Delineating the impact of obesity and its relationship on recovery after total joint arthroplasties.

OBJECTIVE: The primary aim of this study was to determine the impact of obesity in predicting short and long-term pain relief and functional recovery in total joint arthroplasty (TJA) either as an independent risk factor or a factor mediated by two chronic conditions associated with obesity-cardiac disease and diabetes mellitus. METHOD: A prospective observational study of 520 patients with primary joint arthroplasties. Pain and functional outcomes were evaluated with the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index within a month of surgery and then 6 months and 3 years post-operatively. Obesity, cardiac disease and diabetes mellitus were examined as potential risk factors for poor recovery. Patients were classified into four groups based on body mass index (BMI): (normal<25.0 kg/m(2); overweight 25.0-29.9 kg/m(2); obese Class 1 30.0-34.9 kg/m(2); severe obese Class 2&3 35.0 ≥ kg/m(2)). Linear mixed models for each joint type (hip and knee arthroplasty) were developed to examine the pattern of recovery and the effect of obesity. RESULTS: Ninety-nine (19%) patients were severely obese, 127 (24%) had cardiac disease and 58 (11%) had diabetes mellitus. Baseline pain and functional scores were similar regardless of BMI classification. Severe obesity was a significant risk factor for worse pain and functional recovery at 6 months but no longer at 3 years following total hip and knee arthroplasty. Cardiac disease predicted a slower recovery after hip arthroplasty. No significant interactions existed between obesity and cardiac disease or diabetes mellitus. DISCUSSION: Severe obesity is an independent risk factor for slow recovery over 3 years for both hip and knee arthroplasties.

A new diagnostic algorithm for antibody-mediated microcirculation inflammation in kidney transplants.

We studied the significance of microcirculation inflammation in kidney transplants, including 329 indication biopsies from 251 renal allograft recipients, who were mostly nonpresensitized (crossmatch negative). Glomerulitis (g) and peritubular capillaritis (ptc) were often associated with antibody-mediated rejection (65% and 75%, respectively), but were also found in other diseases in the absence of donor-specific antibody (DSA): T-cell-mediated rejection (ptc, g), glomerulonephritis (g) and acute tubular necrosis (ptc). To develop rules for reducing the nonspecificity of microcirculation inflammation and defining the best grading thresholds associated with DSA, we built and validated a decision tree to predict DSA. The decision tree revealed that g + ptc sum (addition of g-score plus ptc-score) was the best predictor of DSA, followed by time posttransplant, then C4d, which had a small role. Late biopsies with g + ptc > 0 showed higher frequency of DSA compared to early biopsies with g + ptc > 0 (79% vs. 27%). Microcirculation inflammation in early biopsies was often false positive (antibody-independent). The decision tree predicted DSA with higher sensitivity and accuracy than C4d staining. Microcirculation inflammation sum score predicted graft failure independently of time, C4d and transplant glomerulopathy. Thus any degree of microcirculation inflammation in late kidney transplant biopsies strongly indicates presence of DSA and predicts progression to graft failure.

Scoring total inflammation is superior to the current Banff inflammation score in predicting outcome and the degree of molecular disturbance in renal allografts.

Emerging molecular analysis can be used as an objective and independent assessment of histopathological scoring systems. We compared the existing Banff i-score to the total inflammation (total i-) score for assessing the molecular phenotype in 129 renal allograft biopsies for cause. The total i-score showed stronger correlations with microarray-based gene sets representing major biological processes during allograft rejection. Receiver operating characteristic curves showed that total-i was superior (areas under the curves 0.85 vs. 0.73 for Banff i-score, p = 0.012) at assessing an abnormal cytotoxic T-cell burden, because it identified molecular disturbances in biopsies with advanced scarring. The total-i score was also a better predictor of graft survival than the Banff i-score and essentially all current diagnostic Banff categories. The exception was antibody-mediated rejection which is able to predict graft loss with greater specificity (96%) but at low sensitivity (38%) due to the fact that it only applies to cases with this diagnosis. The total i-score is able to achieve moderate sensitivities (60-80%) with losses in specificity (60-80%) across the whole population. Thus, the total i-score is superior to the current Banff i-score and most diagnostic Banff categories in predicting outcome and assessing the molecular phenotype of renal allografts.

