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The practical purpose of diagnostic assessment in most cases of obstructive sleep apnea is to predict which patients have symptoms that will improve on treatment. We measured the accuracy with which clinicians make this prediction using polysomnography compared with oximeter-based home monitoring. Patients referred to a sleep center with suspicion of symptomatic obstructive sleep apnea were randomized to have polysomnography or home monitoring. Patients with comorbidity or physiologic consequences of sleep apnea were excluded. Sleep specialists estimated the likelihood of success of treatment as greater than 50% (predicted success) or less than 50% (predicted failure) on the basis of clinical data and test results. All patients were treated for 4 weeks with autoadjusting continuous positive airway pressure. Success was defined as an increase greater than 1.0 in Sleep Apnea Quality of Life Index. Correct prediction rates were compared. Two hundred eighty-eight patients were enrolled. Initial patient characteristics, compliance, and improvement in quality of life at 4 weeks were not different in the two groups. The correct prediction rate was 0.61 with polysomnography and 0.64 with home monitoring (not significant). We conclude that the ability of physicians to predict the outcome of continuous positive airway treatment in individual patients is not significantly better with polysomnography than with home oximeter-based monitoring. [ABSTRACT FROM AUTHOR]

Background: Some observational studies suggest that the use of pulmonary-artery catheters to guide therapy is associated with increased mortality.Methods: We performed a randomized trial comparing goal-directed therapy guided by a pulmonary-artery catheter with standard care without the use of a pulmonary-artery catheter. The subjects were high-risk patients 60 years of age or older, with American Society of Anesthesiologists (ASA) class III or IV risk, who were scheduled for urgent or elective major surgery, followed by a stay in an intensive care unit. Outcomes were adjudicated by observers who were unaware of the treatment-group assignments. The primary outcome was in-hospital mortality from any cause.Results: Of 3803 eligible patients, 1994 (52.4 percent) underwent randomization. The base-line characteristics of the two treatment groups were similar. A total of 77 of 997 patients who underwent surgery without the use of a pulmonary-artery catheter (7.7 percent) died in the hospital, as compared with 78 of 997 patients in whom a pulmonary-artery catheter was used (7.8 percent)--a difference of 0.1 percentage point (95 percent confidence interval, -2.3 to 2.5). There was a higher rate of pulmonary embolism in the catheter group than in the standard-care group (8 events vs. 0 events, P=0.004). The survival rates at 6 months among patients in the standard-care and catheter groups were 88.1 and 87.4 percent, respectively (difference, -0.7 percentage point [95 percent confidence interval, -3.6 to 2.2]; negative survival differences favor standard care); at 12 months, the rates were 83.9 and 83.0 percent, respectively (difference, -0.9 percentage point [95 percent confidence interval, -4.3 to 2.4]). The median hospital stay was 10 days in each group.Conclusions: We found no benefit to therapy directed by pulmonary-artery catheter over standard care in elderly, high-risk surgical patients requiring intensive care. [ABSTRACT FROM AUTHOR]

Purpose: Processed electroencephalography (EEG) monitors support depth-of-hypnosis assessment during anesthesia. This randomized-controlled trial investigated the performance of the NeuroSENSE electroencephalography (EEG) monitor to determine whether its wavelet anesthetic value for central nervous system (WAV CNS ) index distinguishes consciousness from unconsciousness during induction of anesthesia (as assessed by the anesthesiologist) and emergence from anesthesia (indicated by patient responsiveness), and whether it correlates with changes in desflurane minimum alveolar concentration (MAC) during maintenance of anesthesia., Methods: EEG was collected using a fronto-temporal bilateral montage. The WAV CNS was continuously recorded by the NeuroSENSE monitor, to which the anesthesiologist was blinded. Anesthesia was induced with propofol/remifentanil and maintained with desflurane, with randomized changes of -0.4, 0, or +0.4 MAC every 7.5 min within the 0.8-1.6 MAC range, if clinically acceptable to the anesthesiologist. During emergence from anesthesia, desflurane was stepped down by 0.2 MAC every five minutes., Results: Data from 75 patients with a median [interquartile range] age of 41[35-52] yr were obtained. The WAV CNS distinguished consciousness from unconsciousness as assessed by the anesthesiologist, with area under the receiver operating characteristic curve of 99.5% (95% confidence interval [CI], 98.5 to 100.0) at loss of consciousness and 99.4% (95% CI, 98.5 to 100.0) at return of consciousness. Bilateral WAV CNS changes correlated with desflurane concentrations, with -8.0 and -8.6 WAV CNS units, respectively, per 1 MAC change in the 0.8-1.6 MAC range during maintenance of anesthesia and -10.0 and -10.5 WAV CNS units, respectively, in the 0.4-1.6 MAC range including emergence from anesthesia., Conclusion: The NeuroSENSE monitor can reliably discriminate between consciousness and unconsciousness, as assessed by the anesthesiologist, during induction of anesthesia and with a lower level of reliability during emergence from anesthesia. The WAV CNS correlates with desflurane concentration but plateaus at higher concentrations, similar to other EEG monitors, which suggests limited utility to titrate higher concentrations of anesthetic vapour., Trial Registration: clinicaltrials.gov, NCT02088671; registered 17 March, 2014.

