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Intrauterine and early life exposure to folic acid has significantly increased in North America owing to folic acid fortification, widespread supplemental use, and periconceptional supplementation. We investigated the effects of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Female rats were placed on a control or folic acid-supplemented diet prior to mating and during pregnancy and lactation. At weaning, female pups from each maternal diet group were randomized to the control or supplemented diet and mammary tumors were induced with 7,12 dimethylbenz[a]anthracene at puberty. At necropsy, mammary tumor parameters, genomic DNA methylation, and DNA methyltransferase activity were determined in the offspring. Both maternal and postweaning folic acid supplementation significantly increased the risk of mammary adenocarcinomas in the offspring (OR = 2.1, 95% CI 1.2-3.8, P = 0.008 and OR = 1.9, 95% CI 1.1-3.3, P = 0.03, respectively). Maternal folic acid supplementation also significantly accelerated the rate of mammary adenocarcinoma appearance (P = 0.002) and increased the multiplicity of mammary adenocarcinomas (P = 0.008) in the offspring. Maternal, but not postweaning, folic acid supplementation significantly reduced global DNA methylation (P = 0.03), whereas postweaning, but not maternal, folic acid supplementation significantly decreased DNA methyltransferase activity (P = 0.05) in nonneoplastic mammary glands of the offspring. Our findings suggest that a high intrauterine and postweaning dietary exposure to folic acid may increase the risk of mammary tumors in the offspring. Further, they suggest that this tumor-promoting effect may be mediated in part by altered DNA methylation and DNMT activity.

Our research objective was to estimate the technical efficiency of regions in Ontario, Canada delivering home care relative to the 'best performance' frontier. Data Envelopment Analysis (DEA), an efficiency frontier technique, measured the technical efficiency of each geographically-defined Community Care Access Centre (CCAC) controlling for case-mix and service quality. Differences in case-mix and service quality did not fully explain the variation in efficiency scores across CCACs. Most CCACs in our sample were scale inefficient (i.e., not operating at an optimal size). The inability of home care providers to select patients or to adjust the service area is a potential explanation for the observed patterns in inefficiency. Efficiency analysis appears to represent an additional tool for use in assessing the performance of providers in the home and community care sector.

Whether or not folic acid supplementation promotes the progression of colorectal preneoplastic lesions to cancer is an important public health issue, given mandatory fortification and widespread supplemental use of folic acid in North America. We investigated the effect of folic acid supplementation on the progression of aberrant crypt foci (ACF), the earliest precursor of colorectal cancer. Male Sprague-Dawley rats (n = 152) were placed on a control diet (2 mg folic acid/kg diet) at weaning and ACF were induced by azoxymethane. Six weeks post-ACF induction, rats were randomized to receive 0, 2, 5 or 8 mg folic acid/kg diet. At 34 weeks of age, rats were killed, and colorectal tumor parameters, plasma folate and homocysteine (a sensitive inverse indicator of tissue folate status) concentrations and rectal epithelial proliferation were determined. Although the number of ACF increased as dietary folic acid levels increased (P = 0.015), the incidence of colorectal tumors did not differ significantly among the four dietary groups. However, tumor multiplicity was positively correlated with dietary folic acid levels (r = 0.32; P = 0.002) and inversely with plasma homocysteine concentrations (r = -0.32; P = 0.005). Tumor burden was positively correlated with dietary folic acid levels (r = 0.35; P = 0.001) and plasma folate concentrations (r = 0.33; P = 0.008) and inversely with plasma homocysteine concentrations (r = -0.42; P < 0.001). Rectal epithelial proliferation was positively correlated with dietary folic acid levels (r = 0.39; P < 0.001) and plasma folate concentrations (r = 0.34; P < 0.001) and inversely with plasma homocysteine concentrations (r = -0.37; P < 0.001). Our data suggest that folic acid supplementation may promote the progression of ACF to colorectal tumors.

Folate may prevent or promote cancer development and progression depending on the timing of intervention. Intrauterine exposure to folic acid has drastically increased in North America due to mandatory fortification and supplemental use of folic acid, which may influence the risk of breast cancer in the offspring. We investigated the effect of maternal folic acid supplementation, equivalent to the likely average post-fortification folate intake of a North American woman taking multivitamins containing folic acid, on terminal end buds, which reliably predict mammary tumor risk at adulthood in rodents. Female rats were placed on a control or supplemental diet for 3 weeks prior to mating and throughout pregnancy and lactation. Female pups were placed on the control diet at weaning until 50 days of age. The pups from the folic acid supplemented dams had a significantly lower number of terminal end buds than the pups from the dams fed the control diet (p=0.014). Our data suggest for the first time that folic acid supplementation provided in utero and during lactation may lower mammary tumor risk in the offspring.

