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1.  Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis 
BMC Medicine  2016;14(1):137.
Background
To perform a systematic review and network meta-analysis (NMA) to compare the risk of serious infections with immunosuppressive medications and glucocorticoids in lupus nephritis.
Methods
A trained librarian performed two searches: (1) PubMed for all lupus nephritis trials from the end dates for the systematic review for the 2012 American College of Rheumatology (ACR) lupus nephritis treatment guidelines and the 2012 Cochrane Systematic Review on treatments for lupus nephritis, to September 2013; and (2) PubMed and SCOPUS for all lupus trials (excluding lupus nephritis) from inception to February 2014, to obtain additional trials for harms data in any lupus patient. The search was updated to May 2016. Duplicate title/abstract review and duplicate data abstractions by two abstractors independently was performed for all eligible studies, including those studies abstracted for the 2012 ACR lupus nephritis treatment guidelines and the 2012 Cochrane Systematic Review on lupus nephritis treatments. We performed a systematic review and a Bayesian NMA, including randomized controlled trials (RCTs) of immunosuppressive drugs or glucocorticoids in patients with lupus nephritis assessing serious infection risk. Markov chain Monte Carlo methods were used to model 95 % credible intervals (CrI). Sensitivity analyses examined the robustness of estimates.
Results
A total of 32 RCTs with 2611 patients provided data. There were 26 two-arm, five three-arm, and one four-arm trials. We found that tacrolimus was associated with significantly lower risk of serious infections compared to glucocorticoids, cyclophosphamide (CYC), mycophenolate mofetil (MMF), and azathioprine (AZA) with odds ratios (95 % CrI) of 0.33 (0.12–0.88), 0.37 (0.15–0.87), 0.340 (0.18–0.81), and 0.32 (0.12–0.81), respectively. Conversely, CYC low dose (LD), CYC high dose (HD), and HD glucocorticoids were associated with higher odds of serious infections compared to tacrolimus, ranging from 4.84 to 12.83. We also found that MMF followed by AZA (MMF-AZA) was associated with significantly lower risk of serious infections as compared to CYC LD, CYC HD, CYC-AZA, or HD glucocorticoids with odds ratios (95 % CrI) of 0.09 (0.01–0.76), 0.07 (0.01–0.54), 0.14 (0.02–0.71), and 0.03 (0.00–0.56), respectively. Estimates were similar to pair-wise meta-analyses. Sensitivity analyses that varied estimate (odds ratio vs. Peto’s odds ratio), method (random vs. fixed effects model), data (sepsis vs. serious infection data; exclusion of observational studies), treatment grouping (CYC and CYC HD as a combined treatment group vs. separate), made little/no difference to these estimates.
Conclusions
Tacrolimus and MMF-AZA combination were associated with lower risk of serious infections compared to other immunosuppressive drugs or glucocorticoids for lupus nephritis. In conjunction with comparative efficacy data, these data can help patients make informed decisions about treatment options for lupus nephritis.
PROSPERO registration
CRD42016032965
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0673-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-016-0673-8
PMCID: PMC5022202  PMID: 27623861
Network meta-analysis; Serious infections; Immunosuppressive drugs; Glucocorticoids; Lupus nephritis; Lupus; Tacrolimus; Cyclophosphamide; Mycophenolate mofetil
2.  Comparative effectiveness of immunosuppressive drugs and corticosteroids for lupus nephritis: a systematic review and network meta-analysis 
Systematic Reviews  2016;5(1):155.
Background
There is a lack of high-quality meta-analyses and network meta-analyses of immunosuppressive drugs for lupus nephritis. Our objective was to assess the comparative benefits and harms of immunosuppressive drugs and corticosteroids in lupus nephritis.
Methods
We conducted a systematic review and network meta-analysis (NMA) of trials of immunosuppressive drugs and corticosteroids in patients with lupus nephritis. We calculated odds ratios (OR) and 95 % credible intervals (CrI).
Results
Sixty-five studies that met inclusion and exclusion criteria; data were analyzed for renal remission/response (37 trials; 2697 patients), renal relapse/flare (13 studies; 1108 patients), amenorrhea/ovarian failure (eight trials; 839 patients) and cytopenia (16 trials; 2257 patients). Cyclophosphamide [CYC] low dose (LD) and CYC high-dose (HD) were less likely than mycophenolate mofetil [MMF] and azathioprine [AZA], CYC LD, CYC HD and plasmapharesis less likely than cyclosporine [CSA] to achieve renal remission/response. Tacrolimus [TAC] was more likely than CYC LD to achieve renal remission/response. MMF and CYC were associated with a lower odds of renal relapse/flare compared to PRED and MMF was associated with a lower rate of renal relapse/flare than AZA. CYC was more likely than MMF and PRED to be associated with amenorrhea/ovarian failure. Compared to MMF, CYC, AZA, CYC LD, and CYC HD were associated with a higher risk of cytopenia.
Conclusions
In this systematic review and NMA, we found important differences between immunosuppressives used for the treatment of lupus nephritis. Patients and physicians can use this information for detailed informed consent in a patient-centered approach. Study limitations of between-study clinical heterogeneity and small sample size with type II error must be considered when interpreting these findings.