Fourteen years of surveillance of HIV-1 prevalence among pregnant women attending antenatal care clinics in western Uganda.

This study monitored long-term temporal trends in HIV-1 prevalence in antenatal clinic attendees living in western Uganda. Semi-annual data collection was done from 1991 to 2004. For each woman the following data were recorded: HIV-1 status, age, educational status, marital status, occupation and parity. The results show that the overall HIV-1 prevalence was 15.3% during the entire time period (urban 21.3%, semi-urban 12.7% and rural 7.1%). Between 1991 and 2004, we observed a gradual decline in the HIV-1 prevalence. The decline was most pronounced in urban women aged 15-19 years old and least pronounced in rural women aged 20-24 years. Women above 25 years of age did not show any decline in HIV-1 prevalence over time. The declining HIV-1 prevalence in the younger age groups (15-24 years) likely represents a declining risk for acquiring HIV infection as we have previously shown in the urban sub-sample of this data set.

Assessment of psychoeducational outcomes after pediatric liver transplant.

Outcomes research in pediatric liver transplant (LT) has focused on mortality and morbidity but there is a need to also evaluate functional outcomes. Standardized cognitive testing was administered to a cohort of children with infantile chronic liver disease who were transplanted at the University of Alberta during their preschool years. Thirty children had comprehensive assessments with the Bayley Scales of Infant Development or Wechsler testing. Patient variables potentially associated with cognitive delay were analyzed with multiple regression analysis. The mean DQ/IQ score (developmental quotient/intelligence quotient) was 81 +/- 17. Delay (DQ/IQ score < 70), and borderline delay (DQ/IQ 70-84) were each present in 27% of the cohort, with only 46% demonstrating normal cognition. Regression analysis demonstrated that the decreased IQ was associated with pretransplant growth retardation and elevated calcineurin inhibitor levels. Performance IQ had strong correlation with pretransplant growth retardation and elevated serum ammonia, R(2)= 45%, compared to verbal IQ that was associated was elevated calcineurin inhibitor levels, R(2)= 23%. Children post-LT are at high risk for cognitive delay or borderline delay. This is the first study to demonstrate the association calcineurin inhibitors with impaired IQ and also the unique finding of different variables predictive of impaired verbal intelligence quotient (VIQ) versus performance intelligence quotient (PIQ).

FOXP3 expression in human kidney transplant biopsies is associated with rejection and time post transplant but not with favorable outcomes.

Expression of the transcription factor forkhead box P3 (FOXP3) in transplant biopsies is of interest due to its role in a population of regulatory T cells. We analyzed FOXP3 mRNA expression using RT-PCR in 83 renal transplant biopsies for cause in relationship to histopathology, clinical findings and expression of pathogenesis-based transcript sets assessed by microarrays. FOXP3 mRNA was higher in rejection (T-cell and antibody-mediated) than nonrejection. Surprisingly, some native kidney controls also expressed FOXP3 mRNA. Immunostaining for FOXP3 was consistent with RT-PCR, showing interstitial FOXP3+ lymphocytes, even in some native kidney controls. FOXP3 expression correlated with interstitial inflammation, tubulitis, interstitial fibrosis, tubular atrophy, C4d positivity, longer time posttransplant, younger donors, class II panel reactive antibody >20% and transcript sets reflecting inflammation and injury, but unlike these features was time dependent. In multivariate analysis, higher FOXP3 mRNA was independently associated with rejection, T-cell-associated transcripts, younger donor age and longer time posttransplant. FOXP3 expression did not correlate with favorable graft outcomes, even when the analysis was restricted to biopsies with rejection. Thus FOXP3 mRNA expression is a time-dependent feature of inflammatory infiltrates in renal tissue. We hypothesize that time-dependent entry of FOXP3-positive cells represents a mechanism for stabilizing inflammatory sites.

Peritubular capillaritis in renal allografts: prevalence, scoring system, reproducibility and clinicopathological correlates.