Background: Dexmedetomidine is a highly selective α2-adrenergic agonist, which is increasingly used in pediatric anesthesia and intensive care. Potential adverse effects that have not been rigorously evaluated in children include its effects on blood glucose and serum potassium concentrations, which are relevant due to the associations of derangements of both parameters with undesired outcomes. We investigated the effects of 3 different doses of dexmedetomidine on these outcomes in a randomized controlled trial in children undergoing elective surgery., Methods: Sixty-four American Society of Anesthesiologists I-II children were randomized to receive either dexmedetomidine 0.25 µg/kg, dexmedetomidine 0.5 µg/kg, dexmedetomidine 0.75 µg/kg, or 0 µg/kg (control), as a bolus administered over 60 seconds after induction of anesthesia. Changes in plasma glucose and serum potassium concentrations were measured in venous blood sampled before and at 15 and 30 minutes after study drug administration. Data were plotted within and between groups and analyzed using a constrained longitudinal data approach., Results: Forty-nine children completed the study. Mean glucose levels at 15 and 30 minutes were elevated with estimated changes from baseline of 0.37 mmol/L (95% CI, 0.29-0.45 mmol/L) and 0.05 mmol/L (95% CI, 0.00-0.10 mmol/L), respectively. At 15 minutes, there was a linear dose-response relationship (1.07 mmol/L/μg/kg [95% CI, 0.57-1.58 mmol/L/μg/kg]), but there was no appreciable effect of dexmedetomidine at 30 minutes (0.15 mmol/L/μg/kg [95% CI, -0.40 to 0.70 mmol/L/μg/kg]). Potassium levels were depressed relative to baseline, with a mean difference at 15 minutes of -0.20 mEq/L (95% CI, -0.28 to -0.12 mEq/L) and at 30 minutes of -0.12 mEq/L (95% CI, -0.15 to -0.08 mEq/L), but there was no appreciable effect of dexmedetomidine at either time., Conclusions: Small elevations in glucose and decreases in potassium were observed after induction of anesthesia in children. The elevation in glucose at 15 minutes depended on the dose of dexmedetomidine administered. These preliminary data warrant further investigation.

Background: Asymptomatic children with Crohn's disease (CD) require ongoing monitoring to ensure early recognition of a disease exacerbation., Aim: In a cohort of pediatric CD patients, we aimed to assess the utility of serial fecal calprotectin measurements to detect intestinal inflammatory activity and predict disease relapse., Methods: In this prospective longitudinal cohort study, children with CD on infliximab therapy in clinical remission were included. Fecal calprotectin levels were assessed at baseline and at subsequent 2-5 visits. Clinical and biochemical disease activity were assessed using the Pediatric Crohn's Disease Activity Index, C-reactive protein and erythrocyte sedimentation rate at baseline and at visits over the following 18 mo., Results: 53 children were included and eighteen patients (34%) had a clinical disease relapse during the study. Baseline fecal calprotectin levels were higher in patients that developed symptomatic relapse [median (interquartile range), relapse 723 μg/g (283-1758) vs 244 μg/g (61-627), P = 0.02]. Fecal calprotectin levels > 250 μg/g demonstrated good predictive accuracy of a clinical flare within 3 mo (area under the receiver operator curve was 0.86, 95% confidence limits 0.781 to 0.937)., Conclusion: Routine fecal calprotectin testing in children with CD in clinical remission is useful to predict relapse. Levels > 250 μg/g are a good predictor of relapse in the following 3 mo. This information is important to guide monitoring standards used in this population., Competing Interests: Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript.

The analysis and validation of flow cytometry-based biomarkers in clinical studies are limited by the lack of standardized protocols that are reproducible across multiple centers and suitable for use with either unfractionated blood or cryopreserved PBMCs. Here we report the development of a platform that standardizes a set of flow cytometry panels across multiple centers, with high reproducibility in blood or PBMCs from either healthy subjects or patients 100 days after hematopoietic stem cell transplantation. Inter-center comparisons of replicate samples showed low variation, with interindividual variation exceeding inter-center variation for most populations (coefficients of variability <20% and interclass correlation coefficients >0.75). Exceptions included low-abundance populations defined by markers with indistinct expression boundaries (e.g., plasmablasts, monocyte subsets) or populations defined by markers sensitive to cryopreservation, such as CD62L and CD45RA. Automated gating pipelines were developed and validated on an independent data set, revealing high Spearman's correlations (rs >0.9) with manual analyses. This workflow, which includes pre-formatted antibody cocktails, standardized protocols for acquisition, and validated automated analysis pipelines, can be readily implemented in multicenter clinical trials. This approach facilitates the collection of robust immune phenotyping data and comparison of data from independent studies.

Background: Infant behavioral sleep problems are common, with potential negative consequences. We conducted a randomized controlled trial to assess effects of a sleep intervention comprising a two-hour group teaching session and four support calls over 2 weeks. Our primary outcomes were reduced numbers of nightly wakes or parent report of sleep problem severity. Secondary outcomes included improvement in parental depression, fatigue, sleep, and parent cognitions about infant sleep., Methods: Two hundred thirty five families of six-to-eight month-old infants were randomly allocated to intervention (n = 117) or to control teaching sessions (n = 118) where parents received instruction on infant safety. Outcome measures were observed at baseline and at 6 weeks post intervention. Nightly observation was based on actigraphy and sleep diaries over six days. Secondary outcomes were derived from the Multidimensional Assessment of Fatigue Scale, Center for Epidemiologic Studies Depression Measure, Pittsburgh Sleep Quality Index, and Maternal (parental) Cognitions about Infant Sleep Questionnaire., Results: One hundred eight intervention and 107 control families provided six-week follow-up information with complete actigraphy data for 96 in each group: 96.9% of intervention and 97.9% of control infants had an average of 2 or more nightly wakes, a risk difference of -0.2% (95% CI: -1.32, 0.91). 4% of intervention and 14% of control infants had parent-assessed severe sleep problems: relative risk 0.3, a risk difference of -10% (CI: 0.11, 0.84-16.8 to -2.2). Relative to controls, intervention parents reported improved baseline-adjusted parental depression (CI: -3.7 to -0.4), fatigue (CI: -5.74 to -1.68), sleep quality (CI: -1.5 to -0.2), and sleep cognitions: doubts (CI: -2.0 to -0.6), feeding (CI: - 2.1 to - 0.7), anger (CI: - 1.8 to - 0.4) and setting limits (CI: -3.5 to -1.5)., Conclusions: The intervention improved caregivers' assessments of infant sleep problem severity and parental depression, fatigue, sleep, and sleep cognitions compared with controls., Trial Registration: ISRCTN42169337 , NCT00877162.