Systematic review registration
PROSPERO: CRD42016032965
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0328-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13643-016-0328-z
PMCID: PMC5020478  PMID: 27619512
Network meta-analysis; Immunosuppressive drugs; Glucocorticoids; Lupus nephritis; Lupus; Renal remission; Renal relapse; Tacrolimus; Cyclophosphamide; Mycophenolate mofetil
3.  Development of the Canadian Syncope Risk Score to predict serious adverse events after emergency department assessment of syncope 
Background:
Syncope can be caused by serious conditions not evident during initial evaluation, which can lead to serious adverse events, including death, after disposition from the emergency department. We sought to develop a clinical decision tool to identify adult patients with syncope who are at risk of a serious adverse event within 30 days after disposition from the emergency department.
Methods:
We prospectively enrolled adults (age ≥ 16 yr) with syncope who presented within 24 hours after the event to 1 of 6 large emergency departments from Sept. 29, 2010, to Feb. 27, 2014. We collected standardized variables at index presentation from clinical evaluation and investigations. Adjudicated serious adverse events included death, myocardial infarction, arrhythmia, structural heart disease, pulmonary embolism, serious hemorrhage and procedural interventions within 30 days.
Results:
We enrolled 4030 patients with syncope; the mean age was 53.6 years, 55.5% were women, and 9.5% were admitted to hospital. Serious adverse events occurred in 147 (3.6%) of the patients within 30 days after disposition from the emergency department. Of 43 candidate predictors examined, we included 9 in the final model: predisposition to vasovagal syncope, heart disease, any systolic pressure reading in the emergency department < 90 or > 180 mm Hg, troponin level above 99th percentile for the normal population, abnormal QRS axis (< −30° or > 100°), QRS duration longer than 130 ms, QTc interval longer than 480 ms, emergency department diagnosis of cardiac syncope and emergency department diagnosis of vasovagal syncope (C statistic 0.88, 95% confidence interval [CI] 0.85–0.90; optimism 0.015; goodness-of-fit p = 0.11). The risk of a serious adverse event within 30 days ranged from 0.4% for a score of −3 to 83.6% for a score of 11. The sensitivity was 99.2% (95% CI 95.9%–100%) for a threshold score of −2 or higher and 97.7% (95% CI 93.5%–99.5%) for a threshold score of −1 or higher.
Interpretation:
The Canadian Syncope Risk Score showed good discrimination and calibration for 30-day risk of serious adverse events after disposition from the emergency department. Once validated, the tool will be able to accurately stratify the risk of serious adverse events among patients presenting with syncope, including those at low risk who can be discharged home quickly.
doi:10.1503/cmaj.151469
PMCID: PMC5008955  PMID: 27378464
4.  The risk of serious infection with biologics in treating patients with rheumatoid arthritis: A Systematic Review and Meta-analysis 
Lancet (London, England)  2015;386(9990):258-265.
Background
Serious infections are a major concern for patients considering treatmentsfor rheumatoid arthritis (RA). Evidence is inconsistent on whether biologicsare associated with an increased risk of serious infection compared to traditional disease-modifying anti-rheumatic drugs (DMARDs).
Methods
A systematic literature search was undertaken using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and www.clinicaltrials.gov from inception through February 11, 2014. Search terms included biologics, rheumatoid arthritis and their synonyms. Trials were eligible for inclusion if they included any of the biologics and reported serious infections. The risk of bias was assessed using the Cochrane Risk of Bias Tool. We conducted a Bayesian network meta-analysis,using a binomial likelihood model, of published trials to assess the risk of serious infections of biologics in RA patients, compared to traditional DMARDs.
Findings
The systematic review identified 106 trials that included RA patients on biologic and reported on serious infections. Compared to traditional DMARDs, standard-dose biologic (odds ratio [OR],1.31; 95% credible interval [CrI], 1.09 to 1.58) andhigh-dose biologic (OR, 1.90; 95% Crl, 1.50 to 2.39) were associated with an increased risk of serious infections, while low-dose biologics (OR, 0.93; 95% CrI, 0.65 to 1.33) were not. The risk was lower in patients who are methotrexate naïve compared withtraditional DMARD- or anti-TNF-biologic-experienced. The absolute increase in the number of serious infectionsper 1000 patients treated each year compared to traditional DMARDs ranged from 6 for standard-dose biologic to 55 for combination biologic therapy.
Interpretation
Standard-dose and high-dose biologics (with/without traditional DMARDs) are associated with an increase in serious infections compared to traditional DMARDs in RA, while low-dose biologics are not.Clinicians should discuss the balance between benefit and harm with the individual RA patient before initiating biologic therapy.
Funding
Rheumatology division at the University of Alabama at Birmingham.
doi:10.1016/S0140-6736(14)61704-9
PMCID: PMC4580232  PMID: 25975452
rheumatoid arthritis; serious infection; harms; biologics; anti-TNF biologic; non-TNF biologic; methotrexate; DMARD; network meta-analysis; NMA; systematic review; meta analysis
5.  Impact of Center Experience on Patient Radiation Exposure During Transradial Coronary Angiography and Percutaneous Intervention: A Patient‐Level, International, Collaborative, Multi‐Center Analysis 
Background
The adoption of the transradial (TR) approach over the traditional transfemoral (TF) approach has been hampered by concerns of increased radiation exposure—a subject of considerable debate within the field. We performed a patient‐level, multi‐center analysis to definitively address the impact of TR access on radiation exposure.
