Test-Retest and Interreader Reproducibility of Semiautomated Atlas-Based Analysis of Diffusion Tensor Imaging Data in Acute Cervical Spine Trauma in Adult Patients.

BACKGROUND AND PURPOSE: DTI is a tool for microstructural spinal cord injury evaluation. This study evaluated the reproducibility of a semiautomated segmentation algorithm of spinal cord DTI. MATERIALS AND METHODS: Forty-two consecutive patients undergoing acute trauma cervical spine MR imaging underwent 2 axial DTI scans in addition to their clinical scan. The datasets were put through a semiautomated probabilistic segmentation algorithm that selected white matter, gray matter, and 24 individual white matter tracts. Regional and white matter tract volume, fractional anisotropy, and mean diffusivity values were calculated. Two readers performed the nonautomated steps to evaluate interreader reproducibility. The coefficient of variation and intraclass correlation coefficient were used to assess test-retest and interreader reproducibility. RESULTS: Of 42 patients, 30 had useable data. Test-retest reproducibility of fractional anisotropy was high for white matter as a whole (coefficient of variation, 3.8%; intraclass correlation coefficient, 0.93). Test-retest coefficient-of-variation ranged from 8.0%-18.2% and intraclass correlation coefficients from 0.47-0.80 across individual white matter tracts. Mean diffusivity metrics also had high test-retest reproducibility (white matter: coefficient-of-variation, 5.6%; intraclass correlation coefficient, 0.86) with coefficients of variation from 11.6%-18.3% and intraclass correlation coefficients from 0.57-0.74 across individual tracts, with better agreement for larger tracts. The coefficients of variation of fractional anisotropy and mean diffusivity both had significant negative relationships with white matter volume (26%-27% decrease for each doubling of white matter volume, P < .01). CONCLUSIONS: DTI spinal cord segmentation is reproducible in the setting of acute spine trauma, specifically for larger white matter tracts and total white or gray matter.

Rasch analysis of alcohol abuse and dependence diagnostic criteria in persons with spinal cord injury.

STUDY DESIGN: Cross-sectional. OBJECTIVE: The objective of the study is to examine whether alcohol use disorders should be conceptualized categorically as abuse and dependence as in the 'Diagnostic and Statistical Manual of Mental Disorders' 4th edition or on a single continuum with mild to severe category ratings as in the 'Diagnostic and Statistical Manual of Mental Disorders' 5th edition in people with spinal cord injury (SCI). SETTING: United States of America. METHODS: Data from 379 individuals who sustained SCI either traumatically or non-traumatically after the age of 18 and were at least 1 year post injury. Rasch analyses used the alcohol abuse and dependence modules of the Structured Clinical Interview for DSM-IV-TR Axis I Disorders Non-patient Edition (SCID-I/NP). RESULTS: Fifty-seven percent (n=166) of the entire sample endorsed criteria for alcohol abuse, and 25% (n=65) endorsed criteria for alcohol dependence. Fit values were generally acceptable except for one item (for example, alcohol abuse criterion 2), suggesting that the items fit the expectation of unidimensionality. Examination of the principal components analysis did not provide support for unidimensionality. The item-person map illustrates poor targeting of items. CONCLUSIONS: Alcohol abuse and dependence criterion appear to reflect a unidimensional construct, a finding that supports a single latent construct or factor consistent with the DSM-5 diagnostic model.

The influence of age at disease onset on disease activity and disability: results from the Ontario Best Practices Research Initiative.