Passive surveillance using ICD codes for hospital discharges has been used to estimate the incidence of abusive head trauma (AHT) utilizing ICD-9-CM, but not ICD-10, codes. There have been no incidence estimates of AHT in Canada where ICD-10 codes have been used since 2002. The Discharge Abstract Database from the Canadian Institute of Health Information (CIHI) for 2002-2007 was used for analyses conducted in 2011. A case was defined by code combinations that indexed injury specificity (narrow or broad) and degree of certainty (presumptive or probable) that the injury was inflicted. Estimated incidences for the populations at risk in those aged <12 months and 12-23 months from 2002-2007 were determined. For those aged <12 months, the mean incidence for "narrow, presumptive" AHT was 13.0 (95% CIs=11.3, 14.9) per 100,000 person-years; for "broad, probable" it was 15.5 (13.6, 17.6) per 100,000 person-years. For those aged 12-23 months, the "narrow, presumptive" incidence was 2.4 (1.7, 3.3) and the "broad, probable" incidence was 2.8 (2.0, 3.8) per 100,000 person-years, respectively. Month and year of age patterns were similar to previous reports. ICD-10 codes can be used to estimate incidence of AHT. Narrower classifications provide estimates consistent with those from other surveillance programs in Canada and internationally., (Copyright © 2012 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To identify factors that mediate or moderate the effects of exercise on postmenopausal sex hormone concentrations., Methods: Postmenopausal women were randomized to 12 months of aerobic exercise for 200 min/week (n = 160) or to a control group (n = 160). Intention-to-treat analyses were performed using general linear models with sex hormone concentrations at 6 and 12 months as the outcome. Mediation by adiposity and insulin was investigated by examining changes in effect estimates after adjustment for changes in these factors over 12 months. Moderation was studied as the interaction between group assignment and eight baseline characteristics., Results: Intervention effects on sex hormone-binding globulin (SHBG) and estradiol changes were attenuated with adjustment for change in overall body fat, while there was less attenuation adjusting for intra-abdominal fat change. Intervention effects on SHBG levels were unaffected by adjustment for insulin change. Significant interactions were identified between treatment and physical fitness (for SHBG and testosterone) and age (for testosterone), implying subgroup differences in intervention effect., Conclusions: Our data suggest that overall fat loss partially mediated exercise-induced changes in estradiol and SHBG concentrations. No previous RCT in postmenopausal women has studied moderators of exercise-induced sex hormone changes; therefore, future studies are needed to corroborate our results.

Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood. Metabolic factors may be involved. In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women. A year-long aerobic exercise intervention of 225  min/week (n=160) was compared with a control group asked to maintain usual activity levels (n=160). Baseline, 6- and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated. Intention-to-treat analyses were performed using linear mixed models. The treatment effect ratio (TER) of exercisers to controls was calculated. Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months. Across the study period, statistically significant reductions in insulin (TER=0.87, 95% confidence interval (95% CI)=0.81-0.93), HOMA-IR (TER=0.86, 95% CI=0.80-0.93), and leptin (TER=0.82, 95% CI=0.78-0.87), and an increase in the adiponectin/leptin ratio (TER=1.21, 95% CI=1.13-1.28) were observed in the exercise group compared with the control group. No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio. Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer.

Purpose: We examined how an aerobic exercise intervention influenced circulating estradiol, estrone, sex hormone-binding globulin (SHBG), androstenedione, and testosterone levels, which may be involved in the association between physical activity and breast cancer risk., Methods: A two-center, two-arm randomized controlled trial of exercise was conducted in 320 postmenopausal, sedentary women age 50 to 74 years. Participants were randomly assigned to a 1-year aerobic exercise intervention of 225 min/wk (n = 160) or to a control group who maintained their usual level of activity (n = 160). Baseline, 6-month, and 12-month assessments of estrone, estradiol, androstenedione, and testosterone were quantified by radioimmunoassay after extraction, and SHBG was quantified by an immunometric assay. Intent-to-treat analyses were performed using linear mixed models., Results: Blood data were available on 309 women (96.6%) at 12 months. Women in the intervention group exercised an average of 3.6 d/wk for 178 min/wk. At 12 months, statistically significant reductions in estradiol (treatment effect ratio [TER] = 0.93; 95% CI, 0.88 to 0.98) and free estradiol (TER = 0.91; 95% CI, 0.87 to 0.96) and increases in SHBG (TER = 1.04; 95% CI, 1.02 to 1.07) were observed in the exercise group compared with the control group. No significant differences in estrone, androstenedione, and testosterone levels were observed between exercisers and controls at 12 months., Conclusion: This trial found that previously sedentary postmenopausal women can adhere to a moderate- to vigorous-intensity exercise program that results in changes in estradiol and SHBG concentrations that are consistent with a lower risk for postmenopausal breast cancer.