Methods and Results
Overall, 10 centers were included from 6 countries—Canada (2 centers), United Kingdom (2), Germany (2), Sweden (2), Hungary (1), and The Netherlands (1). We compared the radiation exposure of TR versus TF access using measured dose‐area product (DAP). To account for local variations in equipment and exposure, standardized TR:TF DAP ratios were constructed per center with procedures separated by coronary angiography (CA) and percutaneous coronary intervention (PCI). Among 57 326 procedures, we demonstrated increased radiation exposure with the TR versus TF approach, particularly in the CA cohort across all centers (weighted‐average ratios: CA, 1.15; PCI, 1.05). However, this was mitigated by increasing TR experience in the PCI cohort across all centers (r=−0.8; P=0.005). Over time, as a center transitioned to increasing TR experience (r=0.9; P=0.001), a concomitant decrease in radiation exposure occurred (r=−0.8; P=0.006). Ultimately, when a center's balance of TR to TF procedures approaches 50%, the resultant radiation exposure was equivalent.
Conclusions
The TR approach is associated with a modest increase in patient radiation exposure. However, this increase is eliminated when the TR and TF approaches are used with equal frequency—a guiding principle for centers adopting the TR approach.
doi:10.1161/JAHA.116.003333
PMCID: PMC4937274  PMID: 27247332
coronary angiography; dose‐area product; percutaneous coronary intervention; radial artery catheterization; radiation; radiation dosing; transfemoral; transradial; Catheter-Based Coronary and Valvular Interventions; Percutaneous Coronary Intervention; Revascularization; Stent
6.  Yield and Efficiency of Mental Health Screening: A Comparison of Screening Protocols at Intake to Prison 
PLoS ONE  2016;11(5):e0154106.
Background
The value of screening for mental illness has increasingly been questioned in low prevalence settings due to high false positive rates. However, since false positive rates are related to prevalence, screening may be more effective in higher prevalence settings, including correctional institutions. We compared the yield (i.e. newly detected cases) and efficiency (i.e. false positives) of five screening protocols to detect mental illness in prisons against the use of mental health history taking (the prior approach to detecting mental illness).
Methods and Findings
We estimated the accuracy of the six approaches to detect an Axis I disorder among a sample of 467 newly admitted male inmates (83.1% participation rate). Mental health history taking identified only 41.0% (95% CI 32.1, 50.6) of all inmates with mental illness. Screening protocols identified between 61.9 and 85.7% of all cases, but referred between 2 and 3 additional individuals who did not have a mental illness for every additional case detected compared to the mental health history taking approach. In low prevalence settings (i.e. 10% or less) the screening protocols would have had between 4.6 and 16.2 false positives per true positive.
Conclusions
While screening may not be practical in low prevalence settings, it may be beneficial in jails and prisons where the prevalence of mental illness is higher. Further consideration of the context in which screening is being implemented, and of the impacts of policies and clinical practices on the benefits and harms of screening is needed to determine the effectiveness of screening in these settings.
doi:10.1371/journal.pone.0154106
PMCID: PMC4864401  PMID: 27167222
7.  ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions 
The BMJ  2016;355:i4919.
Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.
doi:10.1136/bmj.i4919
PMCID: PMC5062054  PMID: 27733354
9.  Network meta-analysis incorporating randomized controlled trials and non-randomized comparative cohort studies for assessing the safety and effectiveness of medical treatments: challenges and opportunities 
Systematic Reviews  2015;4:147.
Network meta-analysis is increasingly used to allow comparison of multiple treatment alternatives simultaneously, some of which may not have been compared directly in primary research studies. The majority of network meta-analyses published to date have incorporated data from randomized controlled trials (RCTs) only; however, inclusion of non-randomized studies may sometimes be considered. Non-randomized studies can complement RCTs or address some of their limitations, such as short follow-up time, small sample size, highly selected population, high cost, and ethical restrictions. In this paper, we discuss the challenges and opportunities of incorporating both RCTs and non-randomized comparative cohort studies into network meta-analysis for assessing the safety and effectiveness of medical treatments. Non-randomized studies with inadequate control of biases such as confounding may threaten the validity of the entire network meta-analysis. Therefore, identification and inclusion of non-randomized studies must balance their strengths with their limitations. Inclusion of both RCTs and non-randomized studies in network meta-analysis will likely increase in the future due to the growing need to assess multiple treatments simultaneously, the availability of higher quality non-randomized data and more valid methods, and the increased use of progressive licensing and product listing agreements requiring collection of data over the life cycle of medical products. Inappropriate inclusion of non-randomized studies could perpetuate the biases that are unknown, unmeasured, or uncontrolled. However, thoughtful integration of randomized and non-randomized studies may offer opportunities to provide more timely, comprehensive, and generalizable evidence about the comparative safety and effectiveness of medical treatments.
doi:10.1186/s13643-015-0133-0
PMCID: PMC4634799  PMID: 26537988
Network meta-analysis; Randomized controlled trials; Observational studies; Pharmacoepidemiology; Comparative effectiveness research; Distributed research networks
10.  A pilot randomized controlled trial of smoking cessation in an outpatient respirology clinic 
Tobacco smoking is responsible for more than one-third of all respiratory diseases and their progression, and is the leading cause of preventable deaths worldwide. Despite the improvement in respiratory symptoms afforded by smoking cessation, quit rates remain paradoxically low. Pharmacotherapy combined with personalized counselling has been found to be the best approach in patients with respiratory diseases. This study investigated the feasibility and effectiveness of adapting an outpatient version of the Ottawa Model for Smoking Cessation in a tertiary care respirology clinic.
