An evaluation of DistillerSR's machine learning-based prioritization tool for title/abstract screening - impact on reviewer-relevant outcomes.

BACKGROUND: Systematic reviews often require substantial resources, partially due to the large number of records identified during searching. Although artificial intelligence may not be ready to fully replace human reviewers, it may accelerate and reduce the screening burden. Using DistillerSR (May 2020 release), we evaluated the performance of the prioritization simulation tool to determine the reduction in screening burden and time savings. METHODS: Using a true recall @ 95%, response sets from 10 completed systematic reviews were used to evaluate: (i) the reduction of screening burden; (ii) the accuracy of the prioritization algorithm; and (iii) the hours saved when a modified screening approach was implemented. To account for variation in the simulations, and to introduce randomness (through shuffling the references), 10 simulations were run for each review. Means, standard deviations, medians and interquartile ranges (IQR) are presented. RESULTS: Among the 10 systematic reviews, using true recall @ 95% there was a median reduction in screening burden of 47.1% (IQR: 37.5 to 58.0%). A median of 41.2% (IQR: 33.4 to 46.9%) of the excluded records needed to be screened to achieve true recall @ 95%. The median title/abstract screening hours saved using a modified screening approach at a true recall @ 95% was 29.8 h (IQR: 28.1 to 74.7 h). This was increased to a median of 36 h (IQR: 32.2 to 79.7 h) when considering the time saved not retrieving and screening full texts of the remaining 5% of records not yet identified as included at title/abstract. Among the 100 simulations (10 simulations per review), none of these 5% of records were a final included study in the systematic review. The reduction in screening burden to achieve true recall @ 95% compared to @ 100% resulted in a reduced screening burden median of 40.6% (IQR: 38.3 to 54.2%). CONCLUSIONS: The prioritization tool in DistillerSR can reduce screening burden. A modified or stop screening approach once a true recall @ 95% is achieved appears to be a valid method for rapid reviews, and perhaps systematic reviews. This needs to be further evaluated in prospective reviews using the estimated recall.

Rocuronium vs. succinylcholine for rapid sequence intubation: a Cochrane systematic review.

This systemic review was performed to determine whether rocuronium creates intubating conditions comparable to those of succinylcholine during rapid sequence intubation of the trachea. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 2), MEDLINE (1966 to February Week 2 2015), and EMBASE (1988 to February 14 2015) for any randomised controlled trials or controlled clinical trials that reported intubating conditions comparing rocuronium and succinylcholine for rapid or modified rapid sequence intubation. The dose of rocuronium was at least 0.6 mg.kg-1 and succinylcholine was at least 1 mg.kg-1 . Sixty-six studies were identified and 50 included, representing 4151 participants. Overall, succinylcholine was superior to rocuronium for achieving excellent intubating conditions (risk ratio (95%CI) 0.86 (0.81 to 0.92), n = 4151) and clinically acceptable intubation conditions (risk ratio (95%CI) 0.97 (0.95-0.99), n = 3992). A high incidence of detection bias amongst the trials coupled with significant heterogeneity means that the quality of evidence was moderate for these conclusions. Succinylcholine was more likely to produce excellent intubating conditions when using thiopental as the induction agent: risk ratio (95%CI) 0.81 (0.73-0.88), n = 2302) with or without the use of opioids (risk ratio (95%CI) 0.85 (0.78-0.93), n = 2292 or 0.85 (0.76-0.95), n = 1428).

A prospective randomized evaluation of a pharmacogenomic approach to antiplatelet therapy among patients with ST-elevation myocardial infarction: the RAPID STEMI study.

Treatment of carriers of the CYP2C19*2 allele and ABCB1 TT genotype with clopidogrel is associated with increased ischemic complications after percutaneous coronary intervention (PCI). We sought to evaluate a pharmacogenomic strategy among patients undergoing PCI for ST-elevation myocardial infarction (STEMI), by performing a randomized trial, enrolling 102 patients. Point-of-care genetic testing for CYP2C19*2, ABCB1 TT and CYP2C19*17 was performed with carriers of either the CYP2C19*2 allele or ABCB1 TT genotype randomly assigned to a strategy of prasugrel 10 mg daily or an augmented dosing strategy of clopidogrel (150 mg daily for 6 days then 75 mg daily). The primary end point was the proportion of at-risk carriers exhibiting high on-treatment platelet reactivity (HPR), a marker associated with increased adverse cardiovascular events, after 1 month. Fifty-nine subjects (57.8%) were identified as carriers of at least one at-risk variant. Treatment with prasugrel significantly reduced HPR compared with clopidogrel by P2Y12 reaction unit (PRU) thresholds of >234 (0 vs 24.1%, P=0.0046) and PRU>208 (3.3 vs 34.5%, P=0.0025). The sensitivity of point-of-care testing was 100% (95% CI 88.0-100), 100% (86.3-100) and 96.9% (82.0-99.8) and specificity was 97.0% (88.5-99.5), 97.1% (89.0-99.5) and 98.5% (90.9-99.9) for identifying CYP2C19*2, ABCB1 TT and CYP2C19*17, respectively. Logistic regression confirmed carriers as a strong predictor of HPR (OR=6.58, 95% CI 1.24-34.92; P=0.03). We confirmed that concurrent identification of three separate genetic variants in patients with STEMI receiving PCI is feasible at the bedside. Among carriers of at-risk genotypes, treatment with prasugrel was superior to an augmented dosing strategy of clopidogrel in reducing HPR.

Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative.

OBJECTIVE: A patient-derived composite measure of the impact of rheumatoid arthritis (RA), the rheumatoid arthritis impact of disease (RAID) score, takes into account pain, functional capacity, fatigue, physical and emotional wellbeing, quality of sleep and coping. The objectives were to finalise the RAID and examine its psychometric properties. METHODS: An international multicentre cross-sectional and longitudinal study of consecutive RA patients from 12 European countries was conducted to examine the psychometric properties of the different combinations of instruments that might be included within the RAID combinations scale (numeric rating scales (NRS) or various questionnaires). Construct validity was assessed cross-sectionally by Spearman correlation, reliability by intraclass correlation coefficient (ICC) in 50 stable patients, and sensitivity to change by standardised response means (SRM) in 88 patients whose treatment was intensified. RESULTS: 570 patients (79% women, mean ± SD age 56 ± 13 years, disease duration 12.5 ± 10.3 years, disease activity score (DAS28) 4.1 ± 1.6) participated in the validation study. NRS questions performed as well as longer combinations of questionnaires: the final RAID score is composed of seven NRS questions. The final RAID correlated strongly with patient global (R=0.76) and significantly also with other outcomes (DAS28 R=0.69, short form 36 physical -0.59 and mental -0.55, p<0.0001 for all). Reliability was high (ICC 0.90; 95% CI 0.84 to 0.94) and sensitivity to change was good (SRM 0.98 (0.96 to 1.00) compared with DAS28 SRM 1.06 (1.01 to 1.11)). CONCLUSION: The RAID score is a patient-derived composite score assessing the seven most important domains of impact of RA. This score is now validated; sensitivity to change should be further examined in larger studies.

Experimental classical bovine spongiform encephalopathy: definition and progression of neural PrP immunolabeling in relation to diagnosis and disease controls.

Tissues from sequential-kill time course studies of bovine spongiform encephalopathy (BSE) were examined to define PrP immunohistochemical labeling forms and map disease-specific labeling over the disease course after oral exposure to the BSE agent at two dose levels. Study was confined to brainstem, spinal cord, and certain peripheral nervous system ganglia-tissues implicated in pathogenesis and diagnosis or disease control strategies. Disease-specific labeling in the brainstem in 39 of 220 test animals showed the forms and patterns observed in natural disease and invariably preceded spongiform changes. A precise temporal pattern of increase in labeling was not apparent, but labeling was generally most widespread in clinical cases, and it always involved neuroanatomic locations in the medulla oblongata. In two cases, sparse labeling was confined to one or more neuroanatomic nuclei of the medulla oblongata. When involved, the spinal cord was affected at all levels, providing no indication of temporal spread within the cord axis or relative to the brainstem. Where minimal PrP labeling occurred in the thoracic spinal cord, it was consistent with initial involvement of general visceral efferent neurons. Labeling of ganglia involved only sensory ganglia and only when PrP was present in the brainstem and spinal cord. These experimental transmissions mimicked the neuropathologic findings in BSE-C field cases, independent of dose of agent or stage of disease. The model supports current diagnostic sampling approaches and control measures for the removal and destruction of nervous system tissues in slaughtered cattle.

Effects of aerobic exercise, resistance exercise or both, on patient-reported health status and well-being in type 2 diabetes mellitus: a randomised trial.