While glomerulitis is graded according to the Banff classification, no criteria for scoring peritubular capillaritis (PTC) have been established. We retrospectively applied PTC-scoring criteria to 688 renal allograft (46 preimplantation, 461 protocol, 181 indication) biopsies. A total of 26.3% of all analyzed biopsies had peritubular capillaritis (implant 0%, protocol 17.6%, indication 45.5%; p < 0.0001). The most common capillaritis pattern was of moderate severity (5-10 luminal cells), focal in extent (10-50% of PTC), with a minority of neutrophils. A total of 24% of C4d- compared with 75% of C4d+ biopsies showed capillaritis (p < 0.0001). More than 80% of biopsies with glomerulitis had peritubular capillaritis. A total of 50.4% of biopsies with borderline or T-cell mediated rejection (TCMR) and 14.1% of biopsies without TCMR or antibody-mediated rejection (ABMR) showed capillaritis (p < 0.0001). The inter-observer reproducibility of the PTC-scoring features was fair to moderate. Diffuse capillaritis detected in early protocol biopsies had significant negative prognostic impact in terms of glomerular filtration rate 2 years posttransplantation. Indication biopsies show a significantly higher prevalence of capillaritis than protocol biopsies (45.5% vs. 17.6%; p < 0.0001). Capillaritis is more frequent and pronounced in ABMR, but can be observed in TCMR cases. Thus, scoring of peritubular capillaritis is feasible and can provide prognostic and diagnostic information in renal allograft biopsies.

Risk factors for ciprofloxacin resistance in reported Campylobacter infections in southern Alberta.

We conducted a case-control study examining risk factors for ciprofloxacin resistance in Campylobacter infections that were reported in 2004 and 2005 in two health regions in southern Alberta. The study questionnaire included questions about recent travel and antibiotic use, food consumption frequency, use of household and personal hygiene products with antibacterial agents, contact with animals, and potential misuse of antibiotics. Of the 210 patients who participated, 31.0% had ciprofloxacin-resistant Campylobacter infections. Foreign travel was the strongest predictor of resistance. Surprisingly, possession of antibiotics for future use was identified as a risk factor for resistance. We also examined the potential for participation bias and resistance misclassification to affect the resulting multivariable models. Participation bias appears to have had a substantial effect on the model results, but the estimated misclassification effect due to the use of different ciprofloxacin susceptibility testing methods was only slight.

The transcriptome of the implant biopsy identifies donor kidneys at increased risk of delayed graft function.

Improved assessment of donor organ quality at time of transplantation would help in management of potentially usable organs. The transcriptome might correlate with risk of delayed graft function (DGF) better than conventional risk factors. Microarray results of 87 consecutive implantation biopsies taken postreperfusion in 42 deceased (DD) and 45 living (LD) donor kidneys were compared to clinical and histopathology-based scores. Unsupervised analysis separated the 87 kidneys into three groups: LD, DD1 and DD2. Kidneys in DD2 had a greater incidence of DGF (38.1 vs. 9.5%, p < 0.05) than those in DD1. Clinical and histopathological risk scores did not discriminate DD1 from DD2. A total of 1051 transcripts were differentially expressed between DD1 and DD2, but no transcripts separated DGF from immediate graft function (adjusted p < 0.01). Principal components analysis revealed a continuum from LD to DD1 to DD2, i.e. from best to poorest functioning kidneys. Within DD kidneys, the odds ratio for DGF was significantly increased with a transcriptome-based score and recipient age (p < 0.03) but not with clinical or histopathologic scores. The transcriptome reflects kidney quality and susceptibility to DGF better than available clinical and histopathological scoring systems.

Microarray analysis of rejection in human kidney transplants using pathogenesis-based transcript sets.

Microarrays offer potential for objective diagnosis and insights into pathogenesis of allograft rejection. We used mouse transplants to annotate pathogenesis-based transcript sets (PBTs) that reflect major biologic events in allograft rejection-cytotoxic T-cell infiltration, interferon-gamma effects and parenchymal deterioration. We examined the relationship between PBT expression, histopathologic lesions and clinical diagnoses in 143 consecutive human kidney transplant biopsies for cause. PBTs correlated strongly with one another, indicating that transcriptome disturbances in renal transplants have a stereotyped internal structure. This disturbance was continuous, not dichotomous, across rejection and nonrejection. PBTs correlated with histopathologic lesions and were the highest in biopsies with clinically apparent rejection episodes. Surprisingly, antibody-mediated rejection had changes similar to T-cell mediated rejection. Biopsies lacking PBT disturbances did not have rejection. PBTs suggested that some current Banff histopathology criteria are unreliable, particularly at the cut-off between borderline and rejection. Results were validated in 51 additional biopsies. Thus many transcriptome changes previously described in rejection are features of a large-scale disturbance characteristic of rejection but occurring at lower levels in many forms of injury. PBTs represent a quantitative measure of the inflammatory disturbances in organ transplants, and a new window on the mechanisms of these changes.

