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1.  Evidence against the Involvement of Chronic Cerebrospinal Venous Abnormalities in Multiple Sclerosis. A Case-Control Study 
PLoS ONE  2013;8(8):e72495.
Objective
Multiple sclerosis (MS) is a chronic neurodegenerative disease of the CNS. Recently a controversial vascular hypothesis for MS, termed chronic cerebrospinal venous insufficiency (CCSVI), has been advanced. The objective of this study was to evaluate the relative prevalence of the venous abnormalities that define CCSVI.
Methods
A case-control study was conducted in which 100 MS patients aged between 18–65 y meeting the revised McDonald criteria were randomly selected and stratified into one of four MS subtypes: relapsing/remitting, secondary progressive, primary progressive and benign. Control subjects (16–70 y) with no known history of MS or other neurological condition were matched with the MS cases. All cases and controls underwent ultrasound imaging of the veins of the neck plus the deep cerebral veins, and magnetic resonance imaging of the neck veins and brain. These procedures were performed on each participant on the same day.
Results
On ultrasound we found no evidence of reflux, stenosis or blockage in the internal jugular veins (IJV) or vertebral veins (VV) in any study participant. Similarly, there was no evidence of either reflux or cessation of flow in the deep cerebral veins in any subject. Flow was detected in the IJV and VV in all study participants. Amongst 199 participants there was one MS subject who fulfilled the minimum two ultrasound criteria for CCSVI. Using MRI we found no significant differences in either the intra- or extra-cranial venous flow velocity or venous architecture between cases and controls.
Conclusion
This case-control study provides compelling evidence against the involvement of CCSVI in multiple sclerosis.
doi:10.1371/journal.pone.0072495
PMCID: PMC3743778  PMID: 23967312
2.  Clinical Outcome Prediction in Aneurysmal Subarachnoid Hemorrhage Using Bayesian Neural Networks with Fuzzy Logic Inferences 
Objective. The novel clinical prediction approach of Bayesian neural networks with fuzzy logic inferences is created and applied to derive prognostic decision rules in cerebral aneurysmal subarachnoid hemorrhage (aSAH). Methods. The approach of Bayesian neural networks with fuzzy logic inferences was applied to data from five trials of Tirilazad for aneurysmal subarachnoid hemorrhage (3551 patients). Results. Bayesian meta-analyses of observational studies on aSAH prognostic factors gave generalizable posterior distributions of population mean log odd ratios (ORs). Similar trends were noted in Bayesian and linear regression ORs. Significant outcome predictors include normal motor response, cerebral infarction, history of myocardial infarction, cerebral edema, history of diabetes mellitus, fever on day 8, prior subarachnoid hemorrhage, admission angiographic vasospasm, neurological grade, intraventricular hemorrhage, ruptured aneurysm size, history of hypertension, vasospasm day, age and mean arterial pressure. Heteroscedasticity was present in the nontransformed dataset. Artificial neural networks found nonlinear relationships with 11 hidden variables in 1 layer, using the multilayer perceptron model. Fuzzy logic decision rules (centroid defuzzification technique) denoted cut-off points for poor prognosis at greater than 2.5 clusters. Discussion. This aSAH prognostic system makes use of existing knowledge, recognizes unknown areas, incorporates one's clinical reasoning, and compensates for uncertainty in prognostication.
doi:10.1155/2013/904860
PMCID: PMC3639630  PMID: 23690884
3.  Intravenous immunoglobulin for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review and meta-analysis 
Open Medicine  2010;4(3):e154-e166.
Background
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder that targets the myelin sheaths of the peripheral nervous system. Intravenous immunoglobulin (IVIg) is a blood product containing immunoglobulin G pooled from many human donors. In fall 2008, CIDP became an approved indication for IVIg in the United States and Canada.
Objective
To evaluate the clinical effectiveness and safety of IVIg for the treatment of CIDP through a systematic review of published randomized controlled trials.
Methods
We searched the MEDLINE (1996–2009, including in-process and other non-indexed citations), Embase (1996–2009) and other databases through the Ovid interface. We applied a methodological filter to limit retrieval to controlled clinical trials, meta-analyses and systematic reviews, and health technology assessments. Retrieval was limited to studies involving humans, and no language restrictions were employed. We pooled extracted data to estimate the effect size of IVIg treatment based on the random-effects model.
Results
We identified 9 unique randomized controlled trials. Of these, 3 compared IVIg therapy with an active comparator (plasma exchange, plasma exchange using extracorporeal immunoadsorption, oral prednisolone, respectively); the other 6 trials had placebo controls. No incremental benefit was seen in terms of primary outcomes for comparisons of IVIg therapy and an active comparator. Data from 4 of the 6 placebo-controlled trials were included in a meta-analysis. A significant improvement in disability (i.e., reduction in disability score) was found, with a standardized mean difference of 0.65 (95% confidence interval [CI] 0.23 to 1.08) in favour of IVIg. A pooled analysis of the proportion of patients with a response to treatment, as defined by the investigators of each of the trials, resulted in a risk ratio of 2.74 (95% CI 1.80 to 4.15) favouring IVIg.