Background: Studies of total joint arthroplasty (TJA) have not evaluated the costs and outcomes in the context of expected arthritis worsening., Objectives: Using a cost-consequence approach, to examine changes in direct health care costs and arthritis severity after TJA for hip/knee arthritis compared with contemporaneous changes in matched controls., Research Design: Case control study nested in a population-based prospective cohort., Subjects: In a population cohort with disabling hip/knee osteoarthritis followed from 1996 to 2003, primary TJA recipients were matched with cohort nonrecipients on age, sex, region of residence, comorbidity, and inflammatory arthritis diagnosis., Measures: Pre- and postoperative total and arthritis-attributable direct health care costs, arthritis severity, and general health status were compared for cases and matched controls., Results: Of 2109 participants with no prebaseline TJA, 185 cases received a single elective TJA during the follow-up period; of these, 183 cases and controls were successfully matched. Mean age was 71 years, 77.6% were female, 35.5% had > or =2 comorbidities, and 81.5% had > or =2 joints affected. At baseline, controls had less pain and disability and lower total and arthritis-attributable health care costs than cases. After surgery, although overall health care utilization was unchanged, cases experienced significant decreases in arthritis-attributable costs (mean decrease $278 including prescription drugs) and pain and disability (P < 0.0001 for all). Over the same time period, controls experienced a significant increase in total health care costs (mean increase $1978 including prescription drugs, P = 0.04) and no change or worsening of their arthritis status., Conclusion: Compared with matched controls, arthroplasty is associated with significant reductions in pain, disability, and arthritis-attributable direct costs.

Background: Traumatic brain injury (TBI) is a leading cause of death and disability in developed countries. We document trends in TBI-related hospitalizations in Ontario, Canada, between April 1992 and March 2002, focusing on relationships between inpatient hospitalization rates, age, sex, cause of injury, severity level, and in-hospital mortality., Methods: Information on all acute hospital separations in Ontario with a diagnosis of TBI was analyzed using logistic regression., Results: Hospitalization rates fell steeply among children and young adults but remained stable among adults aged 66 and older. The proportion of TBI hospitalizations with mild injuries decreased from 75% to 54%, whereas the proportion with moderate injuries increased from 19% to 37%. Adjusting for other risk factors, in-hospital deaths were higher for injuries because of motor vehicle crashes than those because of falls. In-hospital death rates were stable for patients with moderate or severe injuries, but increased over time among those whose injuries were classified as mild, suggesting a trend toward more serious injury within the "mild" classification., Conclusions: Hospitalizations for TBI involve fewer mild injuries over time and are highest in the oldest segment of the population.

Background: Chronic stable angina (CSA) is a major debilitating health problem in Canada. A paucity of relevant cardiovascular data sets has precluded a detailed examination of the impact of interventions on CSA-related costs and its broader economic burden., Objectives: As part of a larger clinical trial, the authors sought to determine the short-term impact of a standardized self-management training program on CSA-related costs. A secondary objective was to estimate the total annualized cost of CSA per patient from a societal perspective., Methods: Pre- and three-month post-test cost data were collected on 117 participants using the Ambulatory Home Care Record. Mean annualized direct, indirect and system-related CSA costs (2003 to 2005) were estimated; total per-patient CSA costs from a societal perspective were calculated as the sum of these costs., Results: The mean (+/- SD) age of participants was 68+/-11 years; 80% were male. The program did not impact costs in the short-term. Direct annual out-of-pocket costs, including money paid for health care, travel to appointments, medication, equipment and home support totaled $3,267. Indirect costs, reflecting the value of all unpaid time spent by those engaged in angina-related care, were $12,963. System costs, including costs paid by public and private insurers, were $2,979. Total estimated annual CSA costs from a societal perspective were $19,209 per patient., Conclusions: These data suggest that CSA imposes a major economic burden, comparable with other prevalent conditions such as chronic noncancer pain. Advancements in self-management training research are needed to help reduce the economic burden of CSA in Canada.

The Canadian context in which home-based healthcare services are delivered is characterised by limited resources and escalating healthcare costs. As a result, a financing shift has occurred, whereby care recipients receive a mixture of publicly and privately financed home-based services. Although ensuring that care recipients receive efficient and equitable care is crucial, a limited understanding of the economic outcomes and determinants of privately financed services exists. The purposes of this study were (i) to determine costs incurred by families and the healthcare system; (ii) to assess the determinants of privately financed home-based care; and (iii) to identify whether public and private expenditures are complements or substitutes. Two hundred and fifty-eight short-term clients (<90 days of service utilisation) and 256 continuing care clients (>90 days of utilisation) were recruited from six regions across the province of Ontario, Canada, from November 2003 to August 2004. Participants were interviewed by telephone once a week for 4 weeks and asked to provide information about time and monetary costs of care, activities of daily living (ADL), and chronic conditions. The mean total cost of care for a 4-week period was $7670.67 (in 2004 Canadian dollars), with the overwhelming majority of these costs (75%) associated with private expenditures. Higher age, ADL impairment, being female, and a having four or more chronic conditions predicted higher private expenditures. While private and public expenditures were complementary, private expenditures were somewhat inelastic to changes in public expenditures. A 10% increase in public expenditures was associated with a 6% increase in private expenditures. A greater appreciation of the financing of home-based care is necessary for practitioners, health managers and policy decision-makers to ensure that critical issues such as inequalities in access to care and financial burden on care recipients and families are addressed.