Bicycle helmet prevalence two years after the introduction of mandatory use legislation for under 18 year olds in Alberta, Canada.

OBJECTIVE: To determine changes in helmet use in cyclists following the introduction of a bicycle helmet law for children under age 18. METHODS: Cyclists were observed by two independent observers from July to August 2004 (post-legislation) in Edmonton, Alberta. The data were compared with a similar survey completed at the same locations and days in July to August 2000 (pre-legislation). Data were collected for 271 cyclists in 2004 and 699 cyclists in 2000. RESULTS: The overall prevalence of helmet use increased from 43% (95% CI 39 to 47%) in 2000 to 53% (95% CI 47 to 59%) in 2004. Helmet use increased in those under 18, but did not change in those 18 and older. In the cluster adjusted multivariate Poisson regression model, the prevalence of helmet use significantly increased for those under age 18 (adjusted prevalence ratio (APR) 3.69, 95% CI 2.65 to 5.14), but not for those 18 years and older (APR 1.17, 95% CI 0.95 to 1.43). CONCLUSION: Extension of legislation to all age groups should be considered.

Cross-sectional validity of a modified Edmonton symptom assessment system in dialysis patients: a simple assessment of symptom burden.

Subjective symptom assessment should be a fundamental component of health-related quality of life (HRQL) assessment in end-stage renal disease (ESRD). Unfortunately, no symptom checklist has established reliability or validity in ESRD. We report the validation of a modified Edmonton Symptom Assessment System (ESAS) in 507 dialysis patients who concurrently completed the Kidney Dialysis Quality of Life-Short Form (KDQOL-SF) questionnaire. The ESAS demonstrated a mean of 7.5+/-2.5 symptoms. The symptoms reported as most severe were tiredness, well-being, appetite, and pain. The overall symptom distress score was strongly correlated with the KDQOL-SF subscales symptom/problem list (r=-0.69, P<0.01), effects of kidney disease (r=-0.52, P<0.01), and burden of kidney disease (r=-0.50, P<0.01), as well as lower RAND-12 physical health composite (PHC) (r=-0.54, P<0.01) and lower RAND-12 mental health composite (MHC) (r=-0.62, P<0.001). In the multivariate regression analysis, after controlling for potential confounding variables including comorbidity using the modified Charlson Comorbidity Index, the ESAS symptom distress score remained strongly associated with the MHC (slope=-0.82+/-0.07, P<0.01) and PHC (slope=-0.48+/-0.07, P<0.01). The ESAS symptom distress score accounted for 29% of the impairment in PHC and 39% of the impairment in MHC. The intraclass correlation coefficient for the total symptom distress score in a 1-week test-retest was 0.70, P<0.01. Symptom burden is high and adversely affects HRQL in dialysis patients. The modified ESAS is a reliable, valid, simple, and useful method for regular symptom assessment in this patient population.

Effect of pravastatin on blood pressure in people with cardiovascular disease.

Experimental evidence and several small studies in humans suggest that HMG-CoA (3-hydroxy 3-methylglutaryl coenzyme A) reductase inhibitors (statins) reduce blood pressure, perhaps through effects on endothelial function or by reducing inflammation. We tested the hypothesis that pravastatin would reduce blood pressure at 3 months and the risk of developing new hypertension over a follow-up period of 5 years. This was a post hoc subgroup analysis of a randomized double-blind placebo-controlled trial of pravastatin 40 mg daily vs placebo in 4159 participants with previous myocardial infarction and total plasma cholesterol <240 mg/dl (6.2 mmol/l). The primary outcome was the unadjusted change in mean arterial pressure (MAP) from baseline to 3 months. We also considered systolic and diastolic blood pressure (SBP and DBP) and pulse pressure. Analysis of covariance was used to calculate the adjusted effect of treatment on change in these outcomes at 3, 6, 12 and 24 months postrandomization, after controlling for potential confounders. Logistic regression was used to calculate the adjusted effect of treatment on incident hypertension (blood pressure > or =140/90 in those without known hypertension at baseline). This analysis included 4126/4159 (99.2%) participants for whom blood pressure was measured at baseline and during at least one follow-up visit. Median duration of follow-up was 57.8 months. The unadjusted and adjusted change in MAP, SBP, DBP or pulse pressure from baseline was not significantly different for pravastatin or placebo recipients at 3, 6, 12 or 24 months after randomization, or at last follow-up. Pravastatin did not reduce the adjusted risk of incident systolic hypertension (odds ratio 0.99, 95% CI 0.80-1.23), or incident diastolic hypertension (odds ratio 0.97, 95% CI 0.73-1.27). In summary, pravastatin 40 mg daily did not reduce blood pressure in survivors of myocardial infarction without overt hypercholesterolaemia.