OBJECTIVE:
To assess the feasibility and potential effectiveness of a modified version of the Ottawa Model for Smoking Cessation in an outpatient respirology clinic.
METHODS:
Adult tobacco smokers attending the respirology clinic and willing to choose a quit date within one month of enrollment were randomly assigned to receive standard care or the intervention. Standard care participants received smoking cessation advice, a brochure and a prescription for smoking cessation medication if requested. Intervention participants received a $110 voucher to purchase smoking cessation pharmacotherapy and were registered to an automated calling system. Answers to automated calls determined which participants required nurse telephone counselling. Feasibility indicators included recruitment and retention rates, and intervention adherence. The effectiveness indicator was self-reported smoking status at 26 to 52 weeks.
RESULTS:
Forty-nine (54.4%) of 90 eligible smokers were randomly assigned to the intervention (n=23) or control (n=26) group. Self-reported smoking status at 26 to 52 weeks was available for 32 (65.3%) participants. The quit rate for intervention participants was 18.2% compared with 7.7% for controls (OR2.36 [95% CI 0.39 to 14.15]).
CONCLUSION:
It would be feasible to evaluate this intervention in a larger trial. Alternatives to face-to-face follow-up at the clinic are recommended.
PMCID: PMC4390018  PMID: 25647168
Adherence; Automated calls; Feasibility; Subsidized nicotine replacement therapy; Tobacco
11.  Development of EULAR recommendations for the reporting of clinical trial extension studies in rheumatology 
Annals of the Rheumatic Diseases  2014;74(6):963-969.
Objectives
Our initiative aimed to produce recommendations on post-randomised controlled trial (RCT) trial extension studies (TES) reporting using European League Against Rheumatism (EULAR) standard operating procedures in order to achieve more meaningful output and standardisation of reports.
Methods
We formed a task force of 22 participants comprising RCT experts, clinical epidemiologists and patient representatives. A two-stage Delphi survey was conducted to discuss the domains of evaluation of a TES and definitions. A ‘0–10’ agreement scale assessed each domain and definition. The resulting set of recommendations was further refined and a final vote taken for task force acceptance.
Results
Seven key domains and individual components were evaluated and led to agreed recommendations including definition of a TES (100% agreement), minimal data necessary (100% agreement), method of data analysis (agreement mean (SD) scores ranging between 7.9 (0.84) and 9.0 (2.16)) and reporting of results as well as ethical issues. Key recommendations included reporting of absolute numbers at each stage from the RCT to TES with reasons given for drop-out at each stage, and inclusion of a flowchart detailing change in numbers at each stage and focus (mean (SD) agreement 9.9 (0.36)). A final vote accepted the set of recommendations.
Conclusions
This EULAR task force provides recommendations for implementation in future TES to ensure a standardised approach to reporting. Use of this document should provide the rheumatology community with a more accurate and meaningful output from future TES, enabling better understanding and more confident application in clinical practice towards improving patient outcomes.
doi:10.1136/annrheumdis-2013-204948
PMCID: PMC4431343  PMID: 24827533
Rheumatoid Arthritis; DMARDs (biologic); Epidemiology
12.  Differentiation between traumatic tap and aneurysmal subarachnoid hemorrhage: prospective cohort study 
Objectives To describe the findings in cerebrospinal fluid from patients with acute headache that could distinguish subarachnoid hemorrhage from the effects of a traumatic lumbar puncture.
Design A substudy of a prospective multicenter cohort study.
Setting 12 Canadian academic emergency departments, from November 2000 to December 2009.
Participants Alert patients aged over 15 with an acute non-traumatic headache who underwent lumbar puncture to rule out subarachnoid hemorrhage.
Main outcome measure Aneurysmal subarachnoid hemorrhage requiring intervention or resulting in death.
Results Of the 1739 patients enrolled, 641 (36.9%) had abnormal results on cerebrospinal fluid analysis with >1×106/L red blood cells in the final tube of cerebrospinal fluid and/or xanthochromia in one or more tubes. There were 15 (0.9%) patients with aneurysmal subarachnoid hemorrhage based on abnormal results of a lumbar puncture. The presence of fewer than 2000×106/L red blood cells in addition to no xanthochromia excluded the diagnosis of aneurysmal subarachnoid hemorrhage, with a sensitivity of 100% (95% confidence interval 74.7% to 100%) and specificity of 91.2% (88.6% to 93.3%).
Conclusion No xanthochromia and red blood cell count <2000×106/L reasonably excludes the diagnosis of aneurysmal subarachnoid hemorrhage. Most patients with acute headache who meet this cut off will need no further investigations and aneurysmal subarachnoid hemorrhage can be excluded as a cause of their headache.
doi:10.1136/bmj.h568
PMCID: PMC4353280  PMID: 25694274
13.  Comparative Effectiveness of Different Forms of Telemedicine for Individuals with Heart Failure (HF): A Systematic Review and Network Meta-Analysis 
PLoS ONE  2015;10(2):e0118681.
Background
Previous studies on telemedicine have either focused on its role in the management of chronic diseases in general or examined its effectiveness in comparison to standard post-discharge care. Little has been done to determine the comparative impact of different telemedicine options for a specific population such as individuals with heart failure (HF).