Background: There are gaps between what family practitioners do in clinical practice and the evidence-based ideal. The most commonly used strategy to narrow these gaps is the printed educational message (PEM); however, the attributes of successful printed educational messages and their overall effectiveness in changing physician practice are not clear. The current endeavor aims to determine whether such messages change prescribing quality in primary care practice, and whether these effects differ with the format of the message., Methods/design: The design is a large, simple, factorial, unblinded cluster-randomized controlled trial. PEMs will be distributed with informed, a quarterly evidence-based synopsis of current clinical information produced by the Institute for Clinical Evaluative Sciences, Toronto, Canada, and will be sent to all eligible general and family practitioners in Ontario. There will be three replicates of the trial, with three different educational messages, each aimed at narrowing a specific evidence-practice gap as follows: 1) angiotensin-converting enzyme inhibitors, hypertension treatment, and cholesterol lowering agents for diabetes; 2) retinal screening for diabetes; and 3) diuretics for hypertension.For each of the three replicates there will be three intervention groups. The first group will receive informed with an attached postcard-sized, short, directive "outsert." The second intervention group will receive informed with a two-page explanatory "insert" on the same topic. The third intervention group will receive informed, with both the above-mentioned outsert and insert. The control group will receive informed only, without either an outsert or insert.Routinely collected physician billing, prescription, and hospital data found in Ontario's administrative databases will be used to monitor pre-defined prescribing changes relevant and specific to each replicate, following delivery of the educational messages. Multi-level modeling will be used to study patterns in physician-prescribing quality over four quarters, before and after each of the three interventions. Subgroup analyses will be performed to assess the association between the characteristics of the physician's place of practice and target behaviours.A further analysis of the immediate and delayed impacts of the PEMs will be performed using time-series analysis and interventional, auto-regressive, integrated moving average modeling.

Folylpolyglutamyl synthase (FPGS) converts intracellular folates and antifolates to polyglutamates. Polyglutamylated folates and antifolates are retained in cells longer and are better substrates than their monoglutamate counterparts for enzymes involved in one-carbon transfer. FPGS modulation affects the chemosensitivity of cancer cells to antifolates, such as methotrexate, and 5-fluorouracil (5FU) by altering polyglutamylation of antifolates and specific target intracellular folate cofactors. However, this effect may be counterbalanced by FPGS modulation-induced changes in polyglutamylation of other intracellular folate cofactors and total intracellular folate pools. We generated an in vitro model of FPGS overexpression and inhibition in breast cancer cells by stably transfecting human MDA-MB-435 breast cancer cells with the sense FPGS cDNA or FPGS-targeted small interfering RNA, respectively, and investigated the effects of FPGS modulation on chemosensitivity to 5FU and methotrexate. FPGS modulation-induced changes in polyglutamylation of both antifolates and folate cofactors and in intracellular folate pools affected chemosensitivity of breast cancer cells to pemetrexed and trimetrexate whose cytotoxic effects do or do not depend on polyglutamylation, respectively, in a predictable manner. However, the effects of FPGS modulation on the chemosensitivity of breast cancer cells to 5FU and methotrexate seem to be highly complex and depend not only on polyglutamylation of a specific target intracellular folate cofactor or methotrexate, respectively, but also on total intracellular folate pools and polyglutamylation of other intracellular folate cofactors. Whether or not FPGS modulation may be an important clinical determinant of chemosensitivity of breast cancer cells to 5FU and methotrexate-based chemotherapy needs further exploration.

Home-based health services remain one of the fastest-growing sectors in the Canadian healthcare system. While there have been studies addressing the characteristics of home care users and the determinants of utilization, the costs associated with the use of home care services, particularly private costs, have been largely neglected. To gain a comprehensive appreciation of the financing context in which ambulatory and home-based care is delivered and received, it is imperative to assess costs incurred by clients and their family/friends. Accordingly, this study examined the magnitude and determinants of the share of private costs incurred by Ontarians who received in-home publicly financed services and by their unpaid caregivers. The private share of costs was found to be 75%. Determinants of the private share included participants' gender, martial status, functioning in activities of daily living and the type and length of service received. These findings suggest that recipients of home-based health services in Ontario may bear an economic burden when care is shifted into the home setting.

The present quantitative study evaluates the degree to which socioeconomic status (SES), as opposed to perceived need, determines utilisation of publicly funded home care in Ontario, Canada. The Registered Persons Data Base of the Ontario Health Insurance Plan was used to identify the age, sex and place of residence for all Ontarians who had coverage for the complete calendar year 1998. Utilisation was characterised in two dimensions: (1) propensity - the probability that an individual received service, which was estimated using a multinomial logit equation; and (2) intensity - the amount of service received, conditional on receipt. Short- and long-term service intensity were modelled separately using ordinary least squares regression. Age, sex and co-morbidity were the best predictors (P < 0.0001) of whether or not an individual received publicly funded home care as well as how much care was received, with sicker individuals having increased utilisation. The propensity and intensity of service receipt increased with lower SES (P < 0.0001), and decreased with the proportion of recent immigrants in the region (P < 0.0001), after controlling for age, sex and co-morbidity. Although the allocation of publicly funded home care service was primarily based on perceived need rather than ability to pay, barriers to utilisation for those from areas with a high proportion of recent immigrants were identified. Future research is needed to assess whether the current mix and level of publicly funded resources are indeed sufficient to offset the added costs associated with the provision of high-quality home care.

