Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup

Background Lumacaftor/ivacaftor combination therapy demonstrated clinical benefits inpatients with cystic fibrosis homozygous for the Phe508del CFTR mutation.Pretreatment lung function is a confounding factor that potentially impacts the efficacyand safety of lumacaftor/ivacaftor therapy. Methods Two multinational, randomised, double-blind, placebo-controlled, parallelgroupPhase 3 studies randomised patients to receive placebo or lumacaftor (600 mgonce daily [qd] or 400 mg every 12 hours [q12h]) in combination with ivacaftor (250 mgq12h) for 24 weeks. Prespecified analyses of pooled efficacy and safety data by lungfunction, as measured by percent predicted forced expiratory volume in 1 second(ppFEV1), were performed for patients with baseline ppFEV1 <40 (n=81) and ≥40(n=1016) and screening ppFEV1 <70 (n=730) and ≥70 (n=342). These studies wereregistered with ClinicalTrials.gov (NCT01807923 and NCT01807949). Findings The studies were conducted from April 2013 through April 2014.Improvements in the primary endpoint, absolute change from baseline at week 24 inppFEV1, were observed with both lumacaftor/ivacaftor doses in the subgroup withbaseline ppFEV1 <40 (least-squares mean difference versus placebo was 3∙7 and 3.3percentage points for lumacaftor 600 mg qd/ivacaftor 250 mg q12h and lumacaftor 400mg q12h/ivacaftor 250 mg q12h, respectively [p<0∙05] and in the subgroup with baselineppFEV1 ≥40 (3∙3 and 2∙8 percentage points, respectively [p<0∙001]). Similar absoluteimprovements versus placebo in ppFEV1 were observed in subgroups with screening 4ppFEV1 <70 (3∙3 and 3∙3 percentage points for lumacaftor 600 mg qd/ivacaftor 250 mgq12h and lumacaftor 400 mg q12h/ivacaftor 250 mg q12h, respectively [p<0∙001]) and≥70 (3∙3 and 1∙9 percentage points, respectively [p=0.002] and [p=0∙079]). Increases inBMI and reduction in number of pulmonary exacerbation events were observed in bothLUM/IVA dose groups vs placebo across all lung function subgroups. Treatment wasgenerally well tolerated, although the incidence of some respiratory adverse events washigher with active treatment than with placebo. Interpretation Lumacaftor/ivacaftor combination therapy benefits patients homozygousfor Phe508del CFTR who have varying degrees of lung function impairment. Funding Vertex Pharmaceuticals Incorporated.

Efficacy and Safety of Radium-223 Dichloride in Symptomatic Castration-resistant Prostate Cancer Patients With or Without Baseline Opioid Use From the Phase 3 ALSYMPCA Trial

Background: The phase 3 ALSYMPCA trial enrolled metastatic castration-resistant prostate cancer patients with or without baseline opioid use.

Objective: To assess the efficacy and safety of radium-223 dichloride (radium-223) versus placebo in ALSYMPCA patients by baseline opioid use.

Design, setting, and participants: Nine hundred and twenty one patients enrolled at 136 centers globally.

Intervention: Radium-223 (50 kBq/kg, intravenous injection) every 4 wk for six cycles or matching placebo, each plus best standard of care.

Outcome measurements and statistical analysis: Primary endpoint (overall survival [OS]), main secondary efficacy endpoints, and safety were evaluated by baseline opioid use. Additional analyses included time to first opioid use, time to first external beam radiation therapy for bone pain, and safety of concomitant external beam radiation therapy.

Results and limitations: At baseline, 408 (44%) patients had no pain and no analgesic use or mild pain with nonopioid therapy (World Health Organization ladder pain score 0–1 [nonopioid subgroup]), and 513 (56%) had moderate pain with occasional opioids or severe pain with regular daily opioids (World Health Organization ladder pain score 2–3 [opioid subgroup]). Radium-223 significantly prolonged OS versus placebo in nonopioid (hazard ratio [HR] = 0.70; 95% confidence interval [CI]: 0.52–0.93; p = 0.013) and opioid (HR = 0.68; 95% CI: 0.54–0.86; p = 0.001) subgroups, and significantly reduced risk of symptomatic skeletal events versus placebo, regardless of baseline opioid use (nonopioid subgroup: HR = 0.56, 95% CI: 0.39–0.82, p = 0.002; opioid subgroup: HR = 0.72, 95% CI: 0.53–0.98, p = 0.038). Time to first opioid use for bone pain was significantly delayed with radium-223 versus placebo (HR = 0.62, 95% CI: 0.46–0.85,p = 0.002). Adverse event incidences were similar between opioid subgroups.

