Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups

OBJECTIVES: To describe the efficacy, safety, and exposure-response relationship of canakinumab in a subgroup of patients with systemic juvenile idiopathic arthritis (SJIA) aged ≥16 years, representative of adult-onset Still's disease (AOSD) patients, and to compare this subgroup with those of children and young adolescents with SJIA by pooling clinical data collected during the development programme of canakinumab. METHODS: Safety and efficacy data on canakinumab-treated patients were pooled from 4 SJIA studies (NCT00426218, NCT00886769, NCT00889863, and NCT00891046). In the majority of patients, canakinumab was administered at 4 mg/kg every 4 weeks. Efficacy parameters (adapted American College of Rheumatology [aACR] paediatric and juvenile idiopathic arthritis [JIA] ACR responses), quality of life, C-reactive protein levels, safety, and exposure-response relationship were assessed over 12 weeks in 3 age groups (children 2-<12, young adolescents 12-<16 and older adolescents and young adults ≥16 years). RESULTS: Efficacy outcomes were analysed in 216 children, 56 young adolescents and 29 older adolescents and young adults. Efficacy parameters across 3 age groups were largely comparable. At Day 15, at least 50% of patients from each age group exhibited aACR ≥70 and ACR responses. The safety profile of canakinumab was similar across age groups. One death was reported. CONCLUSIONS: Pooled analyses from SJIA studies indicate that older adolescents and young adults SJIA patients show similar efficacy, safety, and exposure-response relationship on a weight-based dosing regimen as observed in children and adolescent SJIA patients. These analyses suggest that canakinumab may be an effective therapy in young adults with Still's disease

Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study

Purpose: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. Methods: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. Results: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to$1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. Conclusions: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research

Establishing the functional role of ORMDL3 in innate immunity

Asthma and allergic diseases are rapidly becoming the most common chronic diseases in the developed world. Nearly 1 in 3 Canadians suffer from some form of allergy and more than 300 million individuals in the developed world suffer from asthma. These complex disorders are caused by the interaction of various genetic and environmental factors. Genome-wide association studies have been widely used to identify genes associated with asthma susceptibility. The gene, ORMDL3, was shown to be associated with early-onset asthma. Asthmatic patients have elevated expression levels of this gene. The gene encodes a transmembrane protein localized in the endoplasmic reticulum (ER) that may be involved in ER stress and inflammation. Its functional role in asthma pathogenesis, however, has yet to be elucidated. In this research, we investigated the functional role of ORMDL3 in innate immunity. Experimentally, ORMDL3 expression levels were manipulated in vitro in airway cells using overexpression plasmid and siRNA technologies. The effects of ORMDL3 expression levels on inflammatory responses were then explored. After manipulation of ORMDL3 expression levels, cells were stimulated with various immune response-inducing factors. Supernatants collected after stimulation were analyzed and no differences in proinflammatory cytokine production were observed. These results suggest that variation in ORMDL3 expression levels does not affect innate immune production of IL-6 and IL-8 in airway cells. ORMDL3 knockdown also did not affect expression of other immune-related genes.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat

HIV-infected women: Barriers to AZT use

AZT has become a mainstay drug in efforts to slow disease progression in HIV-infected individuals. Further, recent evidence indicates that AZT use by pregnant infected women and their neonates may reduce the risk of vertical transmission. In a study of HIV-infected women's treatment-related behavior, attitudes toward the use of this drug were examined. Data were gathered through unstructured interviewing techniques. The data from the first 71 women accrued revealed that negative attitudes towards its use were widely prevalent. Women viewed the drug as highly toxic, prescribed indiscriminately, inadequately tested in women and minorities, promoted for the wrong reasons and inappropriate while they were feeling well. The findings suggest that removing attitudinal barriers to the use of AZT will be important to both primary and secondary prevention efforts.HIV/AIDS HIV-infected women AZT

Perceiving benefits in adversity: stress-related growth in women living with HIV/AIDS