Intracellular folate homeostasis is essential for the 1-carbon transfer reactions necessary for DNA synthesis and biological methylation reactions in colonic epithelial cells. Perturbed 1-carbon transfer reactions resulting from folate depletion predispose normal colonic epithelial cells to neoplastic transformation while inhibiting the growth of colon cancer cells. Using an in vitro model of folate deficiency, we determined the effects of folate deficiency on the steady-state transcript levels of genes involved in intracellular folate metabolism and 1-carbon transfer reactions in HCT116 and Caco2 human colon adenocarcinoma cells. In HCT116 cells, folate depletion was associated with changes in transcript levels of genes favoring increased folate uptake and intracellular folate retention, the provision of metabolically more effective substrates for folate-dependent enzymes, and reduced folate hydrolysis and efflux. In HCT116 cells, folate depletion was associated with changes in transcript levels of genes favoring the preferential shuttling of the flux of 1-carbon units to the methionine cycle over the nucleotide synthesis pathway. In Caco2 cells, some adaptive responses in response to folate depletion were not as apparent as in HCT116 cells, and in some cases, the direction of change was counterintuitive. In Caco2 cells, the metabolic priority in response to folate depletion was to shuttle the available folate pools to the nucleotide biosynthesis pathway at the expense of biological methylation reactions. In both HCT116 and Caco2 cells, folate depletion was associated with the conservation of the existing pattern and extent of DNA methylation.

Place of death was determined for all 58,689 seniors (age > or = 66 years) in Ontario who died during fiscal year 2001/2002. The relationship of place of death to medical and socio-demographic characteristics was examined using a multinomial logit model. Half (49.2 %) of these individuals died in hospital, 30.5 per cent died in a long-term care facility, 9.6 per cent died at home while receiving home care, and 10.7 per cent died at home without home care. Co-morbidities were the strongest predictors of place of death (p < 0.0001). A cancer diagnosis increased the chances of death at home while receiving home care; seniors with dementia were most likely to die in LTC facilities; and those with major acute conditions were most likely to die in hospitals. Higher socio-economic status was associated with greater probability of dying at home but contributed little to the model. Appropriate planning and resource allocation may help move place of death from hospitals to nursing homes or the community, in accordance with individual preferences.

Objective: To examine prospectively the predictors of time to total joint arthroplasty (TJA)., Methods: This was a prospective cohort study with a median followup time of 6.1 years. We included participants from an existing population-based cohort of 2,128 individuals, ages 55 years and older with disabling hip and/or knee arthritis and no prior TJA, from 2 regions of Ontario, Canada, 1 urban with low TJA rates and 1 rural with high rates. The main outcome measure was the occurrence of a TJA based on procedure codes in the hospital discharge abstract database., Results: At baseline, the mean age of the patients was 71.5 years, 67.9% had a high school education or higher, 73.4% were women, the mean arthritis severity (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) score was 41.1 (maximum possible score 100), and 20.0% were willing to consider TJA. Greater probability of undergoing TJA was associated with higher (worse) baseline WOMAC scores (hazard ratio [HR] 1.22 per 10-unit increase, P < 0.001), age (compared with age or=82 years; P < 0.05 for all), better health (HR 1.14 per 10-unit increase in Short Form 36 general health survey score, P < 0.001), and willingness to consider TJA (HR 4.92, P < 0.001). When willingness was excluded from the model, education level, but not sex or income, became a significant predictor of TJA receipt., Conclusion: Willingness to consider TJA was the strongest predictor of the time to first TJA. Given that previous research indicates that willingness is largely explained by perceptions of the indications for and risks associated with TJA and not disease severity, this finding supports the need for population education about arthritis treatments, including TJA.