Conclusions: Radium-223 versus placebo significantly prolonged OS and reduced symptomatic skeletal event risk with a favorable safety profile in castration-resistant prostate cancer patients with symptomatic bone metastases, regardless of baseline opioid use.

Patient summary: In this ALSYMPCA opioid subgroup analysis, baseline symptom levels did not appear to impact radium-223 dichloride efficacy or safety.

Scenic Byways: Their Selection, Designation, Protection and Safety, 1992

There is now a nationwide effort (the Scenic Byways Movement) to focus attention on the need to develop scenic byways and on their potential for enhancing tourism and recreation; to create coalitions and strategies to actually develop the byways; and, alternatively, to see that the job gets done. As part of this nationwide effort, the Transportation Departments of Iowa, Kansas, Missouri and Nebraska sponsored this project so they might obtain guidance related to Scenic Byways programs that may be developed in each state. The following issues are addressed in this report: scenic quality, road safety, scenic byway designation, and scenic byway information.

Audit report on the Wireless E-911 Emergency Communications Fund of the Iowa Department of Homeland Security and Emergency Management for the year ended June 30, 2015

Audit report on the Wireless E-911 Emergency Communications Fund of the Iowa Department of Homeland Security and Emergency Management for the year ended June 30, 2015

Efficient Security and Privacy Enhancing Solutions in Untrusted Environments

Thesis (Ph.D.)--University of Washington, 2016-08

Ensuring Mobile Device Security and Compliance at the Workplace

End users urgently request using mobile devices at their workplace. They know these devices from their private life and appreciate functionality and usability, and want to benefit from these advantages at work as well. Limitations and restrictions would not be accepted by them. On the contrary, companies are obliged to employ substantial organizational and technical measures to ensure data security and compliance when allowing to use mobile devices at the workplace. So far, only individual arrangements have been presented addressing single issues in ensuring data security and compliance. However, companies need to follow a comprehensive set of measures addressing all relevant aspects of data security and compliance in order to play it safe. Thus, in this paper at first technical architectures for using mobile devices in enterprise IT are reviewed. Thereafter a set of compliance rules is presented and, as major contribution, technical measures are explained that enable a company to integrate mobile devices into enterprise IT while still complying with these rules comprehensively. Depending on the company context, one or more of the technical architectures have to be chosen impacting the specific technical measures for compliance as elaborated in this paper. Altogether this paper, for the first time, correlates technical architectures for using mobile devices at the workplace with technical measures to assure data security and compliance according to a comprehensive set of rules.

Pervasive eHealth services a security and privacy risk awareness survey

The human factor is often recognised as a major aspect of cyber-security research. Risk and situational perception are identified as key factors in the decision making process, often playing a lead role in the adoption of security mechanisms. However, risk awareness and perception have been poorly investigated in the field of eHealth wearables. Whilst end-users often have limited understanding of privacy and security of wearables, assessing the perceived risks and consequences will help shape the usability of future security mechanisms. This paper present a survey of the the risks and situational awareness in eHealth services. An analysis of the lack of security and privacy measures in connected health devices is described with recommendations to circumvent critical situations.

Constructivism, constitutionalism and the EU's area of freedom security and justice post-Lisbon

This essay addresses the fundamental conceptual challenges which face the development of the Area of Freedom Security and Justice (AFSJ) in the post-Lisbon Treaty era. It argues that Onuf style constructivism is a valid lens with which to examine the development of the AFSJ to date, involving as it does the development of a shared understanding by practitioners, predominantly law enforcement and prosecution professionals, within the structures provided for them, in order to develop a completely new area of law and practice. While this approach will continue to need to be deployed in the development of further new operational areas, such as cybercrime, a new approach is now required, that of constitutionalism. A variety of forms of constitutionalism are then examined in order to establish their suitability as a mode of analysis for these developments.

