Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): A phase 3 randomised controlled trial
De Stefano N.,University of Siena |
Freedman M.S.,Ottawa Hospital General Campus |
Barkhof F.,Diagnostic Radiology and Image Analysis Center |
Polman C.H.,Medical Center |
And 7 more authors.
The Lancet Neurology | Year: 2012
Background: In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event. Methods: We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18-50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00404352. Findings: 517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p<0·0001, hazard ratio [HR] 0·49 [95% CI 0·38-0·64]; once a week 75·5%, p=0·008, HR 0·69 [0·54-0·87]) versus placebo (85·8%). 2-year rates of conversion to CDMS were lower for both interferon beta-1a dosing regimens (three times a week 20·6%, p=0·0004, HR 0·48 [0·31-0·73]; once a week 21·6%, p=0·0023, HR 0·53 [0·35-0·79]) than for placebo (37·5%). Adverse events were within the established profile for subcutaneous interferon beta-1a. Interpretation: Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study. Funding: Merck Serono SA, Geneva, Switzerland. © 2012 Elsevier Ltd.
Tasca G.A.,Ottawa Hospital General Campus
Psychotherapy | Year: 2014
The application of attachment theory to adult psychotherapy represents a growing area of research and practice. Despite the conceptual overlap between group therapeutic factors, attachment theory, and therapeutic tasks as outlined by Bowlby (1988), there is little research on attachment functioning in group therapy. Hence, there remain substantial questions about the role of attachment theory in understanding group therapy processes and outcomes. The three studies in this special section advance the research in some of these important areas, including showing that positive changes in self-reported attachment insecurity among clients persist long after group therapy ends; attachment anxiety affects the level and rate of interpersonal learning in groups; and change in attachment to the therapy group has an impact on longer term change in individual group members' attachment. Each article also examines the impact of these attachment concepts on treatment outcomes. Numerous areas remain to be explored when it comes to the implications of attachment theory for understanding and conducting group therapy, including the conceptual and practical overlap between attachment concepts such as security and exploration with group therapeutic factors such as cohesion and interpersonal learning. The articles in this special section begin to address some of these issues related to attachment theory and its implications for group therapists. © 2013 American Psychological Association.
Crawley A.M.,Ottawa Hospital Research Institute |
Crawley A.M.,University of Ottawa |
Faucher S.,Center for Infectious Disease Prevention and Control Health Canada |
Angel J.B.,Ottawa Hospital Research Institute |
And 2 more authors.
Journal of Immunology | Year: 2010
Soluble CD127 (sCD127) appears to play an important role in the immunopathogenesis of several chronic infections, multiple sclerosis, and various cancers. The function of sCD127 and whether it influences IL-7 bioavailability or activity is unknown. In this study, we demonstrated that recombinant and native sources of sCD127 significantly inhibited IL-7-mediated STAT5 and Akt phosphorylation in CD8+ T cells. IL-7-mediated proliferation and Bcl-2 expression were similarly reduced by sCD127. In each case, native sCD127 inhibited IL-7 activity to a greater degree than rsCD127. Anti-IL-7 activity was inherent to human plasma and could be reversed by depletion of CD127, revealing for the first time the biological activity of naturally occurring sCD127. Plasma sCD127 concentrations were increased in HIV+ individuals compared with HIV- controls, correlated with IL-7 levels, and remained unchanged in HIV+ individuals following 1 y of effective antiretroviral therapy. Determining the regulation and function of sCD127 may be critical for understanding both the pathogenesis of diseases in which IL-7 likely has a role (e.g., HIV infection, cancer) and its potential impact on IL-7 as a therapeutic approach. Copyright © 2010 by The American Association of Immunologists, Inc.
Glazebrook M.,Dalhousie University |
Younger A.,BC Foot and Ankle Clinic |
Wing K.,BC Foot and Ankle Clinic |
Lalonde K.-A.,Ottawa Hospital General Campus
Foot and Ankle International | Year: 2013
Background: To reduce fusion nonunion, autogenous bone graft is often incorporated into foot and ankle fusion procedures. B2A peptide-coated ceramic granules, with encouraging results in pilot studies of transforaminal lumbar interbody fusion, were here reformulated into Amplex with a coating concentration of 225 ìg B2A/cm3 ceramic granules (B2A-granule) with the goal of eliminating autogenous bone graft in foot and ankle arthrodesis. The purpose of this study was to perform a multicenter prospective randomized pilot clinical trial designed to compare the safety and effectiveness of B2A-granule to autogenous bone graft in patients undergoing foot and ankle arthrodesis surgery. Methods: This study was a multicenter, prospective, randomized, pilot clinical trial designed to compare safety and effectiveness of B2A-granule to autogenous bone graft in patients undergoing foot and ankle arthrodesis surgery. Twentyfour patients were enrolled and randomized (1:1) into 2 groups: autogenous bone graft control and B2A-granule. Primary outcome measures at 6 months (with follow-up at 9 and 12 months) included radiographic fusion assessed by computerized tomography and Ankle Osteoarthritis Scale scores for pain and disability. Results: Radiographic fusion success rates were similar in both groups (100% in the B2A-granule group, 92% autograft). Both the B2A-granule group and the autograft group had improvements in the pain and disability scores over the course of the study. Graft harvest-site pain affected only autograft-treated patients. There were no adverse events attributed to the graft material in either the B2A-granule or autograft group. Conclusion: The results of this pilot study are supportive of a larger clinical trial to assess the safety and efficacy of B2Agranule as a bone graft substitute in foot and ankle fusions. Level of Evidence: Level II, prospective comparative study. © 2013 The Author(s).