AIMS/HYPOTHESIS: The Diabetes Aerobic and Resistance Exercise (DARE) study showed that aerobic and resistance exercise training each improved glycaemic control and that a combination of both was superior to either type alone in patients with type 2 diabetes mellitus. Here we report effects on patient-reported health status and well-being in the DARE Trial. METHODS: We randomised 218 inactive participants with type 2 diabetes mellitus in parallel to 22 weeks of aerobic exercise (n = 51), resistance exercise (n = 58), combined aerobic and resistance exercise (n = 57) or no exercise (control; n = 52). Intervention allocation was managed by a central office. Outcomes included health status as assessed by the physical and mental component scores of the Medical Outcomes Trust Short-Form 36-item version (SF-36) and well-being as measured by the Well-Being Questionnaire 12-item version (WBQ-12); these were measured at the Ottawa Hospital. RESULTS: Using a p value of 0.0125 for statistical significance due to multiple comparisons, mixed model analyses indicated that resistance exercise led to clinically but not statistically significant improvements in the SF-36 physical component score compared with aerobic exercise (Delta = 2.7 points; p = 0.048) and control (i.e. no exercise; Delta = 3.3 points; p = 0.015). For mental component scores, there were clinically important improvements favouring no (control) compared with resistance (Delta = 7.6 points; p < 0.001) and combined (Delta = 7.2 points; p < 0.001) exercise. No effects on WBQ-12 scores were noted. Overall, 59/218 (27%) of participants included in this analysis sustained an adverse event during the course of the study, including 16 participants in the combined exercise group, 19 participants in the resistance exercise group, 16 participants in the aerobic exercise group, and eight participants in the control group. All participants were included in the intent-to-treat analyses. The trial is now closed to follow-up. CONCLUSIONS/INTERPRETATION: Resistance exercise was better than aerobic or no exercise for improving physical health status in these patients. No exercise was superior to resistance or combined exercise for improving mental health status. Well-being was unchanged by intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00195884 FUNDING: This study was funded by the Canadian Institutes of Health Research (grant MCT-44155) and the Canadian Diabetes Association (The Lillian Hollefriend Grant).

Elaboration of the preliminary Rheumatoid Arthritis Impact of Disease (RAID) score: a EULAR initiative.

BACKGROUND: Current response criteria in rheumatoid arthritis (RA) usually assess only three patient-reported outcomes (PROs): pain, functional disability and patient global assessment. Other important PROs such as fatigue are not included. OBJECTIVE: To elaborate a patient-derived composite response index for use in clinical trials in RA, the RA Impact of Disease (RAID) score. METHODS: Ten patients identified 17 domains or areas of health relevant for inclusion in the score, then 96 patients (10 per country in 10 European countries) ranked these domains in order of decreasing importance. The seven most important domains were selected. Instruments were chosen for each domain after extensive literature research of psychometric properties and expert opinion. The relative weight of each of the domains was obtained from 505 patients who were asked to "distribute 100 points" among the seven domains. The average ranks of importance of these domains were then computed. RESULTS: The RAID score includes seven domains with the following relative weights: pain (21%), functional disability (16%), fatigue (15%), emotional well-being (12%), sleep (12%), coping (12%) and physical well-being (12%). Weights were similar across countries and across patient and disease characteristics. Proposed instruments include the Health Assessment Questionnaire and numerical ratings scales. CONCLUSION: The preliminary RAID score is a patient-derived weighted score to assess the impact of RA. An ongoing study will allow the final choice of questionnaires and assessment of validity. This score can be used in clinical trials as a new composite index that captures information relevant to patients.

Ibandronate for the prevention of nonvertebral fractures: a pooled analysis of individual patient data.

UNLABELLED: This analysis was conducted to assess the effect of high versus lower doses of ibandronate on nonvertebral fractures. The results were adjusted for clinical fracture, age, and bone density. The treatment effect was dose-dependent. Higher doses of ibandronate significantly reduced the risk of nonvertebral fractures more effectively compared with lower doses. INTRODUCTION: The objective of this study was to assess the efficacy of different doses of ibandronate on nonvertebral fractures in a pooled analysis. METHODS: Eight randomized trials of ibandronate were reviewed for inclusion. Alternative definitions of high versus low doses based on annual cumulative exposure (ACE) were explored. A time-to-event analysis was conducted using Kaplan-Meier methodology. Hazard ratios (HR) were derived using Cox regression and adjusted for covariates. RESULTS: Combining higher ACE doses of > or = 10.8 mg (150 mg once monthly, 3 mg i.v. quarterly, and 2 mg i.v. every 2 months) versus ACE doses of 5.5 mg, from two trials, resulted in an HR 0.62 (95% CI 0.396-0.974, p = 0.038). There was a dose-response trend with increasing ACE doses (7.2-12 mg) versus ACE of 5.5 mg. CONCLUSIONS: A dose-response effect on nonvertebral fractures was observed when comparing high with low ACE doses. A significant reduction in nonvertebral fractures was noted when pooling data from trials using ACE doses of > or = 10.8 mg versus ACE < or = 7.2 mg; and with ACE > or = 10.8 mg versus ACE of 5.5 mg (38% reduction). Higher ibandronate dose levels (150 mg monthly or 3 mg i.v. quarterly) significantly reduced nonvertebral fracture risk in postmenopausal women.

Socioeconomic status influences bystander CPR and survival rates for out-of-hospital cardiac arrest victims.

