Intravenous dosing of tocilizumab in patients younger than two years of age with systemic juvenile idiopathic arthritis

The anti-interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years.Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2-17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing < 30 kg (n = 38) who received tocilizumab 12 mg/kg IV Q2W in the previous trial (control group).Eleven patients (mean age, 1.3 years) received tocilizumab during the main evaluation period. The primary end point was met: tocilizumab exposures for patients younger than 2 were within the range of the control group (mean [±SD] μg/mL concentration at the end-of-dosing interval [Cmin]: 39.8 [±14.3] vs 57.5 [±23.3]; maximum concentration [Cmax] postdose: 288 [±40.4] vs 245 [±57.2]). At week 12, pharmacodynamic measures were similar between patients younger than 2 and the control group; mean change from baseline in Juvenile Arthritis Disease Activity Score-71 was - 17.4 in patients younger than 2 and - 28.8 in the control group; rash was reported by 14.3 and 13.5% of patients, respectively. Safety was comparable except for the incidence of serious hypersensitivity reactions (27.3% in patients younger than 2 vs 2.6% in the control group).Tocilizumab 12 mg/kg IV Q2W provided pharmacokinetics, pharmacodynamics, and efficacy in sJIA patients younger than 2 comparable to those in patients aged 2 to 17 years. Safety was comparable except for a higher incidence of serious hypersensitivity events in patients younger than 2 years.Juvenile idiopathic arthritis.ClinicalTrials.gov, NCT01455701 . Registered, October 20, 2011, Date of enrollment of first participant: October 26, 2012

Cross-Serotype Immunity Induced by Immunization with a Conserved Rhinovirus Capsid Protein

Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of ∼150 strains. We aimed to define highly conserved areas of the RV proteome and test their usefulness as candidate antigens for a broadly cross-reactive vaccine, using a mouse infection model. Regions of the VP0 (VP4+VP2) capsid protein were identified as having high homology across RVs. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype, cellular and humoral immune responses. Similar cross-reactive responses were observed in the lungs of immunized mice after infection with heterologous RV strains. Immunization enhanced the generation of heterosubtypic neutralizing antibodies and lung memory T cells, and caused more rapid virus clearance. Conserved domains of the RV capsid therefore induce cross-reactive immune responses and represent candidates for a subunit RV vaccine

Enhancing learning for Visually Impaired with technology: MATHVIS

Mathematics for Visually Impaired Students (MATHVIS) is a researched and developed software application that is capable of uplifting the educational background of visually impaired students. This research focuses on providing access to education for all, including the visually impaired, using MATHVIS, which embraces game based learning methodology. The critical factor in the project is the use of sound to communicate with the visually impaired students. All voice instructions were provided along with soundtracks and a menu to enable selecting local languages such as Sinhala and English. The main emphasis of this paper is to discuss the current generation of MATHVIS, which has been extended in several ways, through intensive evaluation and testing. The evaluators selected from categories such as technical personnel, instructors and visually impaired students carried out in depth reviews of the application. This paper discusses the features of the application, evaluation carried out, the technology and learning pedagogy used to develop the application for visually impaired students. The paper also highlights how MATHVIS can be used to provide education for all, including the visually impaired

MATHVIS

MATHVIS is a researched and developed software application that is capable of uplifting the educational background of visually impaired children. Education which is a knowledge gaining activity that all individuals cherish throughout their lives and enables access to a career path is not confined to any age, gender or culture. This research focuses on providing access to education for all, including the visually impaired. MATHVIS has been developed using game based learning properties, mainly targeting the visually impaired. Several resources that facilitate learning for the visually impaired were identified. However, it was noted that resources were limited to learn mathematics using local languages for visually impaired children in Sri Lanka. Hence, the aim of the research was to develop the mathematical knowledge of visually impaired Sri Lankan students. Since the target user group for this game is visually impaired children, the requirements were based on their capabilities and requirements. Sound was a key feature used to facilitate communicating with visually impaired students. Therefore, user input, selection of options and other facilities were provided along with sound tracks and a menu to enable selecting native languages such as Sinhala and English. The game consists of three levels made up of simple maths concepts such as addition, subtraction, number series and equations as well as scenario based questions. Level one consists of simple addition and subtraction questions. Supporting the requirements of the user, the questions for this level are mainly one or two digit number calculations. Level two consists of two sections; the first includes questions from the number series and the second includes questions from equations. In section one, the user is provided with a blank space to input the answer where as in the second, the user calculates the value of a given unknown letter. Level three consists of scenario based questions where the user has to listen and understand the scenario to answer the relevant question correctly. The game was developed mainly using Java Language and applications such as Netbeans 6.0. Microsoft Access was used to store data. The only way in which a visually impaired child can communicate with this application is through sound. Therefore, this game uses voice instructions with the help of software such as Text Aloud and Jet Audio. The evaluators for the game were from different categories, namely; technical evaluators, the users of the system, visually impaired students and instructors for visually impaired. The students requested incorporating changes that would enhance the language selection process. The instructors recommended limiting the number range to two digits. All evaluators provided positive comments about functionalities and ease of use of the tool. This paper discusses features of the application, evaluation carried out and the technology and learning pedagogy used to develop the application. The paper also looks at how this application can be used to provide education for all, including visually impaired children