Study Objective: To compare outcomes after acute acetaminophen poisoning in 2 large cohorts of patients treated with either the 20-hour intravenous or 72-hour oral acetylcysteine protocol., Methods: We conducted a retrospective cohort study with historical control comparing patients treated with one of 2 acetylcysteine regimens. Data for the 20-hour group were obtained from a medical record review of patients on whom the 20-hour intravenous protocol was initiated in Canadian hospitals from 1980 to 2005. The 72-hour group consisted of a historical cohort of patients treated in US hospitals with the 72-hour oral protocol from 1976 to 1985. The primary outcome was hepatotoxicity (aminotransferase levels >1,000 IU/L)., Results: Of the 4,048 patients analyzed, 2,086 were in the 20-hour group and 1,962 were in the 72-hour group. The incidence of hepatotoxicity was 13.9% in the 20-hour group and 15.8% in the 72-hour group (-1.9% absolute difference; 95% confidence interval [CI] -4.2 to 0.3). The relative risk of hepatotoxicity was lower in the 20-hour group when acetylcysteine was initiated within 12 hours of ingestion. The relative risk was lower in the 72-hour group when acetylcysteine was initiated later than 18 hours after ingestion. There was no significant risk difference between groups when acetylcysteine treatment was started 12 to 18 hours after ingestion. One patient in the 20-hour group received a liver transplant and died because of acetaminophen toxicity compared with no liver transplants and 3 deaths in the 72-hour group. Anaphylactoid reactions to intravenous acetylcysteine were reported in 148 of 2,086 patients (7.1%; 95% CI 6.1% to 8.3%). This study is limited by comparison of 2 separate data sets from different countries and study years., Conclusion: The risk of hepatotoxicity differed between the 20-hour and 72-hour protocols according to the time to initiation of acetylcysteine. It favored the 20-hour protocol for patients presenting early and favored the 72-hour protocol for patients presenting late after acute acetaminophen overdose.

Background: Secondary prevention medications in cardiac patients improve outcomes. However, prescription rates for these drugs and long-term adherence are suboptimal., Objective: To determine whether an enhanced secondary prevention program improves outcomes., Methods: Hospitalized patients with indications for secondary prevention medications were randomly assigned to either usual care or an intervention arm, in which an intensive program was used to optimize prescription rates and long-term adherence. Follow-up was 19 months., Results: A total of 2643 patients were randomly assigned in the study; 1342 patients were assigned to usual care and 1301 patients were assigned to the intervention arm. Prescription rates were near optimal except for lipid-lowering medications. Rehospitalization rates per 100 patients were 136.2 and 132.6 over 19 months in the usual care and intervention groups, respectively (P=0.59). Total days in hospital per patient were similar (10.9 days in the usual care group versus 10.2 days in the intervention group; P not significant). Crude mortality was 6.2% and 5.5% in the usual care and intervention groups, respectively, with no significant difference (P=0.15) in overall survival. Post hoc analysis suggested that after the study team became experienced, days in hospital per patient were reduced by the program (11.1+/-0.91 and 8.9+/-0.61 in the usual care and intervention groups, respectively; P<0.05)., Conclusions: The intervention program failed to improve outcomes in the present study. One explanation for these results is the near optimal physician compliance with guidelines in both groups. It is also possible that a substantial learning curve for the staff was involved, as suggested by the reduction in total days in hospital in the intervention patients during the second part of the study.

Objectives: To examine injury mortality rates in Native and non-Native children in the province of Alberta, Canada, over a 10-year period, temporal trends in injury mortality rates (Native vs. non-Native), as well as relative risks of injury mortality (Native vs. non-Native) by injury mechanism and intent, were calculated., Methods: An observational, population-based study design was used. Mortality data were obtained from provincial vital statistics, with injury deaths identified using external injury codes (E-codes). The relative risk (RR) of injury mortality (Native vs. non-Native) along with 95% confidence intervals (CIs) were calculated. Stratified analyses and Poisson regression modeling were used to calculate adjusted relative risk., Results: Injury mortality rates declined over the study period, with no difference in the rate of decline between Native and non-Native children. The adjusted relative risk for all-cause injury death (Native vs. non-Native) was 4.6 (95% CI 4.1 to 5.2). The adjusted relative risks (Native vs. non-Native) by injury intent categories were: unintentional injuries, 4.0 (95% CI 3.5 to 4.6); suicide, 6.6 (95% CI 5.2 to 8.5); and homicide, 5.1 (95% CI 3.0 to 8.5). Injury mortality rates were consistently higher for Native children across all injury mechanism categories. The largest relative risks (Native vs. non-Native) were pedestrian injury (RR = 17.0), accidental poisoning (RR = 15.4), homicide by piercing objects (RR = 15.4), and suicide by hanging (RR = 13.5)., Conclusion: The burden of injury mortality is significantly greater in Native children compared with non-Native children. Therefore, injury prevention strategies that target both intentional and unintentional injuries are needed.

Purpose: A substantial clinical need exists for an alternate to vitamin K antagonists for treating deep vein thrombosis in many patients. Long-term low-molecular-weight heparin (LMWH), body-weight adjusted, avoids anticoagulant monitoring and may be associated with less bleeding. We evaluated the effectiveness and safety of long-term LMWH compared with vitamin K antagonist therapy in a broad spectrum of patients with proximal vein thrombosis., Methods: We performed a multicenter, randomized, open-label clinical trial using objective outcome measures comparing therapy for 3 months. Outcomes were assessed at 3 and 12 months., Results: Of 737 patients, 18 of 369 receiving tinzaparin (4.9%) had recurrent venous thromboembolism at 3 months compared with 21 of 368 (5.7%) receiving usual care (absolute difference, -0.8%, 95% confidence interval -4.1-2.4). Hemorrhagic complications occurred less frequently in the LMWH group largely because of less minor bleeding: 48 of 369 patients (13.0%) versus 73 of 368 patients (19.8%) receiving usual-care anticoagulation (absolute difference -6.8%; P = .011; risk ratio = 0.66). New major bleeding events ceased early (by day 23, P = .034) for patients receiving LMWH but persisted throughout the study treatment interval for patients receiving vitamin K antagonist therapy. No mortality advantage was shown for LMWH., Conclusion: Our study shows that LMWH is similar in effectiveness to the usual-care vitamin K antagonist treatment for preventing recurrent venous thromboembolism in a broad spectrum of patients. It causes less harm and enhances the clinicians' therapeutic options for patients with proximal deep vein thrombosis. Our findings reported here suggest the possibility of a broader role for long-term LMWH in selected patients.