OBJECTIVES: While lower socioeconomic status is associated with lower level of education and increased incidence of cardiovascular diseases, the impact of socioeconomic status on out-of-hospital cardiac arrest outcomes is unclear. We used residential property values as a proxy for socioeconomic status to determine if there was an association with: (1) bystander CPR rates and (2) survival to hospital discharge for out-of-hospital cardiac arrest. METHODS: We performed a secondary data analysis of cardiac arrest cases prospectively collected as part of the Ontario Prehospital Advanced Life Support study, conducted in 20 cities with ALS and BLS-D paramedics. We measured patient and system characteristics for cardiac arrests of cardiac origin, not witnessed by EMS, occurring in a single residential dwelling. We obtained property values from the Municipal Property Assessment Corporation. Analyses included descriptive statistics with 95% CIs and stepwise logistic regression. RESULTS: Three thousand six hundred cardiac arrest cases met our inclusion criteria between 1 January 1995 and 31 December 1999. Patient characteristics were: mean age 69.2, male 67.8%, witnessed 44.7%, bystander CPR 13.2%, VF/VT 33.8%, time to vehicle stop 5:36min:s, return of spontaneous circulation 12.7%, and survival 2.7%. Median property value was $184,000 (range $25,500-2,494,000). For each $100,000 increment in property value, the likelihood of receiving bystander CPR increased (OR=1.07; 95% CI 1.01-1.14; p=0.03) and survival decreased (OR=0.77; 95% CI 0.61-0.97; p=0.03). CONCLUSIONS: This is the largest study showing an association between socioeconomic status and survival, and the first study showing an association with bystander CPR. Our findings suggest targeting CPR training among lower socioeconomic groups.

Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Alendronate belongs to the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts. OBJECTIVES: To assess the efficacy of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007. SELECTION CRITERIA: Women receiving at least one year of alendronate, for postmenopausal osteoporosis, were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence. DATA COLLECTION AND ANALYSIS: We undertook study selection and data abstraction in duplicate. We performed meta-analysis of fracture outcomes using relative risks and a > 15% relative change was considered clinically important. We assessed study quality through reporting of allocation concealment, blinding and withdrawals. MAIN RESULTS: Eleven trials representing 12,068 women were included in the review. Relative (RRR) and absolute (ARR) risk reductions for the 10 mg dose were as follows. For vertebral fractures, a significant 45% RRR was found (RR 0.55, 95% CI 0.45 to 0.67). This was significant for both primary prevention, with 45% RRR (RR 0.55, 95% CI 0.38 to 0.80) and 2% ARR, and secondary prevention with 45% RRR (RR 0.55, 95% CI 0.43 to 0.69) and 6% ARR. For non-vertebral fractures, a significant 16% RRR was found (RR 0.84, 95% CI 0.74 to 0.94). This was significant for secondary prevention, with 23% RRR (RR 0.77, 95% CI 0.64 to 0.92) and 2% ARR, but not for primary prevention (RR 0.89, 95% CI 0.76 to 1.04). There was a significant 40% RRR in hip fractures (RR 0.60, 95% CI 0.40 to 0.92), but only secondary prevention was significant with 53% RRR (RR 0.47, 95% CI 0.26 to 0.85) and 1% ARR. The only significance found for wrist was in secondary prevention, with a 50% RRR (RR 0.50 95% CI 0.34 to 0.73) and 2% ARR. For adverse events, we found no statistically significant differences in any included study. However, observational data raise concerns regarding potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw. AUTHORS' CONCLUSIONS: At 10 mg per day, both clinically important and statistically significant reductions in vertebral, non-vertebral, hip and wrist fractures were observed for secondary prevention ('gold' level evidence, www.cochranemsk.org). We found no statistically significant results for primary prevention, with the exception of vertebral fractures, for which the reduction was clinically important ('gold' level evidence).

Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts. OBJECTIVES: To assess the efficacy of etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007. SELECTION CRITERIA: Women receiving at least one year of etidronate for postmenopausal osteoporosis were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence. DATA COLLECTION AND ANALYSIS: Study selection and data abstraction was done in duplicate. Meta-analysis of fracture outcomes was performed with data presented as relative risks and a relative change greater than 15% was considered clinically important. Study quality was assessed through the reporting of allocation concealment, blinding and withdrawals. MAIN RESULTS: Eleven studies representing a total of 1248 patients were included in the review.A significant 41% relative risk reduction (RRR) in vertebral fractures across eight studies (RR 0.59, 95% CI 0.36 to 0.96) was found. The six secondary prevention trials demonstrated a significant RRR of 47% in vertebral fractures (RR 0.53, 95% CI 0.32 to 0.87) and a 5% absolute risk reduction (ARR); compared with the pooled result for the two primary prevention trials (RR 3.03, 95% CI 0.32 to 28.44), which was not significant. There were no statistically significant risk reductions for non-vertebral (RR 0.98, 95% CI 0.68 to 1.42), hip (RR 1.20, 95% CI 0.37 to 3.88) or wrist fractures (RR 0.87, 95% CI: 0.32 to 2.36). For adverse events, no statistically significant differences were found in the included studies. However, observational data has led to concerns regarding potential risk for upper gastrointestinal injury. AUTHORS' CONCLUSIONS: Etidronate, at 400 mg per day, demonstrated a statistically significant and clinically important benefit in the secondary prevention of vertebral fractures. No statistically significant reductions in vertebral fractures were observed when it was used for primary prevention. In addition, no statistically significant reductions in non-vertebral, hip, or wrist fractures were found, regardless of whether etidronate was used for primary or secondary prevention. The level of evidence for all outcomes is Silver (www.cochranemsk.org.).