Brain volume abnormalities and clinical outcomes following paediatric traumatic brain injury

Long-term outcomes are difficult to predict after paediatric traumatic brain injury. The presence or absence of focal brain injuries often do not explain cognitive, emotional and behavioural disabilities that are common and disabling. In adults, traumatic brain injury produces progressive brain atrophy that can be accurately measured and is associated with cognitive decline. However, the effect of paediatric traumatic brain injury on brain volumes is more challenging to measure because of its interaction with normal brain development. Here we report a robust approach to the individualised estimation of brain volume following paediatric traumatic brain injury and investigate its relationship to clinical outcomes. We first used a large healthy control dataset (N>1200, age 8-22) to describe the healthy development of white and grey matter regions through adolescence. Individual estimates of grey and white matter regional volume were then generated for a group of moderate/severe traumatic brain injury patients injured in childhood (N=39, mean age 13.53±1.76, median time since injury = 14 months, range 4 – 168 months) by comparing brain volumes in patients to age matched controls. Patients were individually classified as having low or normal brain volume. Neuropsychological and neuropsychiatric outcomes were assessed using standardised testing and parent/carer assessments. Relative to head size, grey matter regions decreased in volume during normal adolescence development whereas white matter tracts increased in volume. Traumatic brain injury disrupted healthy brain development, producing reductions in both grey and white matter brain volumes after correcting for age. Of the 39 patients investigated, 11 (28%) had at least one white matter tract with reduced volume and seven (18%) at least one area of grey matter with reduced volume. Those classified as having low brain volume had slower processing speed compared to healthy controls, emotional impairments, higher levels of apathy, increased anger and learning difficulties. In contrast, the presence of focal brain injury and microbleeds were not associated with an increased risk of these clinical impairments. In summary, we show how brain volume abnormalities after paediatric traumatic brain injury can be robustly calculated from individual T1 magnetic resonance imaging using a large normative dataset that allows the effects of healthy brain development to be controlled for. Using this approach we show that volumetric abnormalities are common after moderate/severe traumatic brain injury in both grey and white matter regions, and are associated with higher levels of cognitive, emotional and behavioural abnormalities that are common after paediatric traumatic brain injury

Tbet Deficiency Causes T Helper Cell Dependent Airways Eosinophilia and Mucus Hypersecretion in Response to Rhinovirus Infection

Current understanding of adaptive immune, particularly T cell, responses to human rhinoviruses (RV) is limited. Memory T cells are thought to be of a primarily T helper 1 type, but both T helper 1 and T helper 2 memory cells have been described, and heightened T helper 2/ lessened T helper 1 responses have been associated with increased RV-induced asthma exacerbation severity. We examined the contribution of T helper 1 cells to RV-induced airways inflammation using mice deficient in the transcription factor T-Box Expressed In T Cells (Tbet), a critical controller of T helper 1 cell differentiation. Using flow cytometry we showed that Tbet deficient mice lacked the T helper 1 response of wild type mice and instead developed mixed T helper 2/T helper 17 responses to RV infection, evidenced by increased numbers of GATA binding protein 3 (GATA-3) and RAR-related orphan receptor gamma t (RORγt), and interleukin-13 and interleukin-17A expressing CD4+ T cells in the lung. Forkhead box P3 (FOXP3) and interleukin-10 expressing T cell numbers were unaffected. Tbet deficient mice also displayed deficiencies in lung Natural Killer, Natural Killer T cell and γδT cell responses, and serum neutralising antibody responses. Tbet deficient mice exhibited pronounced airways eosinophilia and mucus production in response to RV infection that, by utilising a CD4+ cell depleting antibody, were found to be T helper cell dependent. RV induction of T helper 2 and T helper 17 responses may therefore have an important role in directly driving features of allergic airways disease such as eosinophilia and mucus hypersecretion during asthma exacerbations