Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial

Background Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease. Methods This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs >= 50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373. Findings 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11.4 mmol/L (SD 3.6) in the mipomersen group and 10.4 mmol/L (3.7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (-24.7%, 95% CI 31.6 to 17.7) than with placebo (-3.3%, 12.1 to 5.5; p=0.0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal. Interpretation Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins.

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING: Merck KGaA, Darmstadt, Germany.

Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.

BACKGROUND: Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses. Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis. METHODS: In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratified by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10-25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20% improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria (ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00106548. FINDINGS: The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4.0 [95% CI 2.6-6.1], p<0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7-3.9], p<0.0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group. INTERPRETATION: Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis. FUNDING: F Hoffmann-La Roche, Chugai Pharmaceutical.

Student and teacher response system : development of an interactive anonymous real-timeformative feedback system

This paper is focusing IT-supported real-time formative feedback in a classroom context. The development of a Student and Teacher Response System (STRS) is described. Since there are a number of obstacles for effective interaction in large classes IT can be used to support the teachers aim to find out if students understand the lecture and accordingly adjust the content and design of the lecture. The system can be used for formative assessment before, during, and after a lecture. It is also possible for students to initiate interaction during lectures by posing questions anonymously. The main contributions of the paper are a) the description of the interactive real-time system and b) the development process behind it.

Development of a Real-time Formative Feedback Student Response System

This paper is focusing IT-supported real-time formative feedback in a classroom context. The development of a Student and Teacher Response System (STRS) is described. Since there are a number of obstacles for effective interaction in large classes, IT can be used to support the teachers aim to find out if students understand the lecture and accordingly adjust the content and design of the lecture. The system can be used for formative assessment before, during, and after a lecture. It is also possible for students to initiate interaction during lectures by posing questions anonymously. The main contributions of the paper are a) the description of the interactive real-time system and b) the development process behind it.

The Effect of Mobile Technology as an Active Student Response System on the Acquisition of U.S. History Content of Secondary Students with Specific Learning Disabilities

Students with specific learning disabilities (SLD) typically learn less history content than their peers without disabilities and show fewer learning gains. Even when they are provided with the same instructional strategies, many students with SLD struggle to grasp complex historical concepts and content area vocabulary. Many strategies involving technology have been used in the past to enhance learning for students with SLD in history classrooms. However, very few studies have explored the effectiveness of emerging mobile technology in K-12 history classrooms. This study investigated the effects of mobile devices (iPads) as an active student response (ASR) system on the acquisition of U.S. history content of middle school students with SLD. An alternating treatments single subject design was used to compare the effects of two interventions. There were two conditions and a series of pretest probesin this study. The conditions were: (a) direct instruction and studying from handwritten notes using the interactive notebook strategy and (b) direct instruction and studying using the Quizlet App on the iPad. There were three dependent variables in this study: (a) percent correct on tests, (b) rate of correct responses per minute, and (c) rate of errors per minute. A comparative analysis suggested that both interventions (studying from interactive notes and studying using Quizlet on the iPad) had varying degrees of effectiveness in increasing the learning gains of students with SLD. In most cases, both interventions were equally effective. During both interventions, all of the participants increased their percentage correct and increased their rate of correct responses. Most of the participants decreased their rate of errors. The results of this study suggest that teachers of students with SLD should consider a post lesson review in the form of mobile devices as an ASR system or studying from handwritten notes paired with existing evidence-based practices to facilitate students’ knowledge in U.S. history. Future research should focus on the use of other interactive applications on various mobile operating platforms, on other social studies subjects, and should explore various testing formats such as oral question-answer and multiple choice.

The effect of mobile technology as an active student response system on the acquisition of U.S. history content of secondary students with specific learning disabilities