Purpose: A substantial clinical need exists for an alternative to vitamin K antagonists for treating deep-vein thrombosis in cancer patients who are at high risk of both recurrent venous thromboembolism and bleeding. Low-molecular-weight heparin, body-weight adjusted, avoids anticoagulant monitoring and has been shown to be more effective than vitamin-K-antagonist therapy., Subjects and Methods: Subjects were patients with cancer and acute symptomatic proximal-vein thrombosis. We performed a multi-centre randomized, open-label clinical trial using objective outcome measures comparing long-term therapeutic tinzaparin subcutaneously once daily with usual-care long-term vitamin-K-antagonist therapy for 3 months. Outcomes were assessed at 3 and 12 months., Results: Of 200 patients, 100 received tinzaparin and 100 received usual care. At 12 months, the usual-care group had an excess of recurrent venous thromboembolism; 16 of 100 (16%) versus 7 of 100 (7%) receiving low-molecular-weight heparin (P=.044; risk ratio=.44; absolute difference -9.0; 95% confidence interval [CI], -21.7 to -0.7). Bleeding, largely minor, occurred in 27 patients (27%) receiving tinzaparin and 24 patients (24%) receiving usual care (absolute difference -3.0; 95% CI, -9.1 to 15.1). In patients without additional risk factors for bleeding at the time of randomization, major bleeding occurred in 0 of 51 patients (0%) receiving tinzaparin and 1 of 48 patients (2.1%) receiving usual care. Mortality at 1 year was high, reflecting the severity of the cancers; 47% in each group died., Conclusion: Our findings confirm the limited but benchmark data in the literature that long-term low-molecular-weight heparin is more effective than vitamin-K-antagonist therapy for preventing recurrent venous thromboembolism in patients with cancer and proximal venous thrombosis.

Purpose: Clot-burden change in patients receiving anticoagulant therapy, by predicting subsequent recurrent venous thromboembolism, may provide a clinically relevant surrogate endpoint of prognostic importance. The validity of this objective measure is yet to be established., Methods: A PubMed search was performed to retrieve articles published up to December 2003. We identified 11 randomized trials reported from 1990 to 2003 that met our study identification and selection criteria. Anticoagulant therapy subsequently approved by regulatory affairs was assessed by clot-burden change and the validated outcome measure, long-term venous thromboembolism. Two additional randomized trials, partly meeting the inclusion criteria, were included in the sensitivity analysis., Results: Individual studies suggested a predictive relationship between clot-burden change and likelihood of recurrent venous thromboembolism irrespective of the particular anticoagulant. The summary treatment effects strongly favored the therapy under evaluation and were in harmony for improved clot-burden (relative risk 0.82; 95% CI, 0.76-0.88; P <0.001) and for recurrent venous thromboembolism (relative risk 0.56; 95% CI, 0.42-0.76; P <0.001). The aggregate data show a striking predictive correlation for clot-burden change and subsequent recurrent venous thromboembolism using meta-regression analysis; (correlation = 0.81, P = 0.005) validating quantitative clot-burden assessment., Conclusion: Clot-burden change predicts long-term outcome, providing clinically relevant, patient-specific prognostic findings that may guide duration of anticoagulant therapy as well as provide a valid surrogate endpoint for clinical trials of innovative antithrombotic therapy, allowing more efficient trials exposing far fewer patients to the hazards of ineffective therapy than is required for outcome studies. Noninvasive assessment (duplex ultrasonography) of clot-burden change is currently being deployed for use in clinical trials.

An age-stratified population-based random digit dial (RDD) telephone survey determined awareness and prevalence of prostate-specific antigen (PSA) testing among Alberta men aged 40 74 years, and assessed the role of indications for PSA testing in explaining patterns of PSA testing. The sample of 1984 men (participation rate 65%) with no history of prostate cancer was divided into three age strata: 40-49, 50-59, and 60-74 years. Awareness of PSA tests was low with fewer than half of the men indicating they had ever heard of PSA tests. The percentage of men who had ever had PSA testing was 4.5%, 13.1%, and 22.2% in the three age strata respectively. PSA testing was strongly associated with having at least one clinical indication for PSA testing (prevalence 21.8%, 26.9%, and 42.2% respectively). PSA testing rates were very low among men who had no clinical indications for PSA testing, suggesting infrequent PSA screening prior to the survey. PSA testing patterns in this population-based sample were consistent with Alberta clinical practice guidelines.