This study aims to compare characteristics between late-onset rheumatoid arthritis (RA) and young-onset RA and determine the association between age at disease onset and disease severity. We cross-sectionally studied 971 patients at the time of entry into the Ontario Best Practices Research Initiative, a registry of RA patients followed up in routine care. We restricted patients to ≤5 years of disease duration. Late-onset RA was defined as an onset ≥60 years of age and young-onset RA <60 years. Group differences were compared, and multivariate linear regression models were used to test the influence of age at onset on Disease Activity Score in 28 Joints with erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), and Health Assessment Questionnaire (HAQ) scores. The swollen joint count (6.2 vs. 5.3), acute phase reactants (C-reactive protein (CRP) 17.4 vs. 11.8 mg/L, ESR 30.6 vs. 21.5 mm/h), and comorbidity burden were higher in late-onset RA compared to young-onset RA (p < 0.01). Mean DAS28-ESR (4.6 vs. 4.3) and HAQ (1.2 vs. 1.1) scores were higher in late-onset RA patients (p < 0.05). Late-onset RA patients received more initial disease-modifying antirheumatic drug (DMARD) monotherapy and corticosteroids in comparison to greater DMARD/biologic combination therapy in young-onset RA patients (p < 0.05). Adjusted multivariate analyses showed that late-onset RA was independently associated with higher mean DAS28-ESR and HAQ scores, but not CDAI. Late-onset RA patients have greater disease activity that may contribute to disability early in the disease course. Despite this, initial treatment consists of less combination DMARD and biologic use in late-onset RA patients. This may have implications for future response to therapy and development of joint damage, disability, and comorbidities in this group.

Screening for neuropathic pain after spinal cord injury with the spinal cord injury pain instrument (SCIPI): a preliminary validation study.

STUDY DESIGN: Cross-sectional. OBJECTIVE: To preliminarily evaluate the validity of an interview-based spinal cord injury (SCI) neuropathic pain screening instrument. SETTING: Six university-based SCI centers in the United States. METHODS: Clinician diagnoses of neuropathic pain (NP) and non-neuropathic pain subtypes were collected independently of descriptions of the pain characteristics provided by the persons with SCI by using the Spinal Cord Injury Pain Instrument (SCIPI); SCIPI information and physician diagnoses for 82 pain sites of which they were most confident were subsequently compared. RESULTS: Four of the SCIPI items correlated significantly with the NP subtype as determined by the clinician. The best cutoff score for identifying NP was an endorsement of two or more of these four items. Using this cutoff, sensitivity of the SCIPI was 78%, specificity was 73% and overall diagnostic accuracy was 76%. CONCLUSION: In this preliminary study, the SCIPI, which can be administered by a nonclinician, appears to have good sensitivity, specificity and diagnostic accuracy in a SCI population; it may have a role as a screening tool for NP after SCI. Further study is needed.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

Use of global assays to understand clinical phenotype in congenital factor VII deficiency.

Congenital factor VII (FVII) deficiency is characterized by genotypic variability and phenotypic heterogeneity. Traditional screening and factor assays are unable to reliably predict clinical bleeding phenotype and guide haemorrhage prevention strategy. Global assays of coagulation and fibrinolysis may better characterize overall haemostatic balance and aid in haemorrhagic risk assessment. We evaluated the ability of novel global assays to better understand clinical bleeding severity in congenital FVII deficiency. Subjects underwent central determination of factor VII activity (FVII:C) as well as clot formation and lysis (CloFAL) and simultaneous thrombin and plasmin generation (STP) global assay analysis. A bleeding score was assigned to each subject through medical chart review. Global assay parameters were analysed with respect to bleeding score and FVII:C. Subgroup analyses were performed on paediatric subjects and subjects with FVII ≥ 1 IU dL(-1). CloFAL fibrinolytic index (FI2 ) inversely correlated with FVII:C while CloFAL maximum amplitude (MA) and STP maximum velocity of thrombin generation (VT max) varied directly with FVII:C. CloFAL FI2 directly correlated with bleeding score among subjects in both the total cohort and paediatric subcohort, but not among subjects with FVII ≥ 1 IU dL(-1) . Among subjects with FVII ≥ 1 IU dL(-1), STP time to maximum velocity of thrombin generation and time to maximum velocity of plasmin generation inversely correlated with bleeding score. These preliminary findings suggest a novel potential link between a hyperfibrinolytic state in bleeding severity and congenital FVII deficiency, an observation that should be further explored.