Methods and Findings
Systematic reviews (SR) of randomized controlled trials (RCTs) that examined telephone support, telemonitoring, video monitoring or electrocardiographic monitoring for HF patients were identified using a comprehensive search of the following databases: MEDLINE, EMBASE, CINAHL and The Cochrane Library. Studies were included if they reported the primary outcome of mortality or any of the following secondary outcomes: all-cause hospitalization and heart failure hospitalization. Thirty RCTs (N = 10,193 patients) were included. Compared to usual care, structured telephone support was found to reduce the odds of mortality(Odds Ratio 0.80; 95% Credible Intervals [0.66 to 0.96]) and hospitalizations due to heart failure (0.69; [0.56 to 0.85]). Telemonitoring was also found to reduce the odds of mortality(0.53; [0.36 to 0.80]) and reduce hospitalizations related to heart failure (0.64; [0.39 to 0.95]) compared to usual post-discharge care. Interventions that involved ECG monitoring also reduced the odds of hospitalization due to heart failure (0.71; [0.52 to 0.98]).
Limitations
Much of the evidence currently available has focused on the comparing either telephone support or telemonitoring with usual care. This has therefore limited our current understanding of how some of the less common forms of telemedicine compare to one another.
Conclusions
Compared to usual care, structured telephone support and telemonitoring significantly reduced the odds of deaths and hospitalization due to heart failure. Despite being the most widely studied forms of telemedicine, little has been done to directly compare these two interventions against one another. Further research into their comparative cost-effectiveness is also warranted.
doi:10.1371/journal.pone.0118681
PMCID: PMC4340962  PMID: 25714962
14.  Differentiation between traumatic tap and aneurysmal subarachnoid hemorrhage: prospective cohort study 
The BMJ  2015;350:h568.
Objectives To describe the findings in cerebrospinal fluid from patients with acute headache that could distinguish subarachnoid hemorrhage from the effects of a traumatic lumbar puncture.
Design A substudy of a prospective multicenter cohort study.
Setting 12 Canadian academic emergency departments, from November 2000 to December 2009.
Participants Alert patients aged over 15 with an acute non-traumatic headache who underwent lumbar puncture to rule out subarachnoid hemorrhage.
Main outcome measure Aneurysmal subarachnoid hemorrhage requiring intervention or resulting in death.
Results Of the 1739 patients enrolled, 641 (36.9%) had abnormal results on cerebrospinal fluid analysis with >1×106/L red blood cells in the final tube of cerebrospinal fluid and/or xanthochromia in one or more tubes. There were 15 (0.9%) patients with aneurysmal subarachnoid hemorrhage based on abnormal results of a lumbar puncture. The presence of fewer than 2000×106/L red blood cells in addition to no xanthochromia excluded the diagnosis of aneurysmal subarachnoid hemorrhage, with a sensitivity of 100% (95% confidence interval 74.7% to 100%) and specificity of 91.2% (88.6% to 93.3%).
Conclusion No xanthochromia and red blood cell count <2000×106/L reasonably excludes the diagnosis of aneurysmal subarachnoid hemorrhage. Most patients with acute headache who meet this cut off will need no further investigations and aneurysmal subarachnoid hemorrhage can be excluded as a cause of their headache.
doi:10.1136/bmj.h568
PMCID: PMC4353280  PMID: 25694274
15.  Internet-Based Implementation of Non-Pharmacological Interventions of the "People Getting a Grip on Arthritis" Educational Program: An International Online Knowledge Translation Randomized Controlled Trial Design Protocol 
JMIR Research Protocols  2015;4(1):e19.
Background
Rheumatoid arthritis (RA) affects 2.1% of the Australian population (1.5% males; 2.6% females), with the highest prevalence from ages 55 to over 75 years (4.4-6.1%). In Canada, RA affects approximately 0.9% of adults, and within 30 years that is expected to increase to 1.3%. With an aging population and a greater number of individuals with modifiable risk factors for chronic diseases, such as arthritis, there is an urgent need for co-care management of arthritic conditions. The increasing trend and present shifts in the health services and policy sectors suggest that digital information delivery is becoming more prominent. Therefore, it is necessary to further investigate the use of online resources for RA information delivery.
Objective
The objective is to examine the effect of implementing an online program provided to patients with RA, the People Getting a Grip on Arthritis for RA (PGrip-RA) program, using information communication technologies (ie, Facebook and emails) in combination with arthritis health care professional support and electronic educational pamphlets. We believe this can serve as a useful and economical method of knowledge translation (KT).
Methods
This KT randomized controlled trial will use a prospective randomized open-label blinded-endpoint design to compare four different intervention approaches of the PGrip-RA program to a control group receiving general electronic educational pamphlets self-management in RA via email. Depending on group allocation, links to the Arthritis Society PGrip-RA material will be provided either through Facebook or by email. One group will receive feedback online from trained health care professionals. The intervention period is 6 weeks. Participants will have access to the Internet-based material after the completion of the baseline questionnaires until the final follow-up questionnaire at 6 months. We will invite 396 patients from Canadian and Australian Arthritis Consumers’ Associations to participate using online recruitment.
Results
This study will build on a pilot study using Facebook, which revealed promising effects of knowledge acquisition/integration of the evidence-based self-management PGrip educational program.
Conclusions
The use of online techniques to disseminate knowledge provides an opportunity to reduce health care costs by facilitating self-management of people with arthritis. Study design strengths include the incorporation of randomization and allocation concealment to ensure internal validity. To avoid intergroup contamination, the Facebook group page security settings will be set to “closed”, thus allowing only invited participants to access it. Study limitations include the lack of participant blinding due to the characteristics of this KT randomized controlled trial and a potential bias of recruiting patients only online, though this was proven effective in the previous pilot study.
