recently led to intense research and innovation, but most efforts are siloed in the software or data spaces. Past integration of data and software engineering used formal ontologies rather than Linked Data. ALIGNED will provide lightweight methods for European data and software engineering industries to exploit the new opportunities in web data. Information companies like Wolters Kluwer need better ways to extract web data and build applications on top of it. Public bodies like the UK National Health Service (NHS) need evolving systems for data collection and re-use. Web data publishers like DBpedia need new methods to improve data quality. Scientific publications, industry workshops, training programs, open source tools and engaging the OMG, W3C and ISO standards bodies will transfer ALIGNED outputs. ALIGNED combines world class researchers in model driven software engineering (Oxford are transforming NHS systems), Linked Data quality (Leipzig and Trinity College have published foundational papers) and web systems (Leipzig are co-creators of DBpedia) with innovative enterprises (Wolters Kluwer have Linked Data in production systems, Semantic Web Company lead the world in enterprise Linked Data) and pioneering expert-curated data publishers (Oxford Anthropology and Posnan).

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