Minimum clinically important improvement and patient acceptable symptom state in pain and function in rheumatoid arthritis, ankylosing spondylitis, chronic back pain, hand osteoarthritis, and hip and knee osteoarthritis: Results from a prospective multinational study.

OBJECTIVE: To estimate the minimum clinically important improvement (MCII) and patient acceptable symptom state (PASS) values for 4 generic outcomes in 5 rheumatic diseases and 7 countries. METHODS: We conducted a multinational (Australia, France, Italy, Lebanon, Morocco, Spain, and The Netherlands) 4-week cohort study involving 1,532 patients who were prescribed nonsteroidal antiinflammatory drugs for ankylosing spondylitis, chronic back pain, hand osteoarthritis, hip and/or knee osteoarthritis, or rheumatoid arthritis. The MCII and PASS values were estimated with the 75th percentile approach for 4 generic outcomes: pain, patient global assessment, functional disability, and physician global assessment, all normalized to a 0-100 score. RESULTS: For the whole sample, the estimated MCII values for absolute change at 4 weeks were -17 (95% confidence interval [95% CI] -18, -15) for pain; -15 (95% CI -16, -14) for patient global assessment; -12 (95% CI -13, -11) for functional disability assessment; and -14 (95% CI -15, -14) for physician global assessment. For the whole sample, the estimated PASS values were 42 (95% CI 40, 44) for pain; 43 (95% CI 41, 45) for patient global assessment; 43 (95% CI 41, 44) for functional disability assessment; and 39 (95% CI 37, 40) for physician global assessment. Estimates were consistent across diseases and countries (for subgroups ≥20 patients). CONCLUSION: This work allows for promoting the use of values of MCII (15 of 100 for absolute improvement, 20% for relative improvement) and PASS (40 of 100) in reporting the results of trials of any of the 5 involved rheumatic diseases with pain, patient global assessment, physical function, or physician global assessment used as outcome criteria.

Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.

OBJECTIVE: To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis (UPIA). METHODS: 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008-9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007-2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 39,756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA. CONCLUSIONS: Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use.

Systematic reviews of low back pain prognosis had variable methods and results: guidance for future prognosis reviews.

OBJECTIVE: Systematic reviews of prognostic factors for low back pain vary substantially in design and conduct. The objective of this study was to identify, describe, and synthesize systematic reviews of low back pain prognosis, and explore the potential impact of review methods on the conclusions. STUDY DESIGN AND SETTING: We identified 17 low back pain prognosis reviews published between 2000 and 2006. One reviewer extracted and a second checked review characteristics and results. Two reviewers independently assessed review quality. RESULTS: Review questions and selection criteria varied; there were both focused and broad reviews of prognostic factors. A quarter of reviews did not clearly define search strategies. The number of potential citations identified ranged from 15 to 4,458 and the number of included prognosis studies ranged from 3 to 32 (of 162 distinct citations included across reviews). Seventy percent of reviews assessed quality of included studies, but assessed only a median of four of six potential biases. All reviews reported associations based on statistical significance; they used various strategies for syntheses. Only a small number of important prognostic factors were consistently reported: older age, poor general health, increased psychological or psychosocial stress, poor relations with colleagues, physically heavy work, worse baseline functional disability, sciatica, and the presence of compensation. We found discrepancies across reviews: differences in some selection criteria influenced studies included, and various approaches to data interpretation influenced review conclusions about evidence for specific prognostic factors. CONCLUSION: There is an immediate need for methodological work in the area of prognosis systematic reviews. Because of methodological shortcomings in the primary and review literature, there remains uncertainty about reliability of conclusions regarding prognostic factors for low back pain.

Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.