Trial Registration
Australian New Zealand Clinical Trials Registry ACTRN12614000397617; http://www.anzctr.org.au/TrialSearch.aspx (Archived by WebCite at http://www.webcitation.org/6PrP0kQf8).
doi:10.2196/resprot.3572
PMCID: PMC4342636  PMID: 25648515
rheumatoid arthritis; technology; knowledge translation; clinical trial; social media
16.  Limitations of free-form-text diagnostic requisitions as a tool for evaluating adherence to appropriate use criteria for transthoracic echocardiography 
Background
Monitoring the adherence to Appropriateness Use Criteria (AUC) has been identified as an important component for the accreditation of echocardiography laboratories. Referral requisitions are a logical tool to rapidly determine the appropriateness of transthoracic echocardiography (TTE) referrals, however data is lacking. We investigated whether standard free-form-text TTE referral requisitions can be used to evaluate AUC adherence.
Methods
Consecutive TTE referral requisitions to the University of Ottawa Heart Institute echocardiography laboratory were reviewed over a four-week period. Indication on the requisition was matched with the relevant indication on the 2011 American College of Cardiology Foundation (ACCF) AUC. Requisitions that did not provide sufficient information to identify the relevant AUC indication were identified as inadequate. For inadequate requisitions, reason for the referral was clarified through medical records and referring physicians.
Results
Of the 1303 requisitions, 26.2% did not provide adequate information to determine adherence to AUC, despite a non-adherence (inappropriate) rate of only 6.1% in the referral population. Indication for referral, physician specialty, outpatient status, and prior echocardiogram were independent predictors of inadequate requisitions (p < 0.001, respectively). The most common reasons for inadequate requisitions were a failure to report: 1) change in clinical status, 2) date of a prior echocardiogram, and 3) type and/or severity of a valve lesion. Inclusion of this information would have decreased the inadequacy rate by 56%.
Conclusion
In a large, academic echocardiography laboratory, over one quarter of free-form-text TTE requisitions are inadequate to evaluate AUC adherence. Structured requisition formats requiring AUC-relevant information are needed to facilitate the practical application of AUC in the echocardiography laboratory.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-7120-13-4) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-7120-13-4
PMCID: PMC4326475  PMID: 25592146
Transthoracic echocardiography; Appropriate use criteria; Diagnostic requisitions
17.  What Guidance Are Researchers Given on How to Present Network Meta-Analyses to End-Users such as Policymakers and Clinicians? A Systematic Review 
PLoS ONE  2014;9(12):e113277.
Introduction
Network meta-analyses (NMAs) are complex methodological approaches that may be challenging for non-technical end-users, such as policymakers and clinicians, to understand. Consideration should be given to identifying optimal approaches to presenting NMAs that help clarify analyses. It is unclear what guidance researchers currently have on how to present and tailor NMAs to different end-users.
Methods
A systematic review of NMA guidelines was conducted to identify guidance on how to present NMAs. Electronic databases and supplementary sources were searched for NMA guidelines. Presentation format details related to sample formats, target audiences, data sources, analysis methods and results were extracted and frequencies tabulated. Guideline quality was assessed following criteria developed for clinical practice guidelines.
Results
Seven guidelines were included. Current guidelines focus on how to conduct NMAs but provide limited guidance to researchers on how to best present analyses to different end-users. None of the guidelines provided reporting templates. Few guidelines provided advice on tailoring presentations to different end-users, such as policymakers. Available guidance on presentation formats focused on evidence networks, characteristics of individual trials, comparisons between direct and indirect estimates and assumptions of heterogeneity and/or inconsistency. Some guidelines also provided examples of figures and tables that could be used to present information.
Conclusions
Limited guidance exists for researchers on how best to present NMAs in an accessible format, especially for non-technical end-users such as policymakers and clinicians. NMA guidelines may require further integration with end-users' needs, when NMAs are used to support healthcare policy and practice decisions. Developing presentation formats that enhance understanding and accessibility of NMAs could also enhance the transparency and legitimacy of decisions informed by NMAs.
doi:10.1371/journal.pone.0113277
PMCID: PMC4269433  PMID: 25517510
18.  Effect of rapid HIV testing on HIV incidence and services in populations at high risk for HIV exposure: an equity-focused systematic review 
BMJ Open  2014;4(12):e006859.
Objective
To assess the effects of rapid voluntary counselling and testing (VCT) for HIV on HIV incidence and uptake of HIV/AIDS services in people at high risk for HIV exposure.
Design
Cochrane systematic review and meta-analysis.
Data sources
We searched PubMed, EMBASE, AIDSearch, LILACS, Global Health, Medline Africa, PsychInfo, CINAHL, Cochrane CENTRAL, Cochrane HIV/AIDS Group Specialized Register and grey literature from 1 January 2001 to 5 June 2014 without language restriction.
Data selection
We included controlled studies that compared rapid VCT with conventional testing among people at risk for HIV exposure.
Data extraction
Two reviewers extracted data. We used Cochrane risk of bias tool and GRADE criteria: risk of bias, inconsistency, indirectness, imprecision and publication bias. For observational studies we used the Newcastle-Ottawa Scale. We used the PRISMA-Equity reporting guideline.