Background: The study objective was to compare a hospital-based and a home-based chemotherapy program for children with acute lymphoblastic leukemia (ALL) in relation to Quality of Life (QOL), safety, caregiver burden, and costs., Procedure: A randomized cross-over trial (RCT) design with repeated measures was conducted with 23 children with ALL who attended the oncology outpatient clinic of a metropolitan university affiliated tertiary level pediatric hospital and who also received home visits from a community health services care provider in central Canada., Results: During the home-treatment phase, children were more capable of maintaining their usual routines than when receiving hospital chemotherapy (Wilcoxon statistic = 80, P = 0.023), but they appeared to experience greater emotional distress (Wilcoxon sign rank statistic S = 66, P = 0.043) according to parental report. Treatment location had no effect on caregiver burden and adverse effects. No significant differences between groups existed with respect to societal costs of care. As the child's age increased, QOL improved relative to younger children (t(20) = -2.37, P = 0.02), the time burden related to child care tasks was reduced (t(21) = -3.56, P = 0.002), caregiver effort/difficulty in physical and behavioral support decreased (t(21) = -2.09, P = 0.049) and the odds of experiencing one or more adverse events decreased (OR = 0.79, CI = (0.63-1.00), chi(1) (2) = 4.01, P = 0.045)., Conclusions: With few differences noted between groups, these results indicate preliminary support for administrating some or all of a child's chemotherapy at home. Home chemotherapy was associated with specific improvements and decrements in parent reported QOL. No effects were seen on burden of care, adverse events, or cost. Overall, young age adversely affected QOL, burden of care, and adverse events. These data provide important information to families and caregivers as they consider home or hospital-based therapy in childhood ALL.

This study compared patient and caregiver perceptions of natural health products (NHPs) and conventional medications in a memory clinic population. A total of 620 mildly cognitively impaired patients and their caregivers participated in interviews enquiring about their perceptions of NHPs in 4 areas: (1) disclosure of NHP usage information to health care professionals, (2) safety and benefits of NHPs, (3) safety and benefits of conventional medications, and (4) physician knowledge about NHPs. Differences in responses between NHP users and nonusers and between patients and caregivers were examined. A total of 51.8% of subjects were current NHP users, with vitamin E, ginkgo biloba, and glucosamine being the most commonly used products. Multivariate analysis of variance showed that NHP use significantly influenced participant interview responses (Pillai's trace, F[4, 613] = 3.488, P = .008), while interviewee (patient or caregiver; Pillai's trace, F[8, 1228] = 1.499, P = .153) and gender (Pillai's trace, F[4, 615] = 0.528, P = .715) did not. Subsequent univariate tests showed that NHP users were significantly more likely to endorse the effectiveness and safety of NHPs compared with nonusers (F[1, 616] = 7.826, P = .005). Careful questioning during visits with health care providers and better counseling may be necessary to reduce the potential for adverse events and NHP-drug interactions.

This article surveyed the processes and policies underlying the routine collection of clinical data in acute care hospitals in Ontario, Canada. Although there is evidence of a small shortfall in the availability of human resources, most health records departments employ experienced staff with health records certification. However, there is much more important variation in the documented and undocumented processes used to generate routinely collected clinical data. Current guidelines and coding schedules are helpful but insufficient to guide the production of good quality data. The variations in the processes used to produce clinical data have important implications for the management, reimbursement, and planning of healthcare. This is particularly critical at a time when hospitals and other stakeholders, such as governments, are relying more and more on accurate, reliable, and comparable data.

Objective: As care shifts to home and community, have nursing jobs followed? We examined changes in the absolute and relative size of the nursing workforce by sector/sub-sectors in Ontario, Canada., Methods: All nurses registered with the Ontario College of Nurses over the 11 years from 1993 to 2003 were categorized as Active, Eligible or Not Eligible. Active nurses were then categorized by sector (Hospital, Community, Other) and sub-sector. The analysis was repeated by age group and for registered nurses and registered practical nurses., Results: The decline in Active and Eligible nurses was particularly pronounced for younger workers. Both the absolute number and proportion of nurses working in the hospital sub-sector has dropped. In the community sector, growth was evident in the use of nurses as case managers (in the CCAC sub-sector), community agencies and community mental health (representing a shift from hospital-based workers). However, the steady growth in the number and proportion of nurses working in home care agencies was reversed in 1999, with this sub-sector shedding 19% of its nurses by 2003., Conclusion: Despite considerable rhetoric to the contrary, nurses still tend to work within institutions (hospitals and long-term-care facilities). However, compared to their numbers in 1993, there were fewer nurses providing direct patient care in Ontario in both the hospital and community sectors, and a higher proportion of older nurses.

Objectives: Although measuring the utilization of ambulatory and home-based healthcare resources is an essential component of economic analyses, very little methodological attention has been devoted to the development and evaluation of resource costing tools. This study evaluated a newly developed tool, the Ambulatory and Home Care Record (AHCR), which comprehensively evaluates costs incurred by the health system and care recipients and their unpaid caregivers., Methods: The level of agreement between self-reports from 110 cystic fibrosis care recipients and administrative data was assessed for four categories of health services: home-based visits with healthcare professionals, ambulatory visits with healthcare professionals, laboratory and diagnostic tests, and prescription medications., Results: Agreement between care recipients' reports on the AHCR and administrative data ranged from moderate (kappa = 0.41; 95 percent confidence interval, 0.16-0.61) for physician specialist visits to perfect (kappa = 1.0) for physiotherapy visits., Conclusions: By evaluating and standardizing a resource and costing tool, such as the AHCR, economic evaluations may be improved and comparisons of the resource implications for different services and for diverse populations are possible.