Students with specific learning disabilities (SLD) typically learn less history content than their peers without disabilities and show fewer learning gains. Even when they are provided with the same instructional strategies, many students with SLD struggle to grasp complex historical concepts and content area vocabulary. Many strategies involving technology have been used in the past to enhance learning for students with SLD in history classrooms. However, very few studies have explored the effectiveness of emerging mobile technology in K-12 history classrooms. ^ This study investigated the effects of mobile devices (iPads) as an active student response (ASR) system on the acquisition of U.S. history content of middle school students with SLD. An alternating treatments single subject design was used to compare the effects of two interventions. There were two conditions and a series of pretest probesin this study. The conditions were: (a) direct instruction and studying from handwritten notes using the interactive notebook strategy and (b) direct instruction and studying using the Quizlet App on the iPad. There were three dependent variables in this study: (a) percent correct on tests, (b) rate of correct responses per minute, and (c) rate of errors per minute. ^ A comparative analysis suggested that both interventions (studying from interactive notes and studying using Quizlet on the iPad) had varying degrees of effectiveness in increasing the learning gains of students with SLD. In most cases, both interventions were equally effective. During both interventions, all of the participants increased their percentage correct and increased their rate of correct responses. Most of the participants decreased their rate of errors. ^ The results of this study suggest that teachers of students with SLD should consider a post lesson review in the form of mobile devices as an ASR system or studying from handwritten notes paired with existing evidence-based practices to facilitate students’ knowledge in U.S. history. Future research should focus on the use of other interactive applications on various mobile operating platforms, on other social studies subjects, and should explore various testing formats such as oral question-answer and multiple choice. ^

Análise de Desempenho e Recomendação para Soluções IVR

Mestrado em Engenharia Informática, Área de Especialização em Tecnologias do Conhecimento e da Decisão

Influence of light intensity and salt-treatment on mode of photosynthesis and enzymes of the antioxidative response system of Mesembryanthemum crystallinum

The metabolic switch From C-3-photosynthesis to crassulacean acid metabolism (CAM),and the antioxidative response of Mesembryanthemum crystallinum L. plants cultured under severe salt stress and high light intensities, and a combination of booth stress conditions, were studied. High light conditions led to a more rapid CAM induction than salinity. The induction time was still shortened when both stress factors were combined. A main pattern observed in CAM plants was a decrease in mitochondrial Mn-superoxide dismutase (SOD) activity during the day. The activities of the chloroplastic Fe-SOD and cytosolic CuZn-SOD were increased due to salt treatment after a lag phase, while catalase activity was decreased. Combination of salt and light stress did not lead to a higher SOD activity as found after application of one stress factor alone, indicating that there is a threshold level of the oxidative stress response. The fact that salt-stressed plants grown under high light conditions showed permanent photoinhibition and lost the ability for nocturnal malate storage after 9 d of treatment indicate serious malfunction of metabolism, leading to accelerated senescence. Comparison of CuZn-SOD activity with CuZn-SOD protein amount, which was determined immunologically, indicates that the activity of the enzyme is at least partially post-translationally regulated.

Avanços em reconhecimento de fala para português brasileiro e aplicações: ditado no libreoffice e unidade de resposta audível com asterisk

O reconhecimento automático de voz vem sendo cada vez mais útil e possível. Quando se trata de línguas como a Inglesa, encontram-se no mercado excelentes reconhecedores. Porem, a situação não e a mesma para o Português Brasileiro, onde os principais reconhecedores para ditado em sistemas desktop que já existiram foram descontinuados. A presente dissertação alinha-se com os objetivos do Laboratório de Processamento de Sinais da Universidade Federal do Pará, que é o desenvolvimento de um reconhecedor automático de voz para Português Brasileiro. Mais especificamente, as principais contribuições dessa dissertação são: o desenvolvimento de alguns recursos necessários para a construção de um reconhecedor, tais como: bases de áudio transcrito e API para desenvolvimento de aplicações; e o desenvolvimento de duas aplicações: uma para ditado em sistema desktop e outra para atendimento automático em um call center. O Coruja, sistema desenvolvido no LaPS para reconhecimento de voz em Português Brasileiro. Este alem de conter todos os recursos para fornecer reconhecimento de voz em Português Brasileiro possui uma API para desenvolvimento de aplicativos. O aplicativo desenvolvido para ditado e edição de textos em desktop e o SpeechOO, este possibilita o ditado para a ferramenta Writer do pacote LibreOffice, alem de permitir a edição e formatação de texto com comandos de voz. Outra contribuição deste trabalho e a utilização de reconhecimento automático de voz em call centers, o Coruja foi integrado ao software Asterisk e a principal aplicação desenvolvida foi uma unidade de resposta audível com reconhecimento de voz para o atendimento de um call center nacional que atende mais de 3 mil ligações diárias.