OBJECTIVES: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. METHODS: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. CONCLUSIONS: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis. METHOD: A systematic review of randomised trials comparing MTX alone and in combination with other non-biological DMARDs was carried out. Trials were identified in Medline, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy. RESULTS: A total of 19 trials (2025 patients) from 6938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (relative risk (RR) = 1.16; 95% CI 0.70 to 1.93). Trials in MTX or non-MTX DMARD inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups (RR = 0.86; 95% CI 0.49 to 1.51 and RR = 0.75; 95% CI 0.41 to 1.35), but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed a better efficacy/toxicity ratio than MTX alone with RR = 0.3 (95% CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effects and liver toxicity. Withdrawals for toxicity were most significant with ciclosporin and azathioprine combinations. CONCLUSION: In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardised operating procedures, which use a three-step approach: (1) expert-based definition of relevant research questions (November 2006); (2) systematic literature search (November 2006 to May 2007); and (3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature the expert panel recommended that each trial should report the following items: (1) disease activity response and disease activity states; (2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; (3) baseline disease activity levels (in general); (4) the percentage of patients achieving a low disease activity state and remission; (5) time to onset of the primary outcome; (6) sustainability of the primary outcome; (7) fatigue. CONCLUSIONS: These recommendations endorsed by EULAR and ACR will help harmonise the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION: These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Setting the agenda for multiple sclerosis rehabilitation research.

BACKGROUND: Recognizing the need for more evidence-based multiple sclerosis (MS) rehabilitation, in the mid-2000s several initiatives were undertaken to explore why there had been a paucity of such research and to determine strategies to reverse this pattern. EXPERT-OPINION-PAPER: In 2004 the National Multiple Sclerosis Society (NMSS) convened an expert opinion panel, reviewed evidence-based MS rehabilitation research, and published the paper on the web. It was concluded that much of the MS rehabilitation carried out was based on experience, with little research backing it up. INCREASING THE QUALITY AND QUANTITY OF MS REHABILITATION RESEARCH: Largely as a result of the conclusions of the Expert-Opinion-Paper, the NMSS convened a conference of a large number of MS and rehabilitation experts in New York in May, 2005. This conference made many recommendations of ways to increase the quantity and quality of MS research. STATE OF THE SCIENCE CONFERENCE: In September, 2006, a follow-up conference was held in Washington, D.C... This conference, primarily sponsored by the University of Washington Multiple Sclerosis Rehabilitation Research and Training Center (MS RRTC), focused on some of the under-studied "hidden" disabilities present in persons with MS. This paper discusses the details and recommendations of these latter two conferences.

Identifying phases of investigation helps planning, appraising, and applying the results of explanatory prognosis studies.

OBJECTIVE: To present an explanatory framework for understanding prognosis and illustrate it using data from a systematic review. STUDY DESIGN AND SETTING: A framework including three phases of explanatory prognosis investigation was adapted from earlier work and a discussion of causal understanding was integrated. For illustration, prognosis studies were identified from electronic and supplemental searches of literature between 1966 and December 2006. We extracted characteristics of the populations, exposures, and outcomes and identified three phases of explanatory prognosis investigation: Phase 1, identifying associations; Phase 2, testing independent associations; and Phase 3, understanding prognostic pathways. The purpose of each phase is exploration, confirmation, and development of understanding, respectively. RESULTS: It is important to consider a framework of explanatory prognosis studies for: (1) defining the study objectives, (2) presenting the study methods and data, and (3) interpreting and applying the results of the study. CONCLUSION: When conducting and reporting prognosis studies, researchers should consider the approach to prognosis (explanatory or outcome prediction) and phase of investigation, use best methods to limit biases, report completely, and cautiously interpret results. Readers of health care research will then be better able to evaluate the goals and interpret and appropriately use the results of prognosis studies.

Influence of factor IX on overall plasma coagulability and fibrinolytic potential as measured by global assay: monitoring in haemophilia B.