Aim: This paper presents the findings of research comparing the incremental costs associated with the provision of home-based vs. hospital-based support for breastfeeding by nurse lactation consultants for term and near-term neonates during the first week of life., Background: A consequence of both consumer demands and increasing health resource constraints is that alternative care delivery models for safe, efficacious and cost-effective breastfeeding programmes have steadily evolved. To date, the economic impact of the setting (home or hospital) where lactation support is delivered has received little research attention., Methods: Mother-infant dyads were stratified by gestational age as term (>37 weeks gestational age; n = 101) or near term (35-37 weeks gestational age; n = 37) and randomized to standard hospital care and postpartum follow-up (standard care), or to standard hospital care plus home support from certified nurse lactation consultants (experimental). Data collection occurred at study entry, hospital discharge and at a seventh day postpartum follow-up session. Costs to the family (out-of-pocket and time costs) and to the healthcare system (during hospitalization and after hospital discharge) were measured. Total societal costs were defined as the sum of both family and healthcare system costs., Results: Compared with standard hospital-based care, home support by nurse lactation consultants showed no statistically significant differences in either time costs to the family or total societal costs. Term infants who received home support had statistically significantly greater postdischarge system costs (P < 0.0001), with a trend towards lower out-of-pocket expenses to their families (P = 0.12). There were no statistically significant differences between the two groups in overall combined family and healthcare system costs., Conclusions: These results suggest that the cost of home lactation support programmes were comparable with the costs of hospital-based standard care. Breastfeeding support at home by lactation consultants should be considered as an option as it was no more costly than support from lactation consultants in the hospital setting. The findings for near-term infants need to be interpreted with caution, given the small sample size.

Objective: To estimate the direct and indirect arthritis-attributable costs to individuals with disabling hip and/or knee osteoarthritis (OA)., Methods: An established population cohort with disabling hip and/or knee OA from two regions of Ontario, Canada was surveyed to determine participant and caregiver costs related to OA, and the predictors of these costs., Results: The response rate was 87.2%. Of 1378 respondents, 1258 had OA (mean age 73.1 yr, range 59-100). Sixty per cent (n = 758) reported OA-related costs. Among these individuals, the average annual cost was 12,200 dollars(CDN dollars in 2002, where 1.00 CDN dollar approximately 0.81 US dollar). Time lost from employment and leisure by participants and their unpaid caregivers accounted for 80% of the total. Men were less likely than women to report costs (adjusted odds ratio 0.54, P < 0.0001), but when they did their expenditures were significantly higher (P = 0.004). Greater disability was associated with higher costs: compared with individuals with WOMAC total scores <15, those with scores > or = 55 were 15 times more likely to report costs, and their costs were 3 times greater (both P < 0.0001). Both the young (<65 yr) and very old were more likely to incur costs (P < 0.0001), and when they did their costs were higher (P < 0.001)., Conclusion: Costs incurred were mainly for time lost from employment and leisure, and for unpaid informal caregivers. Failure to value such indirect costs significantly underestimates the true burden of OA. Costs increased with worsening health status and greater OA severity. After adjustment, men were less likely to incur costs, possibly due to greater social resources.

How models of health care financing and delivery affect patterns of procedure volumes, outcomes, and volume-outcome associations is not known. We compared volume-outcome studies done in Canada, which provides residents with universal, single-payer health care, with those done in the United States, to determine whether there was a difference in the likelihood of finding statistically significant volume-outcome associations. We analyzed 142 articles, most (90.1%) of which were from the United States. The articles described a total of 291 separate analyses. After adjusting for the clustering of multiple analyses in the same study, the likelihood of finding a statistically significant volume-outcome association was substantially lower in Canadian studies as compared with those from the United States (odds ratio 0.24, 95% confidence interval 0.08 to 0.74, p = 0.01). This result persisted after adjustment for the procedure/condition studied, and the number of study subjects. Canadian volume-outcome analyses are less likely to identify statistically significant volume-outcome associations than US studies, possibly because of the smaller size of some Canadian studies. It is also possible that different models of health care financing and delivery affect patterns of procedure volumes and volume-outcome associations. By promoting competition between hospitals and providers, market-based models may exacerbate existing variations in the quality of hospital care.

Background: A significant proportion of invasive group A streptococcal infections are hospital acquired. No large, prospective studies have characterized this subgroup of cases and evaluated the risk of transmission in hospitals., Methods: We conducted prospective, population-based surveillance of invasive group A streptococcal infections in Ontario, Canada, from 1992 to 2000. Epidemiologic and microbiologic investigations were conducted to identify cross-transmission., Results: We identified 291 hospital-acquired cases (12.4%) among 2351 cases of invasive group A streptococcal disease. Hospital-acquired invasive group A streptococcal infections are heterogeneous, including surgical site (96 cases), postpartum (86 cases), and nonsurgical, nonobstetrical infections (109 cases). Surgical site infections affected 1 of 100,000 surgical procedures and involved all organ systems. Postpartum infections occurred at a rate of 0.7 cases per 10,000 live births and exhibited an excellent prognosis. Nonsurgical, nonobstetrical infections encompassed a broad range of infectious syndromes (case-fatality rate, 37%). Nine percent of cases were associated with in-hospital transmission. Transmission occurred from 3 of 142 patients with community-acquired cases of necrotizing fasciitis requiring intensive care unit (ICU) admission, compared with 1 of 367 patients with community-acquired cases without necrotizing fasciitis admitted to the ICU and 1 of 1551 patients with other cases (P<.001). Fifteen outbreaks were identified; 9 (60%) involved only 2 cases. Hospital staff were infected in 1 of 15 outbreaks, but colonized staff were identified in 6 (60%) of 10 investigations in which staff were screened., Conclusions: Presentation of hospital-associated invasive group A streptococcal infections is diverse. Cross-transmission is common; illness occurs in patients but rarely in staff. Isolation of new cases of necrotizing fasciitis and intervention after a single nosocomial case may also prevent transmission.