Strontium ranelate for preventing and treating postmenopausal osteoporosis.

BACKGROUND: Strontium ranelate is a new anti-osteoporosis therapy therefore, its benefits and harms need to be known. OBJECTIVES: To determine the efficacy and safety of strontium ranelate for the treatment and prevention of postmenopausal osteoporosis. SEARCH STRATEGY: We searched MEDLINE (1996 to March 2005), EMBASE (1996 to week 9 2005), the Cochrane Library (1996 to Issue 1 2005), reference lists of relevant articles and conference proceedings from the last two years. Additional data was sought from authors and industry sponsors. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of at least one year duration comparing strontium ranelate versus placebo reporting fracture incidence, bone mineral density (BMD), health related quality of life and/or safety outcomes in postmenopausal women. Treatment (versus prevention) population was defined as women with prevalent vertebral fractures and/or lumbar spine BMD T score < -2.5 SD. DATA COLLECTION AND ANALYSIS: Two reviewers independently determined study eligibility, assessed trial quality and extracted the relevant data. Disagreements were resolved by consensus. RCTs were grouped by dose of strontium ranelate and treatment duration. Where possible, meta-analysis was conducted using the random effects model. MAIN RESULTS: A total of four trials met our inclusion criteria, three of which investigated the effects of strontium ranelate compared to placebo in a treatment population (doses ranged from 0.5 to 2 g daily) and one, in a prevention population (doses 0.125, 0.5 and 1 g daily). In osteoporotic, postmenopausal women a 37% reduction in vertebral fractures (two trials, n = 5082, RR 0.63, 95% CI 0.56 to 0.71) and a 14% reduction in non-vertebral fractures (two trials, n = 6572, RR 0.86, 95% CI 0.75 to 0.98) was demonstrated over a three year period with 2 g of strontium ranelate daily. An increase in BMD at all sites was shown with the same dose: lumbar spine BMD (two trials, n = 1614, WMD adjusted for strontium content 5.44, 95% CI 3.41 to 7.46 and WMD not adjusted 11.29, 95% CI 10.22 to 12.37 over two years), femoral neck and total hip (two trials, n = 4230, WMD 8.25, 95% CI 7.84 to 8.66 and WMD 9.83, 95% CI 9.39 to 10.26 respectively over three years). One gram of strontium ranelate daily in postmenopausal women without osteoporosis increased BMD at all sites over a two year period: lumbar spine (one trial, n = 59, WMD adjusted for strontium content 2.39, 95% CI 0.15 to 4.63 and WMD not adjusted 6.68, 95% CI 5.16 to 8.20), femoral neck (one trial, n= 60, WMD 2.52, 95%CI 0.96 to 4.09) and total hip (one trial, n = 60, WMD 1.02, 95% CI 0.48 to 1.56). In both the treatment and prevention populations, lower doses of strontium ranelate were superior to placebo with the highest dose of strontium ranelate demonstrating the greatest reduction in vertebral fractures and increase in BMD. There is some evidence to suggest that 2 g of strontium ranelate daily compared to placebo may have a beneficial effect on health related quality of life in postmenopausal women after three years of treatment. Two grams of strontium ranelate daily increased the risk of diarrhea (RR 1.38%, 95% CI 1.02 to 1.87); however, adverse events did not affect the risk of discontinuing strontium ranelate nor did it increase the risk of serious side effects, gastritis or death. Additional data obtained suggests that the risk of vascular system disorders including venous thromboembolism (two trials, n = 6669, 2.2% versus 1.5%, OR 1.5, 95% CI 1.1 to 2.1) and pulmonary embolism (two trials, n = 6669, 0.8% versus 0.4%, OR 1.7, 95% CI 1.0 to 3.1) as well as nervous system disorders such as headaches (3.9% versus 2.9%), seizures (0.3% versus 0.1%), memory loss (2.4% versus 1.9%) and disturbance in consciousness (2.5% versus 2.0%) is slightly increased with taking 2 g of strontium ranelate daily over a 3 to 4 year period. AUTHORS' CONCLUSIONS: There is silver level evidence to support the efficacy of strontium ranelate for the reduction of vertebral fractures (and to a lesser extent non-vertebral fractures) in postmenopausal osteoporotic women and an increase in BMD (all sites) in postmenopausal women with and without osteoporosis. Diarrhea may occur however, adverse events leading to study withdrawal were not significantly increased in the strontium ranelate group. Potential risks to the vascular and neurological system associated with taking 2 g of strontium ranelate daily need to be further explored and quantified.