Security and Trust in Distributed Computation

We propose three research problems to explore the relations between trust and security in the setting of distributed computation. In the first problem, we study trust-based adversary detection in distributed consensus computation. The adversaries we consider behave arbitrarily disobeying the consensus protocol. We propose a trust-based consensus algorithm with local and global trust evaluations. The algorithm can be abstracted using a two-layer structure with the top layer running a trust-based consensus algorithm and the bottom layer as a subroutine executing a global trust update scheme. We utilize a set of pre-trusted nodes, headers, to propagate local trust opinions throughout the network. This two-layer framework is flexible in that it can be easily extensible to contain more complicated decision rules, and global trust schemes. The first problem assumes that normal nodes are homogeneous, i.e. it is guaranteed that a normal node always behaves as it is programmed. In the second and third problems however, we assume that nodes are heterogeneous, i.e, given a task, the probability that a node generates a correct answer varies from node to node. The adversaries considered in these two problems are workers from the open crowd who are either investing little efforts in the tasks assigned to them or intentionally give wrong answers to questions. In the second part of the thesis, we consider a typical crowdsourcing task that aggregates input from multiple workers as a problem in information fusion. To cope with the issue of noisy and sometimes malicious input from workers, trust is used to model workers' expertise. In a multi-domain knowledge learning task, however, using scalar-valued trust to model a worker's performance is not sufficient to reflect the worker's trustworthiness in each of the domains. To address this issue, we propose a probabilistic model to jointly infer multi-dimensional trust of workers, multi-domain properties of questions, and true labels of questions. Our model is very flexible and extensible to incorporate metadata associated with questions. To show that, we further propose two extended models, one of which handles input tasks with real-valued features and the other handles tasks with text features by incorporating topic models. Our models can effectively recover trust vectors of workers, which can be very useful in task assignment adaptive to workers' trust in the future. These results can be applied for fusion of information from multiple data sources like sensors, human input, machine learning results, or a hybrid of them. In the second subproblem, we address crowdsourcing with adversaries under logical constraints. We observe that questions are often not independent in real life applications. Instead, there are logical relations between them. Similarly, workers that provide answers are not independent of each other either. Answers given by workers with similar attributes tend to be correlated. Therefore, we propose a novel unified graphical model consisting of two layers. The top layer encodes domain knowledge which allows users to express logical relations using first-order logic rules and the bottom layer encodes a traditional crowdsourcing graphical model. Our model can be seen as a generalized probabilistic soft logic framework that encodes both logical relations and probabilistic dependencies. To solve the collective inference problem efficiently, we have devised a scalable joint inference algorithm based on the alternating direction method of multipliers. The third part of the thesis considers the problem of optimal assignment under budget constraints when workers are unreliable and sometimes malicious. In a real crowdsourcing market, each answer obtained from a worker incurs cost. The cost is associated with both the level of trustworthiness of workers and the difficulty of tasks. Typically, access to expert-level (more trustworthy) workers is more expensive than to average crowd and completion of a challenging task is more costly than a click-away question. In this problem, we address the problem of optimal assignment of heterogeneous tasks to workers of varying trust levels with budget constraints. Specifically, we design a trust-aware task allocation algorithm that takes as inputs the estimated trust of workers and pre-set budget, and outputs the optimal assignment of tasks to workers. We derive the bound of total error probability that relates to budget, trustworthiness of crowds, and costs of obtaining labels from crowds naturally. Higher budget, more trustworthy crowds, and less costly jobs result in a lower theoretical bound. Our allocation scheme does not depend on the specific design of the trust evaluation component. Therefore, it can be combined with generic trust evaluation algorithms.