Agent Based Intrusion Detection and Response System for Wireless LANs

Wireless LAN technology, despite the numerous advantages it has over competing technologies, has not seen widespread deployment. A primary reason for markets not adopting this technology is its failure to provide adequate security. Data that is sent over wireless links can be compromised with utmost ease. In this project, we propose a distributed agent based intrusion detection and response system for wireless LANs that can detect unauthorized wireless elements like access points, wireless clients that are in promiscuous mode etc. The system reacts to intrusions by either notifying the concerned personnel, in case of rogue access points and promiscuous nodes, or by blocking unauthorized users from accessing the network resources.

Distributed Hybrid Agent Based Intrusion Detection and Real Time Response System

Wireless LANs are growing rapidly and security has always been a concern. We have implemented a hybrid system, which will not only detect active attacks like identity theft causing denial of service attacks, but will also detect the usage of access point discovery tools. The system responds in real time by sending out an alert to the network administrator.

MHP Oriented Interactive Augmented Reality System for Sports Broadcasting Environments

Television and movie images have been altered ever since it was technically possible. Nowadays embedding advertisements, or incorporating text and graphics in TV scenes, are common practice, but they can not be considered as integrated part of the scene. The introduction of new services for interactive augmented television is discussed in this paper. We analyse the main aspects related with the whole chain of augmented reality production. Interactivity is one of the most important added values of the digital television: This paper aims to break the model where all TV viewers receive the same final image. Thus, we introduce and discuss the new concept of interactive augmented television, i. e. real time composition of video and computer graphics - e.g. a real scene and freely selectable images or spatial rendered objects - edited and customized by the end user within the context of the user's set top box and TV receiver.

An evaluation of the personal response system program for the elderly in Harris County, Texas

The Personal Response System Program at Huffington Center on Aging, Baylor College of Medicine, provides emergency call systems for elderly people living independently in Houston, Texas. The goal of the project was to complete a formative evaluation of the Personal Response System Program. The specific aims of the evaluation were three-fold. One aim was to evaluate participant health status and level of disability. The second aim was to develop a health care cost estimation strategy. Finally, a preliminary cost-effectiveness analysis was completed to evaluate the program's impact on health care costs and health status among the elderly target population. ^ The evaluation was a longitudinal, randomized experimental design. After the screening of 120 volunteers for eligibility, clients were asked to complete a written questionnaire and a monthly health service contact diary. Volunteers were contacted by telephone interviewers to collect health status information from 100 eligible clients (83%) on three occasions during the six months of follow-up. ^ Initially, volunteers were randomized to two experimental groups. The two groups were found to be comparable at the beginning of the study. No significant differences were detected related to health status, level of disability, or history of physician visits at baseline. However, the group with the Personal Response System (PRS) device had more adverse health events, higher IADL scores, more frequent use of walkers, lower average health status scores, and fewer community volunteers hours than the usual care comparison group. ^ The health care costs were estimated based on an algorithm adapted from the American Medical Association guidelines. Average total health care costs for the group with the PRS device ($912) were greater than the usual care group ($464). However, median health care values for the PRS group ($263) were similar to the usual care comparison group ($234). The preliminary findings indicated that the use of the PRS device was not associated with health care cost savings. ^ In the preliminary cost-effectiveness analysis, use of the personal response system was found to be associated with increased mental health status among elderly clients. The cost-effectiveness evaluation indicated that the associated cost for six months was $710 per unit increase in mental component score when the $150 PRS subscription was included. However, clients with the PRS device were found to have a greater decline in physical health status during the six-month follow-up. The beneficial effect on mental health status was found to be in contrast to negative findings associated with changes in physical health status. The implications for future research relate to the need to identify risk factors among geriatric populations to better target groups that would most likely benefit from PRS Program enrollment. ^

Enhancing web-based learning resources with quizzes through an Authoring Tool and an Audience Response System

Quizzes are among the most widely used resources in web-based education due to their many benefits. However, educators need suitable authoring tools that can be used to create reusable quizzes and to enhance existing materials with them. On the other hand, if teachers use Audience Response Systems (ARSs) they can get instant feedback from their students and thereby enhance their instruction. This paper presents an online authoring tool for creating reusable quizzes and enhancing existing learning resources with them, and a web-based ARS that enables teachers to launch the created quizzes and get instant feedback from the class. Both the authoring tool and the ARS were evaluated. The evaluation of the authoring tool showed that educators can effectively enhance existing learning resources in an easy way by creating and adding quizzes using that tool. Besides, the different factors that assure the reusability of the created quizzes are also exposed. Finally, the evaluation of the developed ARS showed an excellent acceptance of the system by teachers and students, and also it indicated that teachers found the system easy to set up and use in their classrooms.