Strontium ranelate for preventing and treating postmenopausal osteoporosis.

BACKGROUND: Strontium ranelate is a new treatment for osteoporosis therefore, its benefits and harms need to be known. OBJECTIVES: To determine the efficacy and safety of strontium ranelate for the treatment and prevention of postmenopausal osteoporosis. SEARCH STRATEGY: We searched MEDLINE (1996 to March 2005), EMBASE (1996 to week 9 2005), the Cochrane Library (1996 to Issue 1 2005), reference lists of relevant articles and conference proceedings from the last two years. Additional data was sought from authors. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of at least one year duration comparing strontium ranelate versus placebo reporting fracture incidence, bone mineral density (BMD), health related quality of life or safety in postmenopausal women. Treatment (versus prevention) population was defined as women with prevalent vertebral fractures and/or lumbar spine BMD T score < -2.5 SD. DATA COLLECTION AND ANALYSIS: Two reviewers independently determined study eligibility, assessed trial quality and extracted the relevant data. Disagreements were resolved by consensus. RCTs were grouped by dose of strontium ranelate and treatment duration. Where possible, meta-analysis was conducted using the random effects model. MAIN RESULTS: Four trials met the inclusion criteria. Three included a treatment population (0.5 to 2 g of strontium ranelate daily) and one a prevention population (0.125 g, 0.5 g and 1 g daily). A 37% reduction in vertebral fractures (RR 0.63, 95% CI 0.56, 0.71) and a 14% reduction in non-vertebral fractures (RR 0.86, 95% CI 0.75, 0.98) were demonstrated over three years with 2 g of strontium ranelate daily in a treatment population. An increase in BMD was shown at all BMD sites after two to three years in both populations. Lower doses of strontium ranelate were superior to placebo and the highest dose demonstrated the greatest reduction in vertebral fractures and increase in BMD. An increased risk of diarrhea with 2 g of strontium ranelate was found; however, adverse events did not affect the risk of discontinuing treatment nor did it increase the risk of serious side effects, gastritis or death. Additional data suggests that the risk of vascular and nervous system side-effects is slightly increased with taking 2 g of strontium ranelate daily over three to four years. AUTHORS' CONCLUSIONS: There is silver level evidence (www.cochranemsk.org) to support the efficacy of strontium ranelate for the reduction of fractures (vertebral and to a lesser extent non-vertebral) in postmenopausal osteoporotic women and an increase in BMD in postmenopausal women with/without osteoporosis. Diarrhea may occur however, adverse events leading to study withdrawal were not significantly increased with taking 2 g of strontium ranelate daily. Potential vascular and neurological side-effects need to be further explored.

Neuroprotective effect of mild hypothermia in patients undergoing coronary artery surgery with cardiopulmonary bypass: a randomized trial.

BACKGROUND: Neuropsychological deficits occur in 30% to 80% of patients undergoing heart surgery and are due in part to ischemic cerebral injury during cardiopulmonary bypass. We tested whether mild hypothermia, the most efficacious neuroprotective strategy found in laboratory studies, improved cognitive outcome in patients undergoing coronary artery surgery. METHODS AND RESULTS: Patients 60 years or older scheduled for coronary artery surgery were enrolled. During cardiopulmonary bypass, patients were initially cooled to 32 degrees C then randomly assigned to rewarming to 37 degrees C (control) or 34 degrees C (hypothermic), with no further intraoperative warming. Testing was scheduled preoperatively and 1 week and 3 months postoperatively. Eleven tests were combined into 3 cognitive domains: memory, attention, and psychomotor speed and dexterity. A patient was classified as having a cognitive deficit if a decrease of >/=0.50 SD was realized in 1 or more domains. The incidence of cognitive deficits 1 week after surgery, which was the primary outcome, was 62% () in the control group and 48% () in the hypothermic group (relative risk 0.77, P=0.048). In the hypothermic group, the magnitude of deterioration in attention and in speed and dexterity was reduced by 55.6% (P=0.038) and 41.3% (P=0.042), respectively. At 3 months, the hypothermic group still performed better on one test of speed and dexterity (grooved pegboard). There was no difference in morbidity or mortality. CONCLUSIONS: Our findings support a neuroprotective effect of mild hypothermia in patients undergoing coronary artery surgery and should encourage physicians and perfusionists to pay careful attention to brain temperature during cardiopulmonary bypass.