Background: Folylpoly-gamma-glutamate synthetase (FPGS) converts intracellular folates and antifolates (for example, methotrexate (MTX)) to polyglutamates. Polyglutamylated folates and antifolates are retained in cells longer and are better substrates than their monoglutamate counterparts for enzymes involved in one carbon transfer. Polyglutamylation of intracellular 5,10-methylenetetrahydrofolate may also enhance the cytotoxicity of 5-fluorouracil (5-FU) by allowing more efficient formation and stabilisation of the inhibitory ternary complex involving thymidylate synthase and a 5-FU metabolite., Aim: We investigated the effects of FPGS modulation on the chemosensitivity of colon cancer cells to 5-FU and MTX., Methods: Human HCT116 colon cancer cells were stably transfected with the sense or antisense FPGS cDNA or blank (control). FPGS protein expression and enzyme activity, growth rate, intracellular folate content and composition, and in vitro chemosensitivity to 5-FU and MTX were determined., Results: Compared with cells expressing endogenous FPGS, those overexpressing FPGS had significantly faster growth rates and higher concentrations of total folate and long chain folate polyglutamates while antisense FPGS inhibition produced opposite results. FPGS overexpression significantly enhanced, whereas FPGS inhibition decreased, chemosensitivity to 5-FU. No significant difference in chemosensitivity to MTX was observed., Conclusions: These data provide functional evidence that FPGS overexpression and inhibition modulate chemosensitivity of colon cancer cells to 5-FU by altering intracellular folate polyglutamylation, providing proof of principle. Thus FPGS status may be an important predictor of chemosensitivity of colon cancer cells to 5-FU based chemotherapy, and FPGS gene transfer may increase the sensitivity of colon cancer cells to 5-FU-based chemotherapy.

Aim: To examine the relation between socio-economic status and (1) receipt of paediatric otolaryngological surgery, and (2) inclusion of adjuvant procedures., Methods: Using data on myringotomies with insertion of tympanostomy tube and tonsillectomies for all children in Ontario, Canada, from 1996 to 2000, and census data on socio-economic status, we examined the association between socio-economic status and (1) the probability of surgery (myringotomy or tonsillectomy), and (2) the probability that surgery was accompanied by an adjuvant procedure., Results: Lower socio-economic status was associated with increased likelihood that a child's initial surgery was a tonsillectomy rather than a myringotomy (odds ratio per unit increase in the deprivation index = 1.09, p = 0.01, confidence interval 1.06-1.11), and with increased likelihood that those children having a myringotomy would undergo a tonsillectomy during the same hospitalization (odds ratio 1.14, p < 0.0001, confidence interval 1.11-1.16). Children from neighbourhoods with larger immigrant populations were less likely to receive either procedure (odds ratios per 1% increase in the proportion of immigrants = 0.97 (p < 0.0001, confidence interval 0.96-0.97) for myringotomies and 0.97 (p < 0.0001, confidence interval 0.97-0.98) for tonsillectomies)., Conclusions: Socio-economic status was associated with treatment selection for the two most common paediatric surgical procedures. Further research should examine whether differences in treatment arise at the level of the primary care physician, the specialist, and/or are due to parental preference.

Background: Although single nucleotide polymorphisms may be potentially important pharmacogenetic determinants of cancer therapy, functional evidence regarding their relevance is currently lacking. The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with changes in cellular composition of folates. We hypothesized that this polymorphism may modulate the cytotoxic effect of 5-fluorouracil (5FU) and methotrexate (MTX), two commonly used chemotherapeutic agents for colon and breast cancers, because the modes of action of 5FU and MTX are critically dependent on cellular composition of folates., Methods: Human HCT116 colon and MDA-MB-435 breast cancer cells were stably transfected with wild-type or mutant 677T human MTHFR cDNA. MTHFR enzyme activity and thermolability, intracellular folate composition, growth rate, and catalytic thymidylate synthase activity were determined. In vitro chemosensitivity to 5FU and MTX was determined using the sulforhodamine B assay. In vivo chemosensitivity of HCT116 cells to 5FU was determined in nude mice., Results: Compared with cells expressing the wild-type MTHFR, HCT116 and MDA-MB-435 cells expressing the mutant 677T MTHFR had decreased MTHFR activity, MTHFR thermolability, changed intracellular folate distribution, accelerated cellular growth rate, and increased thymidylate synthase activity. The MTHFR 677T mutation increased chemosensitivity of colon and breast cancers to 5FU, but decreased chemosensitivity of breast cancer cells to MTX. In nude mice, xenografts expressing the mutant 677T MTHFR grew faster, but were more sensitive to 5FU, than xenografts expressing the wild-type protein., Conclusions: Our data provide evidence that the MTHFR C677T polymorphism affects the concentration and intracellular distribution of folates and changes the growth and chemosensitivity of colon and breast cancer cells. The MTHFR C677T polymorphism may be a useful pharmacogenetic determinant for providing rational and effective tailored chemotherapy.