This study examines perceptions of illness-related positive of change or stress-related growth among a sample of African American, Puerto Rican, and non-Hispanic White women (n=54) living with HIV/AIDS in New York City, USA. While these women acknowledged the negative stresses of living with HIV/AIDS, 83% reported at least one positive change in their lives that they attributed to their illness experience. A number of different domains of potential growth were identified including: health behaviors, spirituality, interpersonal relationships, view of the self, value of life, and career goals. While growth was reported by nearly all the women, some variation was found in the forms of growth reported in relation to the women's ethnic/racial background, class, and IV drug use history. These data suggest an expanded conceptualization of stress-related growth that includes behavioral aspects of growth in response to stress and illness, and which takes into account the diverse ways in which growth may be experienced.Stress-related growth Coping HIV/AIDS Women New York City

Functional analysis of the impact of ORMDL3 expression on inflammation and activation of the unfolded protein response in human airway epithelial cells

Background: The gene ORMDL3 was shown to be associated with early-onset asthma susceptibility in multiple independent genome-wide and candidate-gene association studies. Asthmatic patients have elevated expression levels of this gene. ORMDL3 encodes a transmembrane protein localized in the endoplasmic reticulum (ER) that may be involved in ER stress and inflammation. It is essential to validate the genetic associations linking ORMDL3 with asthma through functional studies that confirm the biological relevance of this gene in disease. We investigated the effects of manipulating ORMDL3 expression levels in vitro in airway cells on innate immune inflammatory responses, ER stress and activation of the unfolded protein response (UPR). Methods: ORMDL3 expression levels were manipulated in airway cells using an overexpression plasmid and siRNA technologies. Successful modulation of ORMDL3 was confirmed at both the gene and protein level. The functional impact of modulation of ORMDL3 expression levels on inflammatory responses and activation of the UPR were quantified using complementary cellular and molecular immunology techniques. Results: Cells with altered ORMDL3 levels responded equally well to innate immune stimuli and produced similar levels of pro-inflammatory cytokines compared to wild-type cells. Treatment with ER stress inducers, thapsigargin and tunicamycin, resulted in activation of the unfolded protein response (UPR). However, we observed no difference in UPR activation in cells with ORMDL3 knockdown compared to cells with normal ORMDL3 levels. Conclusions: Our results suggest that ORMDL3 variation in the airway epithelium is unlikely to play a significant role in modulating innate immune responses and the UPR in the lung.Medicine, Faculty ofOther UBCNon UBCReviewedFacult

¿Es justificable para las instituciones de salud la inclusión de urgentólogos en los equipos de emergencias médicas?

Purpose of the review: This review aims at answering whether it is justified to include emergency physicians in the medical emergency teams (METs). Material and methods: The relevant literature was analyzed and selected in Pubmed and Medline, using the following terms: �Medical Emergency Teams�, �Rapid Response Teams�, �Acute Teams�, and combined with �Emergency Medicine�, �Emergency Physicians� and �Emergency Departments� from 1990 until 2009. Results: It is currently recommended to set up METs as a measure in favor of intra-hospital patient safety. Nevertheless, the literature shows some discrepancies because some studies suggest that the intervention of such teams do not reduce the frequency of heart and respiratory failure nor admissions to the intensive care units. Therefore, it cannot be recommended to include emergency physicians within those teams given that the economic overcost involved for health institutions in emergency services may not compensate for the results achieved by METs.Propósito: esta revisión pretende responder a la pregunta si se justifica incluir médicos especialistas en medicina de urgencias en los equipos de emergencias médicas (EEM). Materiales y Métodos: se realizó la búsqueda y selección de la literatura relevantes en Pubmed y Medline, usando los términos: �Medical Emergency Teams�, �Rapid Response Teams�, �Acute Teams�; combinándolos con �Emergency Medicine�, �Emergency Physicians� y �Emergency Departments� desde 1990 hasta el año 2009. Resultados: Actualmente es recomendada la conformación de los EEM como una medida en pro de la seguridad intrahospitalaria del paciente; sin embargo la literatura es conflictiva ya que algunos estudios sugieren que las intervenciones de estos equipos no disminuyen la frecuencia de presentación del paro cardiorrespiratorio, ni las admisiones a las unidades de cuidados intensivos. No es posible justificar la presencia de urgentólogos en estos equipos desde el punto de vista terapéutico, pues no existe literatura que compare los resultados de estos equipos en cuanto a los miembros que los conforman, aunque desde el punto de vista administrativo la presencia de urgentólogos en los EEM potencialmente impacta negativamente en la dinámica del servicio de urgencias. En vista de lo anterior no es recomendable incluir médicos especialistas de medicina de urgencias en los EEM