Cost effectiveness of defibrillation by targeted responders in public settings.

BACKGROUND: Out-of-hospital cardiac arrest is frequent and has poor outcomes. Defibrillation by trained targeted nontraditional responders improves survival versus historical controls, but it is unclear whether such defibrillation is a good value for the money. Therefore, this study estimated the incremental cost effectiveness of defibrillation by targeted nontraditional responders in public settings by using decision analysis. METHODS AND RESULTS: A Markov model evaluated the potential cost effectiveness of standard emergency medical services (EMS) versus targeted nontraditional responders. Standard EMS included first-responder defibrillation followed by advanced life support. Targeted nontraditional responders included standard EMS supplemented by defibrillation by trained lay responders. The analysis adopted a US societal perspective. Input data were derived from published or publicly available data. Future costs and effects were discounted at 3%. Monte Carlo simulation and sensitivity analyses assessed the robustness of results. Standard EMS had a median of 0.47 (interquartile range [IQR]=0.32 to 0.69) quality-adjusted life years and a median of 14 100 dollars (IQR=8600 dollars to 21 900 dollars) costs per arrest. Targeted nontraditional responders in casinos had an incremental cost of a median 56 700 dollars (IQR=44 100 dollars to 77 200 dollars) per additional quality-adjusted life year. The results were sensitive to changes in time to defibrillation, incidence of arrest, and number of devices required to implement rapid defibrillation. CONCLUSIONS: Where cardiac arrest is frequent and response time intervals are short, rapid defibrillation by targeted nontraditional responders may be a good value for the money compared with standard EMS. The incidence of arrest should be considered when choosing locations to implement public access defibrillation.

Neuropathological findings in cats with clinically suspect but histologically unconfirmed feline spongiform encephalopathy.

Central nervous system (CNS) tissues from 192 cats with neurological signs were examined histologically, and tissues from 173 of them were later examined immunohistochemically as part of a survey to determine the prevalence of feline spongiform encephalopathy (FSE). One of the cats was from Norway and the others were from Great Britain. The most commonly recorded clinical signs were ataxia, behavioural changes and epilepsy, but none of the cats had histopathological evidence of FSE. The most common organic CNS lesions were non-suppurative encephalomyelitis in 28 per cent, neoplasia in 15 per cent and a heterogeneous group of degenerative encephalopathies in 9 per cent of the cats. A range of minor histological lesions of uncertain significance was also observed. No histological lesions were observed in the tissues of 63 (33 per cent) of the cats. Disease-specific prion protein (PrP(Sc)) was observed in only one of the 173 cats examined by immunohistochemistry.

Pathogenesis of experimental bovine spongiform encephalopathy: preclinical infectivity in tonsil and observations on the distribution of lingual tonsil in slaughtered cattle.

The infectivity in tissues from cattle exposed orally to the agent of BSE was assayed by the intracerebral inoculation of cattle. In addition to the infectivity in the central nervous system and distal ileum at stages of pathogenesis previously indicated by mouse bioassay, traces of infectivity were found in the palatine tonsil of cattle killed 10 months after exposure. Because the infectivity may therefore be present throughout the tonsils in cattle infected with BSE, observations were made of the anatomical and histological distribution of lingual tonsil in the root of the tongue of cattle. Examinations of tongues derived from abattoirs in Britain and intended for human consumption showed that macroscopically identifiable tonsillar tissue was present in more than 75 per cent of them, and even in the tongues in which no visible tonsillar tissue remained, histological examination revealed lymphoid tissue in more than 90 per cent. Variations in the distribution of the lingual tonsil suggested that even after the most rigorous trimming of the root of the tongue, traces of tonsillar tissue may remain.

Cost-effectiveness analysis of neoadjuvant pertuzumab and trastuzumab therapy for locally advanced, inflammatory, or early HER2-positive breast cancer in Canada.