The Corporate Manslaughter and Corporate Homicide Act 2007 or the Health and Safety (Offences) Act 2008: corporate killing and the law

This thesis examines the regulatory and legislative approach taken in the United Kingdom to deal with deaths arising from work related activities and, in particular, deaths that can be directly attributed to the behaviour of corporations and other organisations. Workplace health and safety has traditionally been seen in the United Kingdom as a regulatory function which can be traced to the very earliest days of the Industrial Revolution. With an emphasis on preventing workplace accidents and ill-health through guidance, advice and support, the health and safety legislation and enforcement regime which had evolved over the best part of two centuries was considered inadequate to effectively punish corporations considered responsible for deaths caused by their activities following a series of disasters in the late twentieth and early twenty-first centuries. To address this apparent inadequacy, the Corporate Manslaughter and Corporate Homicide Act 2007 was introduced creating the offence of corporate manslaughter and corporate homicide. Based on a gross breach of a relevant duty of care resulting in the death of a person, the Act effectively changed what had previously considered a matter of regulation, an approach that had obvious weaknesses and shortcomings, to one of crime and criminal law. Whether this is the best approach to dealing with deaths caused by an organisation is challenged in this thesis and the apparent distinction between ‘criminal’ and ‘regulatory’ offences is also examined. It was found that an amended Health and Safety at Work etc. Act 1974 to include a specific offence of corporate killing, in conjunction with the Health and Safety (Offences) Act 2008 would almost certainly have resulted in a more effective approach to dealing with organisations responsible for causing deaths as consequence of their activities. It was also found that there was no substantive difference between ‘regulatory’ and ‘criminal’ law other than the stigma associated with the latter, and that distinction would almost certainly disappear, at least in the context of worker safety, as a consequence of the penalties available following the introduction of the Health and Safety (Offences) Act 2008.

Children's mental representations of attachment: associations with attachment security and parent-child narrative quality

The goal of this study was to examine the antecedents and correlates of children’s mental representations of attachment at 5 years (Attachment Story Completion Task, Bretherton, Ridgeway, & Cassidy, 1990; MacArthur Story Stem Battery, Bretherton, Oppenheim, Buchsbaum, Emde, & the MacArthur Narrative Group, 1990). Predictors included children’s attachment security with mothers and fathers assessed via the Attachment Q-Set (AQS, Waters, 1987) at 3 years, and parent-child narrative quality regarding positive and negative events at 5 years. Participants included 71 children and their mothers and fathers. Structural equation models (SEM) indicated that children’s attachment security exerted a significant indirect effect on children’s mental representations through parent-child narrative quality. Specifically, children’s attachment security with fathers was related to their mental representations via father-child reminiscing about positive events, and children’s attachment security with mothers was related to their mental representations via mother-child reminiscing about negative events. Results are discussed in terms of the development and implications of attachment relationships within the family context.

Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study

BACKGROUND: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP).

The impact of cooking methods on the nutritional quality and safety of chicken breaded nuggets

The impact of cooking methods (industrial pre-frying, deep-fat frying and baking) on the nutritional quality and safety of chicken breaded nugget samples from supermarket and commercial brands was evaluated. The changes in the quality characteristics (nutritional composition, fatty acids profile, cholesterol and salt) of the fried food and frying oil, after ten consecutive frying operations, were evaluated. The total fat content of nuggets varied between 10.9 and 22.7 g per 100 g of edible portion and the salt content ranged from 0.873 to 1.63 g per 100 g. Taking into account one portion of nuggets, the daily intake of salt can reach 49%, which can have a significant impact on the health of those who regularly consume this type of food, especially considering the prevalence of hypertension around the world. The analysed chicken breaded nuggets are rich in unsaturated fatty acids, which have been related with potential health benefits, namely regarding cardiovascular diseases. The cholesterol content of baked samples was two times higher when compared with the fried ones. The trans fatty acids and polar compounds contents of the frying oil used for frying significantly increased, but the values were still away from the maximum recommended by legal entities for its rejection. From a nutritional point of view, it is possible to conclude that the applied cooking methods can significantly influence the nutritional quality and safety of the analysed chicken breaded nuggets. This study will contribute to important knowledge on how the applied cooking methods can change the nutritional quality and safety of foods, namely of chicken nuggets, and can be very useful for dietary recommendations and nutritional assessment.

Social security and railroad retirement enactments in the 97th Congress within jurisdiction of the Committee on Ways and Means : Omnibus Budget Reconciliation Act and Economic Recovery Tax Act of 1981 /

At head of title: 97th Congress, 1st session. Committee print. WMCP: 97-15.