Hack K.,Ottawa Hospital General Campus |
Di Primio G.,Ottawa Hospital General Campus |
Rakhra K.,Ottawa Hospital General Campus |
Beaule P.E.,Ottawa Hospital General Campus
Journal of Bone and Joint Surgery - Series A | Year: 2010
Background: Femoroacetabular impingement is a cause of hip pain in adults and is a possible precursor of osteoarthritis, with the cam type of impingement being the most common. The purpose of this study was to determine the prevalence of cam-type morphology of the hip in asymptomatic patients. Methods: Two hundred asymptomatic volunteers with no prior hip surgery or childhood hip problems underwent magnetic resonance imaging targeted to both hips. The subjects were examined at the time of magnetic resonance imaging for internal rotation of the hips at 90° of hip flexion and for a positive impingement sign. The contour of the femoral head-neck junction was quantified with use of the alpha angle. A value of >50.5° was considered positive for cam morphology. Measurements were performed independently by two musculoskeletal radiologists. Results: The mean age of the individuals was 29.4 years (range, 21.4 to 50.6 years); 79% were white, and 55.5% were women. The mean alpha angle anteriorly at the three o'clock position was 40.9° ± 7.0° on the right and 40.6° ± 7.1° on the left, whereas the mean alpha angle anterosuperiorly at the 1:30 position was 50.2° ± 8.0° on the right and 50.1° ± 8.3° on the left. Fourteen percent of the volunteers had at least one hip with cam morphology: 10.5% had an elevated alpha angle on either the right or the left side, and 3.5% had the deformity in both hips. Seventy-nine percent (twenty-two) of twenty-eight individuals who had an elevated alpha angle were men, and 21% (six) were women. Individuals with an elevated alpha angle on at least one side tended to be male (p < 0.001), with 24.7% (twenty-two) of eighty-nine men having cam morphology compared with only 5.4% (six) of 111 women. Conclusions: The prevalence of cam-type femoroacetabular impingement deformity is higher in men as well as in individuals with decreased internal rotation. Defining what represents a normal head-neck contour is important for establishing treatment strategies in patients presenting with prearthritic hip pain. Copyright © 2010 by The Journal of Bone and Joint Surgery, Incorporated.
Crawley A.M.,Ottawa Hospital Research Institute |
Crawley A.M.,University of Ottawa |
Angel J.B.,Ottawa Hospital Research Institute |
Angel J.B.,University of Ottawa |
Angel J.B.,Ottawa Hospital General Campus
Seminars in Immunology | Year: 2012
Interleukin-7 (IL-7) is critical for early T-cell development and plays an important role in T-cell homeostasis, differentiation and function. Signalling via the IL-7 receptor is dependent on the expression of its components, IL-7Rα (CD127) and IL-2Rγ (CD132) and is mediated in part by alterations in CD127 expression levels in different cell subsets. Naïve and memory T-cells express high levels of CD127, while effector cells are CD127 lo and retention of the receptor is thought to influence the development of memory cells. Reduced expression of CD127 has been associated with markers of disease severity in HIV infection and other chronic viral infections as well as in various cancers. In HIV infection, decreased CD127 expression on T-cells is correlated with reduced CD4 + T-cell counts, increased viral replication and immune activation. The loss of IL-7 activity, due to decreased CD127 expression, may contribute to the observed loss of CD8 + cytotoxic T lymphocyte (CTL) activity in HIV infection. The downregulation of CD127 expression in HIV infection may be due to host (e.g. IL-7, IL-4, immune activation) and/or viral (e.g. HIV-tat) factors and mechanisms of receptor regulation may differ by cell type. In addition, the expression of a soluble form of CD127 (sCD127) has been shown to be increased in HIV infection. This protein may affect IL-7 activity in vivo and therefore may have implications for IL-7-based therapies which are currently being tested in clinical trials. Understanding how CD127 is regulated during HIV infection will provide insight for the development of novel therapeutics to improve immune function and anti-viral T-cell activity. © 2012 Elsevier Ltd.