Purpose: Evidence-based medicine guidelines based on venographic end points recommend in-hospital prophylaxis with low-molecular-weight heparin (LMWH) in patients having elective hip surgery. Emerging data suggest that out-of-hospital use may offer additional protection; however, uncertainty remains about the risk-benefit ratio. To provide clinicians with a practical pathway for translating clinical research into practice, we systematically reviewed trials comparing extended out-of-hospital LMWH prophylaxis versus placebo., Data Sources: Studies were identified by 1) searching PubMed, MEDLINE, and the Cochrane Library Database for reports published from January 1976 to May 2001; 2) reviewing references from retrieved articles; 3) scanning abstracts from conference proceedings; and 4) contacting pharmaceutical companies and investigators of the original reports., Study Selection: Randomized, controlled trials comparing extended out-of-hospital prophylaxis with LMWH versus placebo in patients having elective hip arthroplasty., Data Extraction: Two reviewers extracted data independently. Reviewers evaluated study quality by using a validated four-item instrument., Data Synthesis: Six of seven original articles met the defined inclusion criteria. The included studies were double-blind trials that used proper randomization procedures. Compared with placebo, extended out-of-hospital prophylaxis decreased the frequency of all episodes of deep venous thrombosis (placebo rate, 150 of 666 patients [22.5%]; relative risk, 0.41 [95% CI, 0.32 to 0.54; P < 0.001]), proximal venous thrombosis (placebo rate, 76 of 678 patients [11.2%]; relative risk, 0.31 [CI, 0.20 to 0.47; P < 0.001]), and symptomatic venous thromboembolism (placebo rate, 36 of 862 patients [4.2%]; relative risk, 0.36 [CI, 0.20 to 0.67; P = 0.001]). Major bleeding was rare, occurring in only one patient in the placebo group., Conclusions: Extended LMWH prophylaxis showed consistent effectiveness and safety in the trials (regardless of study variations in clinical practice and length of hospital stay) for venographic deep venous thrombosis and symptomatic venous thromboembolism. The aggregate findings support the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty surgery.

Background: Perioperative and postoperative venous thrombosis are common in patients undergoing elective hip surgery. Prophylactic regimens include subcutaneous low-molecular-weight heparin 12 hours or more before or after surgery and oral anticoagulants. Recent clinical trials suggest that low-molecular-weight heparin initiated in closer proximity to surgery is more effective than the present clinical practice. We performed a systematic review of the literature to assess the efficacy and safety of low-molecular-weight heparin administered at different times in relation to surgery vs oral anticoagulant prophylaxis., Methods: Reviewers (A.F.M. and S.M.M.) identified studies by searching MEDLINE, reviewing references from retrieved articles, scanning abstracts from conference proceedings, and contacting investigators and pharmaceutical companies. Randomized trials comparing low-molecular-weight heparin administered at different times relative to surgery with oral anticoagulants in patients undergoing elective hip arthroplasty, evaluated using contrast phlebography, were selected. Two reviewers (A.F.M. and S.M.M.) extracted data independently., Results: The literature review identified 4 randomized trials meeting predefined inclusion criteria. The results indicate that low-molecular-weight heparin initiated in close proximity to surgery resulted in absolute risk reductions of 11% to 13% for deep vein thrombosis, corresponding to relative risk reductions of 43% to 55% compared with oral anticoagulants. Low-molecular-weight heparin initiated 12 hours before surgery or 12 to 24 hours postoperatively was not more effective than oral anticoagulants. Low-molecular-weight heparin initiated postoperatively in close proximity to surgery at half the usual dose was not associated with a clinically or statistically significant increase in major bleeding rates (P =.16)., Conclusions: The timing of initiating low-molecular-weight heparin significantly influences antithrombotic effectiveness. The practice of delayed initiation of low-molecular-weight heparin prophylaxis results in suboptimal antithrombotic effectiveness without a substantive safety advantage.

Background: Pulmonary embolism (PE) occurs in 50% or more of patients with proximal deep-vein thrombosis. Low-molecular-weight heparin treatment is effective and safe in patients with deep vein thrombosis and may also be so in patients with PE. Recent rigorous clinical trials have established objective criteria for determining a high probability of PE by perfusion lung scanning., Objective: To compare low-molecular-weight heparin with intravenous heparin for the treatment of patients with objectively documented PE and underlying proximal deep vein thrombosis., Methods: In a multicenter, double-blind, randomized trial, we compared fixed-dose subcutaneous low-molecular-weight heparin (tinzaparin sodium) given once daily with dose-adjusted intravenous heparin given by continuous infusion using objective documentation of clinical outcomes. Pulmonary embolism at study entry was documented by the presence of high-probability lung scan findings., Results: Of 200 patients with high-probability lung scan findings at study entry, none of the 97 who received low-molecular-weight heparin had new episodes of venous thromboembolism compared with 7 (6.8%) of 103 patients who received intravenous heparin (95% confidence interval for the difference, 1.9%-11.7%; P = .01). Major bleeding associated with initial therapy occurred in 1 patient (1.0%) who was given low-molecular-weight heparin and in 2 patients (1.9%) given intravenous heparin (95% confidence interval for the difference, -2.4% to 4.3%)., Conclusions: Low-molecular-weight heparin administered once daily subcutaneously was no less effective and probably more effective than use of dose-adjusted intravenous unfractionated heparin for preventing recurrent venous thromboembolism in patients with PE and associated proximal deep vein thrombosis. Our findings extend the use of low-molecular-weight heparin without anticoagulant monitoring to patients with submassive PE.

Objectives: To determine prevalence and incidence of carpal tunnel syndrome (CTS) in a modern meat packing plant. The secondary objective was to explore the relation between ethnicity and CTS., Methods: Six hundred and sixty five workers were interviewed and examined to find the prevalence of CTS. Subsequently, 421 workers without CTS were followed up and examined at a median interval of 253 days; of those, 333 remained without CTS and were again examined at a median interval of 148 days., Results: The prevalence and incidence of CTS was 21% and 11/100 person-years, respectively. The incidence for Asian mixed, white, and other ethnicities was 12.0, 12.2, and 7.2 cases/100 person-years, respectively. The observed incidence for men and women was 9.7 and 18.4 cases/100 person-years, respectively. This difference was not quite significant (p = 0.068) with an estimated relative risk (women v men) of 1.9 (95% confidence interval (95% CI) 0.9 to 3.8). The interaction between sex and use of tools was significant (p = 0.04), however, although the relative risk for CTS in women who used tools was 4.2 the numbers were small and not significant. The relative risk for men who used tools was 0.64 and not significant. The percentage of incident cases with comorbid disease was only 6.3% (3/47)., Conclusions: The prevalence and incidence of CTS in this workforce were higher than in the general population. However, the prevalence of CTS in this modern, mechanised plant was not significantly different from that reported in older plants. No relation was found between ethnicity, age, body mass index, and CTS for either prevalence or incidence. Comorbid disease among the cases of CTS is significantly less than that found in other industry.