Results
From 2441 articles, we included 8 randomised controlled trials and 5 observational studies. Rapid VCT was associated with a threefold increase in HIV-testing uptake (relative risk (RR)=2.95 95% CI 1.69 to 5.16) and a twofold increase in the receipt of test results (RR=2.14, 95% CI 1.08 to 4.24). Women accepted testing more often than men in rapid VCT arm, but no differences in effect for age or socioeconomic status. Observational studies also showed rapid VCT led to higher rates of uptake of testing. Heterogeneity was high. A cluster-randomised trial reported an 11% reduction in HIV incidence in intervention communities (RR=0.89, 95% CI=0.63 to 1.24) over 3 years trial.
Conclusions
Rapid VCT in health facilities and communities was associated with a large increase in HIV-testing uptake and receipt of results. This has implications for WHO guidelines. The routine use of rapid VCT may also help avoid human rights violations among marginalised populations where testing may occur without informed consent and where existing stigma may create barriers to testing.
doi:10.1136/bmjopen-2014-006859
PMCID: PMC4267075  PMID: 25510889
HIV Testing; Rapid VCT; HIV Services
19.  Updating the OMERACT Filter: Implications for imaging and soluble biomarkers 
The Journal of rheumatology  2014;41(5):1016-1024.
Objective
The OMERACT Filter provides a framework for the validation of outcome measures for use in rheumatology clinical research. However, imaging and biochemical measures may face additional validation challenges due to their technical nature. The Imaging and Soluble Biomarker Session at OMERACT 11 aimed to provide a guide for the iterative development of an imaging or biochemical measurement instrument so it can be used in therapeutic assessment.
Methods
A hierarchical structure was proposed, reflecting 3 dimensions needed for validating an imaging or biochemical measurement instrument: outcome domain(s), study setting and performance of the instrument. Movement along the axes in any dimension reflects increasing validation. For a given test instrument, the 3-axis structure assesses the extent to which the instrument is a validated measure for the chosen domain, whether it assesses a patient or disease centred-variable, and whether its technical performance is adequate in the context of its application. Some currently used imaging and soluble biomarkers for rheumatoid arthritis, spondyloarthritis and knee osteoarthritis were then evaluated using the original OMERACT filter and the newly proposed structure. Break-out groups critically reviewed the extent to which the candidate biomarkers complied with the proposed step-wise approach, as a way of examining the utility of the proposed 3 dimensional structure.
Results
Although there was a broad acceptance of the value of the proposed structure in general, some areas for improvement were suggested including clarification of criteria for achieving a certain level of validation and how to deal with extension of the structure to areas beyond clinical trials.
Conclusion
General support was obtained for a proposed tri-axis structure to assess validation of imaging and soluble biomarkers; nevertheless, additional work is required to better evaluate its place within the OMERACT Filter 2.0.
doi:10.3899/jrheum.131313
PMCID: PMC4223089  PMID: 24584916
biomarkers; imaging; OMERACT filter; validation framework
20.  Adiposity significantly modifies genetic risk for dyslipidemia[S] 
Journal of Lipid Research  2014;55(11):2416-2422.
Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain <12% of variation in lipid traits. Adiposity is also an important determinant of plasma lipoproteins, particularly plasma TGs and HDL cholesterol (HDLc) concentrations. Thus, interactions between genes and clinical phenotypes may contribute to this unexplained heritability. We have applied a weighted genetic risk score (GRS) for both plasma TGs and HDLc in two large cohorts at the extremes of BMI. Both BMI and GRS were strongly associated with these lipid traits. A significant interaction between obese/lean status and GRS was noted for each of TG (PInteraction = 2.87 × 10−4) and HDLc (PInteraction = 1.05 × 10−3). These interactions were largely driven by SNPs tagging APOA5, glucokinase receptor (GCKR), and LPL for TG, and cholesteryl ester transfer protein (CETP), GalNAc-transferase (GALNT2), endothelial lipase (LIPG), and phospholipid transfer protein (PLTP) for HDLc. In contrast, the GRSLDL cholesterol × adiposity interaction was not significant. Sexual dimorphism was evident for the GRSHDL on HDLc in obese (PInteraction = 0.016) but not lean subjects. SNP by BMI interactions may provide biological insight into specific genetic associations and missing heritability.
doi:10.1194/jlr.P052522
PMCID: PMC4617143  PMID: 25225679
obesity; genetic risk score; lipoproteins; single nucleotide polymorphism; statistical interaction
21.  Updating the OMERACT Filter: Implications of Filter 2.0 to select outcome instruments through assessment of ‘Truth’: content, face and construct validity 
The Journal of rheumatology  2014;41(5):1000-1004.
Objective
The OMERACT Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The ‘Truth’ section of the OMERACT Filter requires that criteria be met to demonstrate that the outcome instrument meets the criteria for content, face and construct validity.
Method
Discussion groups critically reviewed the variety of ways in which case studies of current OMERACT Working Groups complied with the ‘Truth’ component of the Filter and what issues remained to be resolved.
Results
The case studies showed that there is broad agreement on criteria for meeting the ‘Truth’ criteria through demonstration of content, face and construct validity; however several issues were identified that the Filter Working Group will need to address.
Conclusion
These issues will require resolution in order to reach consensus on how ‘Truth’ will be assessed for the proposed Filter 2.0 framework, for instruments to be endorsed by OMERACT.
doi:10.3899/jrheum.131310
PMCID: PMC4212637  PMID: 24692531
23.  Assessing bias in osteoarthritis trials included in Cochrane reviews: protocol for a meta-epidemiological study 
BMJ Open  2014;4(10):e005491.