Nighttime impaired driving in rural Alberta.

A nighttime roadside survey of rural Alberta drivers was conducted to quantify the nature and extent of impaired driving on Alberta's rural roads during nighttime. The survey also sought to describe driver demographics and information about the trip, such as origin and destination, among rural Alberta's nighttime drivers. Surveys were administered to drivers of vehicles that were randomly sampled at rural locations in Alberta between the hours of 10:00 PM and 4:00 AM between 22 August and 1 September 2001. Drivers who agreed to participate were asked a series of short questions. The interview concluded with the driver providing a breath sample to measure the driver's BAC level. Of the drivers surveyed, 3% had a BAC that was over the legal limit of 80 mg%. A total of 13% of drivers tested had detectable amounts of alcohol in their system.

A multicentre study of the usefulness of liver biopsy in hepatitis C.

The role of liver biopsy in the assessment of chronic hepatitis C is generally accepted yet there is no prospective data available to quantify its contribution. A previous single centre pilot study suggested that the clinician could predict the amount of fibrosis and to a lesser extent, inflammation with moderate accuracy. The 2002 National Institute of Health Hepatitis C Consensus Conference recommended further study of the role of liver biopsy. Our objective was to compare a prediction of biopsy findings by expert clinicians using usually available clinical and laboratory data to actual biopsy results in order to determine whether biopsy is required routinely. This was a prospective observational study conducted at seven university centres in which the accuracy of clinician's predictions of the degree of inflammation and fibrosis were compared with the actual liver biopsy using an adaptation of a standard histological scoring system. We studied 81 adults with previously untreated chronic hepatitis C, raised serum transaminases and positive HCV-RNA in serum. Clinicians predicted the inflammatory grade in 44 of 80 cases (55%) and the fibrosis stage in 46 of 81 cases (57%). Nine of 17 cirrhotic cases were predicted (sensitivity 53%, specificity 56%). No unexpected additional diagnoses were made on the biopsies. Thus despite knowledge of the clinical and laboratory investigations of patients with hepatitis C, clinicians are unable to accurately predict the hepatic inflammatory grade and fibrotic stage. Liver biopsy is an essential investigation to accurately evaluate the grade and stage of liver disease patients with hepatitis C.

Gastric cancer: establishing predictors of biologic behavior with use of population-based data.

BACKGROUND: Tumor thickness and nodal status are important predictors of survival following curative resection for gastric cancer. Lymphovascular invasion (LVI) is a potential predictor of biological behavior. The relationship between LVI and tumor thickness (T status) has not been established in population-based studies. METHODS: Clinicopathological and survival data of 577 patients at nine centers, from between 1991 and 1997, was collected from patient records and a Provincial Cancer Registry. The primary endpoint of the study was death. A secondary analysis of a node-negative subgroup examined the significance of LVI with respect to T status. RESULTS: The population disease-specific survival was 28%. In a multivariate analysis, T, N, M, esophageal margin, tumor morphology, and residual tumor category were independent predictors of survival. LVI was documented in 58% of resected tumors. LVI correlated with advancing T and N status but was not significant in a multivariate population model. Subgroup analysis of node-negative gastric cancer found T status and LVI to be independent predictors of survival. LVI was associated with a 5-year survival of 8%, versus 43% among patients in whom it was absent (P <.001). CONCLUSIONS: T status and N status were the most important independent predictors of survival in a population-based study of gastric cancer. LVI correlated with advancing N and T status. Multivariate analysis of node-negative patients showed LVI and T status are independent predictors of survival.