Background: Although preoperative and postoperative initiation of prophylaxis for deep vein thrombosis (DVT) with low-molecular-weight heparin (LMWH) are effective, the relative effectiveness and safety of these approaches is unknown. In the absence of a published definitive level 1 trial addressing this question, a meta-analysis is appropriate., Objective: To report a meta-analysis comparing preoperative with postoperative initiation of prophylaxis of DVT in patients undergoing elective hip replacement., Methods: Relevant trials were identified, and potential biases in the meta-analysis were minimized by analyzing all rigorously performed randomized trials that met all of the following criteria for conduct of the trial: (1) double-blind design, (2) objective documentation of the frequencies of DVT by ascending contrast venography, (3) venography performed before or at the time of discharge from the hospital, (4) initiation of the same LMWH preoperatively or postoperatively in dosages shown to be effective, (5) compliance with the criteria for a level 1 trial, and (6) objective documentation of major and minor bleeding according to strict criteria., Results: Treatment with LMWH initiated preoperatively was associated with a DVT frequency of 10.0% compared with a frequency of 15.3% when the LMWH was initiated postoperatively (P = .02, Fisher exact test). Major bleeding was less frequent in patients receiving preoperatively initiated LMWH than in patients receiving postoperatively initiated LMWH (0.9%, vs. 3.5%; P = .01, Fisher exact test)., Conclusions: Our findings support the need for a randomized comparison of preoperative and postoperative initiation of pharmacological prophylaxis of DVT. Such a trial would resolve the divergent practices for DVT prophylaxis between Europe and the North American countries, the United States and Canada, and would affect the treatment for thousands of patients on both continents.

Objective: This study was a blinded, concurrent assessment of a historical cohort derived from a provincial registry (1978 to 1986) of breast implant recipients (cosmetic, not reconstructive) and controls (other cosmetic surgery) to test the hypothesis that connective tissue disease (CTD) is increased in breast implant recipients., Methods: Women who underwent breast implant or other cosmetic surgery during the interval from 1978 to 1986 were contacted confidentially by Alberta Health and asked to participate in the study. Those willing to participate completed an extensive questionnaire and supplied a blood sample, subsequent to which all surgical records were reviewed to confirm implant type(s) or cosmetic surgery(ies). All participants with any suggestion of rheumatic disease were assessed blindly by a rheumatologist for CTD., Results: One thousand five hundred seventy-six breast implant recipients were recruited, including 1112 who had received silicone gel-filled implants (> 13,500 person yrs exposure). Seven hundred twenty-six controls were recruited. Prevalence rates adjusted for sex and age for rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and Sjögren's syndrome (the principal targeted conditions) were consistent with published reports for Caucasian women. While breast implant recipients self-reported significantly greater rates of symptoms than controls, post-surgical diagnoses of the principal targeted conditions did not indicate an increased incidence of typical or atypical CTD., Conclusion: The results of the study do not support the hypothesis that silicone gel-filled implants induce or promote CTD.

Objective: To develop a disease-specific quality-of-life scale for symptomatic cholelithiasis for use in clinical trials, and to evaluate its reliability, construct validity and responsiveness., Design: Questionnaire., Participants: Health care professionals, patients with symptomatic cholelithiasis and their significant others., Interventions: A 114-item questionnaire was developed from open-ended questions completed by the participants. Questions dealt with physical symptoms, activities of daily living, job performance, leisure activities, emotional factors, marital and sexual relations, support networks and financial situation. The questionnaire was administered by an interviewer to 50 subjects booked for elective cholecystectomy: frequency-importance products were calculated for each of the 114 items. A final shortened scale (the Gallstone Impact Checklist [GIC]) contained 41 items and was completed by patients with symptomatic cholelithiasis on two occasions, 4 to 6 weeks apart., Results: The checklist requires 10 to 15 minutes to complete. Reliability of the questionnaire and its four subscales was assessed by Cronbach's alpha (overall questionnaire 0.88, pain 0.60, dyspepsia 0.73, emotional impact 0.78 and food and eating 0.84). Construct validity was established by comparison of questionnaire subscales with global ratings of physical and emotional health. Among subjects who reported a difference in their symptoms attributed to gallstones, there was a significant change in total GIC score and in each of the four subscales. Among patients who had undergone cholecystectomy, the absolute value of the effect size was 1.63., Conclusions: The GIC has content validity and appears to be a reliable, responsive measure of within-person change for subjects with symptomatic cholelithiasis.

The effects of three different degrees of intraoperative graft tensioning on measures of ex vivo laxity, viscoelastic behaviour, and structural and material failure of isolated healing medial collateral ligament autografts were investigated in a rabbit model. The grafts were orthotopically replaced at one of three different loads (too tight, anatomic, or too loose) and were mechanically evaluated after 0, 12, 24, and 48 weeks of healing. Laxity of the ligament was influenced by intraoperative graft tensioning at time zero. However, after 12 weeks of healing, values for laxity were indistinguishable among the experimental groups. Cyclic load relaxation, a measure of viscoelastic behaviour, was significantly influenced by intraoperative graft tensioning, and this effect persisted even after 48 weeks of healing. Grafts placed under excessive tension relaxed one-third less than grafts placed under abnormally low in situ tension. The relevance of these differences remains to be determined. Intraoperative tensioning had no significant influence on characteristics of structural or material failure of the graft during the first year of healing. These results suggest that, in this model, control of graft tension at the time of placement and fixation does not improve the failure characteristics of the medial collateral ligament. The structural strength of the grafts collectively improved to nearly normal values after 48 weeks; however, material recovery was less complete. Failure loads averaged 89% of control values, whereas failure stress averaged only 52% after 48 weeks of healing.