Introduction
The validity of systematic reviews and meta-analysis depends on methodological quality and unbiased dissemination of trials. Our objective is to evaluate the association of estimates of treatment effects with different bias-related study characteristics in meta-analyses of interventions used for treating pain in osteoarthritis (OA). From the findings, we hope to consolidate guidance on interpreting OA trials in systematic reviews based on empirical evidence from Cochrane reviews.
Methods and analysis
Only systematic reviews that compare experimental interventions with sham, placebo or no intervention control will be considered eligible. Bias will be assessed with the risk of bias tool, used according to the Cochrane Collaboration’s recommendations. Furthermore, center status, trial size and funding will be assessed. The primary outcome (pain) will be abstracted from the first appearing forest plot for overall pain in the Cochrane review. Treatment effect sizes will be expressed as standardised mean differences (SMDs), where the difference in mean values available from the forest plots is divided by the pooled SD. To empirically assess the risk of bias in treatment benefits, we will perform stratified analyses of the trials from the included meta-analyses and assess the interaction between trial characteristics and treatment effect. A relevant study-level covariate is defined as one that decreases the between-study variance (τ2, estimated as Tau-squared) as a consequence of inclusion in the mixed effects statistical model.
Ethics and dissemination
Meta-analyses and randomised controlled trials provide the most reliable basis for treatment of patients with OA, but the actual impact of bias is unclear. This study will systematically examine the methodological quality in OA Cochrane reviews and explore the effect estimates behind possible bias. Since our study does not collect primary data, no formal ethical assessment and informed consent are required.
Trial registration number
PROSPERO (CRD42013006924).
doi:10.1136/bmjopen-2014-005491
PMCID: PMC4187994  PMID: 25280805
osteoarthritis; meta-analysis; meta-epidemiology; risk of bias
24.  A Microsoft-Excel-based tool for running and critically appraising network meta-analyses—an overview and application of NetMetaXL 
Systematic Reviews  2014;3:110.
Background
The use of network meta-analysis has increased dramatically in recent years. WinBUGS, a freely available Bayesian software package, has been the most widely used software package to conduct network meta-analyses. However, the learning curve for WinBUGS can be daunting, especially for new users. Furthermore, critical appraisal of network meta-analyses conducted in WinBUGS can be challenging given its limited data manipulation capabilities and the fact that generation of graphical output from network meta-analyses often relies on different software packages than the analyses themselves.
Methods
We developed a freely available Microsoft-Excel-based tool called NetMetaXL, programmed in Visual Basic for Applications, which provides an interface for conducting a Bayesian network meta-analysis using WinBUGS from within Microsoft Excel. . This tool allows the user to easily prepare and enter data, set model assumptions, and run the network meta-analysis, with results being automatically displayed in an Excel spreadsheet. It also contains macros that use NetMetaXL’s interface to generate evidence network diagrams, forest plots, league tables of pairwise comparisons, probability plots (rankograms), and inconsistency plots within Microsoft Excel. All figures generated are publication quality, thereby increasing the efficiency of knowledge transfer and manuscript preparation.
Results
We demonstrate the application of NetMetaXL using data from a network meta-analysis published previously which compares combined resynchronization and implantable defibrillator therapy in left ventricular dysfunction. We replicate results from the previous publication while demonstrating result summaries generated by the software.
Conclusions
Use of the freely available NetMetaXL successfully demonstrated its ability to make running network meta-analyses more accessible to novice WinBUGS users by allowing analyses to be conducted entirely within Microsoft Excel. NetMetaXL also allows for more efficient and transparent critical appraisal of network meta-analyses, enhanced standardization of reporting, and integration with health economic evaluations which are frequently Excel-based.
doi:10.1186/2046-4053-3-110
PMCID: PMC4195340  PMID: 25267416
Network meta-analysis; Software; Microsoft Excel; WinBUGS; Systematic review; Health technology assessment
25.  OMERACT endorsement of measures of outcome for studies of acute gout 
The Journal of rheumatology  2013;41(3):569-573.
Objective
To determine the extent to which OMERACT participants agree that instruments that have been used in clinical trials and measure OMERACT core outcome domains in acute gout fulfil the filter requirements of truth, discrimination and feasibility and to determine where future research efforts need to be directed.
Methods
The results of a systematic literature review and analysis of individual-level data from recent clinical studies of acute gout were presented to OMERACT participants. The information was discussed in breakout groups and opinion was defined by subsequent voting in a plenary session. Endorsement was defined as at least 70% of participants voting in agreement with the proposition (where the denominator excluded those participants who did not vote or who voted ‘don’t know’).
Results
The following measures were endorsed for use in clinical trials of acute gout: (1) 5-point Likert scale and/or VAS (0 to 100mm) to measure pain; (2) 4-point Likert scale for joint swelling; (3) 4-point Likert scale for joint tenderness; and (4) 5-point Likert scale for patient global assessment of response to treatment. Measures for the activity limitations domain were not endorsed.
Conclusions
Measures of pain, joint swelling, joint tenderness and patient global assessment in acute gout were endorsed at OMERACT-11. These measures should now be used in clinical trials of acute gout.
doi:10.3899/jrheum.131246
PMCID: PMC4162875  PMID: 24334651
gout; outcome measures; psychometrics

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