Interpretation
IVIg therapy was statistically superior to placebo in reducing disability and impairment among patients with CIDP. The effectiveness of IVIg was similar to that of the alternative treatment strategies of plasma exchange and oral prednisolone.
PMCID: PMC3090105  PMID: 21687335
4.  Cost-utility of Intravenous Immunoglobulin (IVIG) compared with corticosteroids for the treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in Canada 
Objectives
Intravenous immunoglobulin (IVIG) has demonstrated improvement in chronic inflammatory demyelinating polyneuropathy (CIDP) patients in placebo controlled trials. However, IVIG is also much more expensive than alternative treatments such as corticosteroids. The objective of the paper is to evaluate, from a Canadian perspective, the cost-effectiveness of IVIG compared to corticosteroid treatment of CIDP.
Methods
A markov model was used to evaluate the costs and QALYs for IVIG and corticosteroids over 5 years of treatment for CIDP. Patients initially responding to IVIG could remain a responder or relapse every 12 week model cycle. Non-responding IVIG patients were assumed to be switched to corticosteroids. Patients on corticosteroids were at risk of a number of adverse events (fracture, diabetes, glaucoma, cataract, serious infection) in each cycle.
Results
Over the 5 year time horizon, the model estimated the incremental costs and QALYs of IVIG treatment compared to corticosteroid treatment to be $124,065 and 0.177 respectively. The incremental cost per QALY gained of IVIG was estimated to be $687,287. The cost per QALY of IVIG was sensitive to the assumptions regarding frequency and dosing of maintenance IVIG.
Conclusions
Based on common willingness to pay thresholds, IVIG would not be perceived as a cost effective treatment for CIDP.
doi:10.1186/1478-7547-8-14
PMCID: PMC2903512  PMID: 20565778
5.  GPs' approach to insulin prescribing in older patients: a qualitative study 
Background
Evidence suggests that insulin is under-prescribed in older people. Some reasons for this include physician's concerns about potential side-effects or patients' resistance to insulin. In general, however, little is known about how GPs make decisions related to insulin prescribing in older people.
Aim
To explore the process and rationale for prescribing decisions of GPs when treating older patients with type 2 diabetes.
Design of study
Qualitative individual interviews using a grounded theory approach.
Setting
Primary care.
Method
A thematic analysis was conducted to identify themes that reflected factors that influence the prescribing of insulin.
Results
Twenty-one GPs in active practice in Ontario completed interviews. Seven factors influencing the prescribing of insulin for older patients were identified: GPs' beliefs about older people; GPs' beliefs about diabetes and its management; gauging the intensity of therapy required; need for preparation for insulin therapy; presence of support from informal or formal healthcare provider; frustration with management complexity; and GPs' experience with insulin administration. Although GPs indicated that they would prescribe insulin allowing for the above factors, there was a mismatch in intended approach to prescribing and self-reported prescribing.
Conclusion
GPs' rationale for prescribing (or not prescribing) insulin is mediated by both practitioner-related and patient-related factors. GPs intended and actual prescribing varied depending on their assessment of each patient's situation. In order to improve prescribing for increasing numbers of older people with type 2 diabetes, more education for GPs, specialist support, and use of allied health professionals is needed.
doi:10.3399/bjgp08X319639
PMCID: PMC2566521  PMID: 18682013
insulin; primary health care; qualitative research; type 2 diabetes mellitus
6.  Do patients’ expectations influence their use of medications? 
Canadian Family Physician  2008;54(3):384-393.
OBJECTIVE
To investigate whether patients’ expectations influence how they take their medications by looking at the expectations patients have of their medications and the factors that affect these expectations.
DESIGN
Qualitative study using in-depth interviews and a grounded-theory approach.
SETTING
A large city in Ontario.
PARTICIPANTS
A total of 18 community-dwelling adult patients taking medication for at least 6 months.
METHOD
Both purposive and convenience sampling techniques were used. The initial strategy comprised stratified, maximum variation, and typical case sampling. The research team developed a semistructured interview guide after a preliminary review of the literature. Individual, face-to-face, in-depth interviews were conducted and audiotaped. At the end of the interviews, basic demographic information was collected. Interviewers were debriefed following each interview and their comments on relevant contextual information, general impressions of the interview, and possible changes to the interview guide were audiotaped. Audiotapes of each interview, including the debriefing, were transcribed verbatim, cleaned, and given a unique identifying number. At least 2 team members participated in analyzing the data using an operational code book that was modified to accommodate emerging themes as analysis continued.
MAIN FINDINGS
Patients’ expectations were more realistic than idealistic. Many participants acted on their expectations by changing their medication regimens on their own or by seeking additional information on their medications. Expectations were affected by patients’ beliefs, past experiences with medications, relationships with their health care providers, other people’s beliefs, and the cost of medication. Patients actively engaged in strategies to confirm or modify their expectations of their medications.
CONCLUSION
A range of factors (most notably past experiences with medications and relationships with health care providers) influenced patients’ expectations of their medications. More comprehensive discussion between patients and their health care providers about these factors could affect whether medications are used optimally.