OBJECTIVE: The NeoSphere trial demonstrated that the addition of pertuzumab to trastuzumab and docetaxel for the neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early breast cancer (eBC) resulted in a significant improvement in pathological complete response (pCR). Furthermore, the TRYPHAENA trial supported the benefit of neoadjuvant dual anti-HER2 therapy. Survival data from these trials is not yet available; however, other studies have demonstrated a correlation between pCR and improved event-free survival (EFS) and overall survival (OS) in this patient population. This study represents the first Canadian cost-effectiveness analysis of pertuzumab in the neoadjuvant treatment of HER2-positive eBC. METHODS: A cost-utility analysis (CUA) was conducted using a three health state Markov model ('event-free', 'relapsed', and 'dead'). Two separate analyses were conducted; the first considering total pCR (ypT0/is ypN0) data from NeoSphere, and the second from TRYPHAENA. Published EFS and OS data partitioned for patients achieving/not achieving pCR were used in combination with the percentage achieving pCR in the pertuzumab trials to estimate survival. This CUA included published utility values and direct medical costs including drugs, treatment administration, management of adverse events, supportive care, and subsequent therapy. To address uncertainty, a probabilistic sensitivity analysis (PSA) and alternative scenarios were explored. RESULTS: Both analyses suggested that the addition of pertuzumab resulted in increased life-years and quality-adjusted life-years (QALYs). The incremental cost per QALY ranged from $25,388 (CAD; NeoSphere analysis) to $46,196 (TRYPHAENA analysis). Sensitivity analyses further support the use of pertuzumab, with cost-effectiveness ratios ranging from $9230-$64,421. At a threshold of $100,000, the addition of pertuzumab was cost-effective in nearly all scenarios (93% NeoSphere; 79% TRYPHAENA). CONCLUSION: Given the improvement in clinical efficacy and a favorable cost per QALY, the addition of pertuzumab in the neoadjuvant setting represents an attractive treatment option for HER2-positive eBC patients.

Protocol for the development of a CONSORT-equity guideline to improve reporting of health equity in randomized trials.

BACKGROUND: Health equity concerns the absence of avoidable and unfair differences in health. Randomized controlled trials (RCTs) can provide evidence about the impact of an intervention on health equity for specific disadvantaged populations or in general populations; this is important for equity-focused decision-making. Previous work has identified a lack of adequate reporting guidelines for assessing health equity in RCTs. The objective of this study is to develop guidelines to improve the reporting of health equity considerations in RCTs, as an extension of the Consolidated Standards of Reporting Trials (CONSORT). METHODS/DESIGN: A six-phase study using integrated knowledge translation governed by a study executive and advisory board will assemble empirical evidence to inform the CONSORT-equity extension. To create the guideline, the following steps are proposed: (1) develop a conceptual framework for identifying "equity-relevant trials," (2) assess empirical evidence regarding reporting of equity-relevant trials, (3) consult with global methods and content experts on how to improve reporting of health equity in RCTs, (4) collect broad feedback and prioritize items needed to improve reporting of health equity in RCTs, (5) establish consensus on the CONSORT-equity extension: the guideline for equity-relevant trials, and (6) broadly disseminate and implement the CONSORT-equity extension. DISCUSSION: This work will be relevant to a broad range of RCTs addressing questions of effectiveness for strategies to improve practice and policy in the areas of social determinants of health, clinical care, health systems, public health, and international development, where health and/or access to health care is a primary outcome. The outcomes include a reporting guideline (CONSORT-equity extension) for equity-relevant RCTs and a knowledge translation strategy to broadly encourage its uptake and use by journal editors, authors, and funding agencies.

The neuropathology and epidemiology of bovine spongiform encephalopathy.

Bovine spongiform encephalopathy (BSE), defined originally from its characteristic neuropathology, retains a place of particular interest in the scrapie-like or prion disease group, presenting uniquely an example of such diseases occurring as a nationwide food-borne epidemic in Great Britain. Comprehensive monitoring of the epidemic, both pathologically and epidemiologically, has facilitated our present understanding of the disease. BSE presents the classical neuropathological features of the transmissible spongiform encephalopathies. Although particularly similar to natural scrapie of sheep, BSE has, unlike scrapie, a stereotypic lesion profile from which it has been concluded that host and agent factors, including probably the strain of agent, which influence the profile, are constant in this disease. Neuronal loss in BSE may make an important but hitherto inapparent contribution to functional deficits. Preliminary ultrastructural studies have confirmed light microscopic features of brain changes in BSE but have as yet not established significant new findings. Immunohistochemical studies of PrP accumulation reveal distinctive forms and distributions of immunolabelling, confirming features reported previously in experimental models of scrapie, including perineuronal and perineuritic "synapse-like" reactivity. The histopathological diagnosis of BSE, validated on a single section of the medulla for the statutory diagnosis of large numbers of cases, is supplemented where necessary by fibril (SAF) examination which performs similarly to the histological diagnosis in the majority of cases. Epidemiological studies of BSE have supported the pathological findings that there is no detectable variation in susceptibility within the cattle population. The detailed monitoring of the epidemic has revealed the expected effects on the incidence as a result of statutory measures intended to prevent food-borne exposure after July 1988. The main effect has been a reduction in the national incidence during 1993 which has been continued into 1994. Analytical studies have not revealed any means of transmission, other than the food-borne source, capable of maintaining the epidemic in Great Britain. An international comparison of risk factors for the occurrence of BSE indicates that an epidemic of similar magnitude outside the British Isles is unlikely.