Connective tissue allografts are treated commonly with deep freezing to facilitate their storage in tissue banks and to reduce their immunogenicity. The influence of freezing on the healing of these grafts is unknown. The effect of an aggressive freezing protocol on ligament graft healing in a nonimmunogenic autograft model was investigated. The femoral-medial collateral ligament-tibial complex of the rabbit knee was transplanted orthotopically into the site from which it had just been harvested. The fresh group had their grafts rinsed in normal saline, and the frozen-thawed group had their grafts repetitively frozen-thawed in liquid nitrogen immediately before reimplantation. The healing of the ligament complexes were evaluated mechanically at intervals as long as 1 year after transplantation. Repeated freezing had little effect on the initial mechanical behavior of the graft complexes but was found to be detrimental to subsequent graft incorporation. The frozen-thawed grafts were weaker than the fresh grafts overall, and this effect persisted over time. The failure load and stress of the frozen-thawed grafts reached only 87% and 75% of that of the fresh grafts after 48 weeks. Because the initial mechanical effects of freezing were minimal, subsequent effects on graft healing must be attributed to factors other than gross structural injury. Despite showing almost no signs of damage to bone-ligament-bone grafts initially, freezing procedures may have important subsequent biologic consequences that may influence the clinical success of stored connective tissue grafts used in ligament reconstruction.

Radiographs of the wrist often do not include the entire third metacarpal, so the standard method for measurement of the carpal height ratio (the carpal height divided by the length of the third metacarpal) cannot be used. In this study, the ratio of the carpal height relative to the length of the capitate was evaluated for its suitability as a reproducible alternative. The revised carpal height ratio (the carpal height divided by the capitate length) was evaluated for reproducibility and clinical utility in both in vitro and in vivo studies: it was determined from the radiographs of ten cadaveric wrists; those of 100 wrists (fifty pairs) of normal volunteers, made with controlled positioning; those of 100 wrists, drawn at random from radiographs that had been previously interpreted as showing normal findings; and those of fifty wrists of twenty-nine patients who had documented rheumatoid arthritis. The new ratio was found to be constant in the normal population, consistent bilaterally, decreased in patients who had carpal collapse, and reproducible.

We examined the study design features and data collection methods from 13 case-control studies of colorectal cancer and diet, which had been previously combined and analyzed, to determine whether they influenced the results obtained from a pooled analysis. We assessed the methods used in each study, estimated a quality score, and used random effects models to re-estimate the pooled odds ratio for the association between dietary fiber and colorectal cancer for these data. Key features of the methods used in each study and the quality score were examined in random effects models to determine whether the heterogeneity found between study-specific risk estimates could be explained by these variables. The odds ratio for dietary fiber and colorectal cancer was 0.46 (95% confidence interval = 0.34-0.64) for the 13 case-control studies as estimated with a random effects model. Two factors, whether the diet questionnaire had been validated before use in the case-control study and whether qualitative data on dietary habits and cooking methods had been incorporated into the nutrient estimation, explained some of the heterogeneity found between studies. Risk estimates for dietary fiber and colorectal cancer were closer to the null for the studies that had these two characteristics. Quality score did not explain any between-study heterogeneity. Random effects models, which included fixed effects covariates, explained some between-study heterogeneity in these data and would be useful for future pooled analyses.

Objective: To determine whether there is an association between prenatal ultrasound exposure and delayed speech in children., Design: Case-control study., Setting: Network of community physicians affiliated with the Primary Care Research Unit, University of Calgary., Subjects: Thirty-four practitioners identified 72 children aged 24 to 100 months who had undergone a formal speech-language evaluation and were found to have delayed speech of unknown cause by a speech-language pathologist. For each case subject the practitioners found two control subjects matched for sex, date of birth, sibling birth order and associated health problems., Main Outcome Measures: Rates of prenatal ultrasound exposure and delayed speech., Results: The children with delayed speech had a higher rate of ultrasound exposure than the control subjects. The findings suggest that a child with delayed speech is about twice as likely as a child without delayed speech to have been exposed to prenatal ultrasound waves (odds ratio 2.8, 95% confidence limit 1.5 to 5.3; p = 0.001)., Conclusion: An association between prenatal ultrasonography exposure and delayed speech was found. If there is no obvious clinical indication for diagnostic in-utero ultrasonography, physicians might be wise to caution their patients about the vulnerability of the fetus to noxious agents.

Assessment of therapy in patients with rheumatoid arthritis is important but difficult. We examined 4 different methods of analyzing pretreatment data and assessed the difference that each made in detecting a positive effect of intramuscular gold on the patient's overall disability. The methods were (1) calculating the arithmetic mean of prior data points, (2) taking the last data point pretreatment, (3) fitting a straight line to pretreatment points and (4) fitting the pretreatment points with a quadratic equation. After comparison with matched controls (not taking remittive agents) the most significant difference was found by fitting a straight line to pretreatment data. This technique demonstrated about one-third more of intramuscular gold's effectiveness than the usual technique of using the last data point pretreatment. We conclude that statistical power is improved by obtaining and analyzing longitudinal pretreatment data appropriately.