PMCID: PMC2278356  PMID: 18337533
7.  Measurement of fractionated plasma metanephrines for exclusion of pheochromocytoma: Can specificity be improved by adjustment for age? 
Background
Biochemical testing for pheochromocytoma by measurement of fractionated plasma metanephrines is limited by false positive rates of up to 18% in people without known genetic predisposition to the disease. The plasma normetanephrine fraction is responsible for most false positives and plasma normetanephrine increases with age. The objective of this study was to determine if we could improve the specificity of fractionated plasma measurements, by statistically adjusting for age.
Methods
An age-adjusted metanephrine score was derived using logistic regression from 343 subjects (including 33 people with pheochromocytoma) who underwent fractionated plasma metanephrine measurements as part of investigations for suspected pheochromocytoma at Mayo Clinic Rochester (derivation set). The performance of the age-adjusted score was validated in a dataset of 158 subjects (including patients 23 with pheochromocytoma) that underwent measurements of fractionated plasma metanephrines at Mayo Clinic the following year (validation dataset). None of the participants in the validation dataset had known genetic predisposition to pheochromocytoma.
Results
The sensitivity of the age-adjusted metanephrine score was the same as that of traditional interpretation of fractionated plasma metanephrine measurements, yielding a sensitivity of 100% (23/23, 95% confidence interval [CI] 85.7%, 100%). However, the false positive rate with traditional interpretation of fractionated plasma metanephrine measurements was 16.3% (22/135, 95% CI, 11.0%, 23.4%) and that of the age-adjusted score was significantly lower at 3.0% (4/135, 95% CI, 1.2%, 7.4%) (p < 0.001 using McNemar's test).
Conclusion
An adjustment for age in the interpretation of results of fractionated plasma metanephrines may significantly decrease false positives when using this test to exclude sporadic pheochromocytoma. Such improvements in false positive rate may result in savings of expenditures related to confirmatory imaging.
doi:10.1186/1472-6823-5-1
PMCID: PMC553971  PMID: 15737232
8.  A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma 
Background
Fractionated plasma metanephrine measurements are commonly used in biochemical testing in search of pheochromocytoma.
Methods
We aimed to critically appraise the diagnostic efficacy of fractionated plasma free metanephrine measurements in detecting pheochromocytoma. Nine electronic databases, meeting abstracts, and the Science Citation Index were searched and supplemented with previously unpublished data. Methodologic and reporting quality was independently assessed by two endocrinologists using a checklist developed by the Standards for Reporting of Diagnostic Studies Accuracy Group and data were independently abstracted.
Results
Limitations in methodologic quality were noted in all studies. In all subjects (including those with genetic predisposition): the sensitivities for detection of pheochromocytoma were 96%–100% (95% CI ranged from 82% to 100%), whereas the specificities were 85%–100% (95% CI ranged from 78% to 100%). Statistical heterogeneity was noted upon pooling positive likelihood ratios when those with predisposition to disease were included (p < 0.001). However, upon pooling the positive or negative likelihood ratios for patients with sporadic pheochromocytoma (n = 191) or those at risk for sporadic pheochromocytoma (n = 718), no statistical heterogeneity was noted (p = 0.4). For sporadic subjects, the pooled positive likelihood ratio was 5.77 (95% CI = 4.90, 6.81) and the pooled negative likelihood ratio was 0.02 (95% CI = 0.01, 0.07).
Conclusion
Negative plasma fractionated free metanephrine measurements are effective in ruling out pheochromocytoma. However, a positive test result only moderately increases suspicion of disease, particularly when screening for sporadic pheochromocytoma.
doi:10.1186/1472-6823-4-2
PMCID: PMC459231  PMID: 15225350
9.  The management of hypertension in Canada: a review of current guidelines, their shortcomings and implications for the future 
CLINICIANS ARE EXPOSED to numerous hypertension guidelines. However, their enthusiasm for these guidelines, and the impact of the guidelines, appears modest at best. Barriers to the successful implementation of a guideline can be identified at the level of the clinician, the patient or the practice setting; however, the shortcomings of the guidelines themselves have received little attention. In this paper, we review the hypertension guidelines that are most commonly encountered by Canadian clinicians: the “1999 Canadian Recommendations for the Management of Hypertension,” “The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure” in the United States and the “1999 World Health Organization–International Society of Hypertension Guidelines for the Management of Hypertension.” The key points of these guidelines are compared and the shortcomings that may impede their ability to influence practice are discussed. The main implications for future guideline developers are outlined.
PMCID: PMC80782  PMID: 11233874
10.  Thwarting sore throats 
PMCID: PMC80764  PMID: 11233863
12.  Root-Canal Therapy: A Means of Treating Oral Pain and Infection 
Canadian Family Physician  1988;34:1357-1365.
What is root-canal treatment? This article shows how endodontic treatment (root-canal therapy) can preserve teeth that would otherwise be extracted, and how tooth-pulp pathology can be diagnosed. Some clinical examples illustrate how non-dental infections can masquerade as dental problems, and vice versa.
Images
PMCID: PMC2219109  PMID: 21253195
endodontics; root-canal therapy; toothache

Results 1-12 (12)