Rakhra K.S.,Ottawa Hospital General Campus
Journal of Bone and Joint Surgery - Series A | Year: 2011
The acetabular labrum plays an important role in hip biomechanical function and stability. Labral tears can result in appreciable clinical symptoms and joint dysfunction and may predispose the hip to chondral damage and osteoarthritis. Magnetic resonance imaging is an effective tool for detecting and characterizing labral tears. Direct magnetic resonance arthrography is the most commonly used and validated technique for evaluating the labrum. However, indirect magnetic resonance arthrography and non-arthrographic magnetic resonance imaging are two less invasive and less resource-intensive techniques that should also be considered. Orthopaedic surgeons and radiologists should strive to develop and implementminimally and noninvasive diagnostic magnetic resonance imaging protocols for the investigation of labral pathology. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.
Cooper C.,Ottawa Hospital General Campus |
MacKie D.,Ottawa Hospital General Campus
Expert Review of Vaccines | Year: 2011
Immunization represents the most effective approach to the prevention of hepatitis B virus infection and the long-term complications of chronic disease, including liver cancer and liver failure. Current vaccines require three doses to achieve maximal immunogenicity and fail to produce long-lasting protection in 5-10% of immune-competent individuals and in a much larger proportion of immune-compromised patients. Immunostimulatory DNA sequence (ISS) vaccine adjuvants, when combined with vaccine antigens, may increase immunogenicity and reduce the number of required doses to achieve this goal. 1018 ISS plus recombinant hepatitis B surface antigen has been demonstrated to achieve these goals in immune competent and vaccine-hyporesponsive populations without compromising recipient safety. © 2011 Expert Reviews Ltd.
Freedman M.S.,University of Ottawa |
Freedman M.S.,Ottawa Hospital General Campus
Neurology | Year: 2011
Goals in the treatment of multiple sclerosis (MS) focus on reducing symptoms and disease progression. Registry data indicate that the accumulation of significant disability can take decades. Therefore, long-term follow-up (LTFU) studies are needed to understand the impact of disease-modifying therapy (DMT) in MS. Based on analyses of available LTFU study data, recommendations for future LTFU studies can be made. A disability milestone may be considered because exploratory data show that DMT may slow the progression of disability. Achievement of the EDSS steps 4 or 6 may be sufficient milestones because, once reached, MS progresses inevitably. Since a placebo control cannot be ethically used in LTFU studies, a standard-of-care comparator could be considered. The ideal LTFU study should be performed according to the highest possible standards. A high-quality LTFU study would achieve high retention rates, capture complete data at prespecified assessment intervals, and be powered to the key outcome measure. In addition, propensity scoring is an approach used to reduce bias in treatment comparisons in observational studies and might be a suitable approach for analyzing LTFU studies. With careful consideration of LTFU limitations and study design, it is possible to attain a high degree of rigor in future studies. Copyright © 2011 by AAN Enterprises, Inc.
Beaule P.E.,Ottawa Hospital General Campus |
Hynes K.,Ottawa Hospital General Campus |
Parker G.,Ottawa Hospital General Campus |
Kemp K.A.,Ottawa Hospital General Campus
Clinical Orthopaedics and Related Research | Year: 2012
Background: Substantial acetabular cartilage damage is commonly present in patients suffering from femoral acetabular impingement (FAI). A better understanding of which patient is at risk of developing substantial cartilage damage is critical for establishing appropriate treatment guidelines. Questions/Purposes: We asked: (1) Does the cam deformity severity in FAI as assessed by alpha angle predict acetabular cartilage delamination? And (2) what are the clinical and radiographic findings in patients with acetabular cartilage delamination? Methods: One hundred sixty-seven patients (129 males, 38 females) with a mean age of 38 years (range, 17-59 years) underwent joint preservation surgery for cam-type FAI. All data were collected prospectively. We assessed center-edge angle and Tönnis grade on AP radiographs and alpha angle on specialized lateral radiographs. Acetabular cartilage damage was assessed intraoperatively using the classification of Beck et al., with Type 3 and greater qualifying as delamination. Results: For all hips, mean alpha angle was 65.5° (range, 41°-90°), and mean center-edge angle was 33.3° (range, 21°-52.5°). Patients with an alpha angle of 65° or greater had an odds ratio (OR) of 4.00 (95% CI, 1.26-12.71) of having Type 3 or greater damage. Increased age (OR, 1.04; 95% CI, 1.01-1.07) and male sex (OR, 2.24; 95% CI, 1.09-4.62) were associated with Type 3 or greater damage, while this was the opposite for acetabular coverage as assessed by center-edge angle (OR, 0.94; 95% CI, 0.89-0.99). Conclusions: Patients with cam-type FAI and an alpha angle of 65° or more are at increased risk of substantial cartilage damage while increasing acetabular coverage appears to have a protective effect. Level of Evidence: Level III, prognostic study. See the Instructions for Authors for a complete description of levels of evidence. © The Association of Bone and Joint Surgeons® 2012.