Evaluation of an education program for elementary school children with asthma.

To evaluate the effectiveness of a comprehensive asthma management education program for 7- to 12-year-old children with asthma, entitled Roaring Adventures of Puff (RAP), 18 elementary schools in Edmonton were randomized to intervention and control groups. Participating in the program were 76 students with asthma in the intervention schools and 86 in the control schools. Children in the intervention schools had statistically significant improvements in unscheduled doctor visits, missed school days, moderate-to-severe parent rating of severity, severity of shortness of breath, limitations in the kind of play, and correct use of medications. Unscheduled doctor visits and missed school days were the only significant improvements in the control group; however, improvements were about half that of the intervention group. The results showed that a comprehensive, school-based asthma education program is feasible and improves outcomes.

Predicting the liver histology in chronic hepatitis C: how good is the clinician?

OBJECTIVE: Liver biopsy is believed to be necessary before antiviral treatment in hepatitis C. Studies have found symptoms and biochemistry poorly predictive of grade and stage. In practice, a combination of factors is used to anticipate histology. The aim of this study is to evaluate the ability of global clinical assessment to predict histology in hepatitis C. METHODS: Fifty-four consecutive patients referred to a university center for consideration of antiviral therapy were enrolled. Clinical and laboratory data were recorded as was a prediction of the inflammatory grade (0-3) and fibrotic stage (0-3), with fibrotic stage 3 referring to cirrhosis. Liver biopsies were read by a blinded pathologist. The predictive value of the clinical assessment and individual parameters was assessed. RESULTS: All predictions were < or = 1 point off the actual grade and stage. Thirty-six (66.7%) patients' grades and 41 (75.9%) patients' stages were exactly predicted. All four cirrhotic patients (sensitivity 100%, specificity 94%) and one case of hemochromatosis were correctly predicted. Spider nevi, organomegaly, white blood cell count < or = 4 x 10(9)/L, ALT > 120 U/L, bilirubin > 20 micromol/L, albumin < or = 35 g/L, and ferritin > 200 microg/L predicted grade > or =2. Stage > or =2 was associated with age > 40 yr, previous decompensation, spider nevi, organomegaly, white blood cell count < or = 4 x 10(9)/L, albumin < or = 35 g/L, platelets < or = 150 x 10(9)/L, and international normalized ratio > 1.2. Grade correlated with stage (Spearman coefficient = 0.54, p < 0.001). By multivariate analysis, ferritin plus spider nevi or hypoalbuminemia was independently predictive of inflammation. Spider nevi and thrombocytopenia, with either splenomegaly or hypoalbuminemia, were useful three-variable models for predicting fibrosis. The corresponding scoring systems produced useful likelihood ratios. CONCLUSIONS: Global clinical assessment mirroring clinical practice in a tertiary liver transplant center is moderately accurate in predicting grade and stage in hepatitis C. Liver biopsy is the current gold standard; however, the amount of new information gleaned is less than was perceived. The need for routine biopsy before antiviral treatment in hepatitis C should be reevaluated in a multicenter study.

Neuroactive steroid levels in patients with generalized anxiety disorder.

Serum levels of allopregnanolone, pregnenolone sulfate, and dehydroepiandrosterone sulfate were measured in 8 male patients with generalized anxiety disorder (GAD) and 8 healthy control subjects. Results suggest that patients with GAD have significantly lower levels of pregnenolone sulfate than control subjects.

Effect of medroxyprogesterone pretreatment on pentagastrin-induced panic symptoms in females with panic disorder.

Clinical observation, as well as epidemiological and research data, suggest that female gonadal hormones influence the course of panic disorder (PD). Panicogenic agents such as pentagastrin are useful tools with which to study the pathophysiology of panic attacks. Nine women with PD were randomly assigned to receive, in a crossover design, a 3-day pretreatment with medroxyprogesterone acetate (MP) prior to an injection of pentagastrin, and a 3-day pretreatment with a placebo prior to another injection of pentagastrin. The panic response and the anxiety response to pentagastrin were decreased after MP pretreatment. These preliminary results support the use of laboratory models for investigations of the interactions between progestins and anxiety.