We sought to determine the influence of factor IX (FIX) deficiency upon overall coagulative and fibrinolytic capacities in plasma using the clot formation and lysis (CloFAL) assay, and to investigate the role of this global assay as an adjunctive monitoring tool in haemophilia B. CloFAL assay parameters were measured in vitro in platelet-poor plasma in relation to FIX activity and antigen (FIX:Ag), and were determined ex vivo among FIX-deficient patients (n = 41) in comparison to healthy individuals (n = 48). Supplementation of FIX-deficient plasma with FIX in vitro demonstrated a non-linear concentration dependence of FIX upon overall plasma coagulability. Ex vivo, coagulability was significantly decreased in FIX-deficient vs. healthy subjects among adults [median coagulation index (CI): 4% vs. 104% respectively; P < 0.001] and children (median CI: 9% vs. 63%; P < 0.001). Fibrinolytic capacity was increased in adult FIX-deficient vs. healthy subjects (median fibrinolytic index: 216% vs. 125%, respectively, P < 0.001), and was supported by a trend in shortened euglobulin lysis time (ELT). Severe haemophilia B patients showed heterogeneity in aberrant CloFAL assay waveforms, influenced partly by FIX:Ag levels. Patients with relatively preserved FIX:Ag (i.e. dysfunctional FIX) exhibited a shorter time to maximal amplitude in clot formation than those with type I deficiency. During patient treatment monitoring, markedly hypocoagulable CloFAL assay waveforms normalized following 100% correction with infused FIX. The CloFAL global assay detects FIX deficiency, demonstrates differences in coagulability between dysfunctional FIX and type I deficiency, and appears useful as an adjunctive test to routine FIX measurement in monitoring haemophilia B treatment.

Quality of life in patients with rheumatoid arthritis: does abatacept make a difference?

Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disease that, in addition to causing joint damage, is associated with pain, fatigue, disability and functional loss, which can substantially decrease a patient's quality of life (QoL). Along with improvements in signs and symptoms, QoL benefits have become increasingly important in optimizing treatment outcomes in RA. Measurements of QoL have previously been under-used in all areas of medicine and only recently have clinical trials included them as a measure of treatment effectiveness. The existence of a positive relationship between improvements in signs and symptoms and concomitant improvements in QoL provides additional evidence that QoL measures are useful benchmarks for evaluating the effectiveness of treatment for RA. Furthermore, since these outcome measures evaluate the real-life, patient-centered benefits of RA therapies, they are likely to become increasingly central to the assessment of disease impact in clinical trials and practice, and to both drug approval and reimbursement decisions. This article reviews the impact of abatacept, a selective co-stimulation modulator, on the QoL of patients with active RA across a number of pivotal clinical trials. Firstly, an overview of the key QoL measurements used in abatacept clinical trials is provided, including those such as the Short Form-36, Health Assessment Questionnaire and Visual Analog Scale for pain, sleep and fatigue. We then present QoL data obtained in a wide range of patients with RA, including those with an inadequate response to either methotrexate or anti-tumor necrosis factor therapy, who have been treated with abatacept. Analysis of these data demonstrates that abatacept therapy has the potential to improve QoL across a range of patients with RA.

Effect sizes of non-surgical treatments of non-specific low-back pain.

Numerous randomized trials have been published investigating the effectiveness of treatments for non-specific low-back pain (LBP) either by trials comparing interventions with a no-treatment group or comparing different interventions. In trials comparing two interventions, often no differences are found and it raises questions about the basic benefit of each treatment. To estimate the effect sizes of treatments for non-specific LBP compared to no-treatment comparison groups, we searched for randomized controlled trials from systematic reviews of treatment of non-specific LBP in the latest issue of the Cochrane Library, issue 2, 2005 and available databases until December 2005. Extracted data were effect sizes estimated as Standardized Mean Differences (SMD) and Relative Risk (RR) or data enabling calculation of effect sizes. For acute LBP, the effect size of non-steroidal anti-inflammatory drugs (NSAIDs) and manipulation were only modest (ES: 0.51 and 0.40, respectively) and there was no effect of exercise (ES: 0.07). For chronic LBP, acupuncture, behavioral therapy, exercise therapy, and NSAIDs had the largest effect sizes (SMD: 0.61, 0.57, and 0.52, and RR: 0.61, respectively), all with only a modest effect. Transcutaneous electric nerve stimulation and manipulation had small effect sizes (SMD: 0.22 and 0.35, respectively). As a conclusion, the effect of treatments for LBP is only small to moderate. Therefore, there is a dire need for developing more effective interventions.