Background: Thrombosis is the primary cause of access failure in polytetrafluoroethylene grafts and arteriovenous fistulas. It can lead to significant patient and access morbidity and mortality, and is difficult to prevent medically. Intervention is largely limited to maximizing access patency by detecting culprit lesions early and intervening with angioplasty or surgical revision. The most efficacious monitoring strategy is undetermined., Methods: This 3 year prospective study took advantage of a change in monitoring strategy used in a large dialysis centre to compare the efficacy of two methods used to monitor grafts and fistulas in order to prevent access thrombosis. Accesses were monitored using Duplex ultrasonography in year 1, while the saline ultrasound dilution technique (Transonic) became the primary monitoring strategy in year 3 (year 2 was a transition year). Risk factors for thrombosis were determined using multivariate survival analysis, and the performance of Duplex ultrasonography and Transonic monitoring was assessed., Results: A total of 303 656 access days at risk were assessed, with 344, 385 and 425 accesses in years 1, 2 and 3, respectively. The total thrombosis rate was 1.01/1000 access days in year 1 compared with 0.66/1000 access days in year 3. This was accomplished despite a reduction in procedure rates of 55% for angiograms, 13% for angioplasties and 31% for thrombolysis., Conclusion: Low flow rates detected using Transonic monitoring were associated with increased thrombosis, while stenosis detected using Duplex ultrasonography was not a strong predictor of incipient thrombosis; however, these different access characteristics were compared using monitoring techniques that may be ideal in different clinical situations.

Context: There is limited information on the identity and antibiotic susceptibility of bacterial pathogens in children with chronic otitis media whose repeated antibiotic use may place them at increased risk of antibiotic-resistant bacteria., Objective: To determine, at myringotomy for tympanostomy tube placement, (1) the prevalence of bacteria, (2) the extent and patterns of antibiotic resistance, and (3) the risk factors associated with the presence and resistant status of pathogens., Design: Prospective, multi-site, cohort study., Setting and Patients: Children undergoing myringotomy for tympanostomy tube placement between November 1, 1999 and March 31, 2000 in seven hospitals in Toronto, Ontario, were identified. If fluid was present, aspirates were submitted for bacteriologic testing. A follow-up telephone questionnaire was administered to patient caregivers in order to identify risk factors for the presence of (1) culturable pathogens and (2) resistant pathogens., Main Outcome Measures: The identification and prevalence of bacteria cultured from the middle ears of subjects, and the degree of nonsusceptibility to commonly prescribed antibiotics., Results: Among 601 patients (mean age 3.9 years, 60.7% male), both a telephone interview (n=544) and an ear specimen (n=527) were obtained for 478. Pathogens were found in middle ear effusions of 37% of the children in the study; including at least one 'definite' pathogen in 189 children (31.4%), and a further 32 children (5.3%) with at least one 'possible' pathogen. Definite pathogens included Haemophilus influenzae in 17% of the children, followed by Moraxella catarrhalis (9%) and Streptococcus pneumoniae (6%); ampicillin nonsusceptibility was found in 40, 100 and 24%, respectively. Overall, 123 children (20.5%) were found to have definite pathogens with resistance to ampicillin/penicillin, trimethoprim-sulfamethoxazole, or clarithromycin/erythromycin. Patient characteristics included premature birth and/or long length of stay in the nursery (23%), first infection before the age of 6 months (26%), put to bed with a bottle (28%), household smoker (34%), in out-of-home child care (38%), history of eczema, bronchiolitis and/or asthma (39%), and use of pacifiers (40%). Household characteristics were smoking (34%), married/common law parents (85%), and 60% had completed college or university; in 26% both parents were born outside of Canada; 73% of children were Caucasian. Of the 75% who responded to the question regarding income, 42% had household income over $60,000 (CAN). Risk factors for the presence of a pathogen and for a resistant pathogen in multivariate analysis included younger age, lower maternal education, day care centre attendance, no previous adenoidectomy and bilateral, primarily winter infections as well as amoxicillin use in the previous 6 months., Conclusion: Modifiable risk factors for otitis media including household smoking and pacifier use are present in many children undergoing tympanostomy tube placement; child care centre attendees are over-represented. Multiple antibiotic courses were commonly prescribed prior to surgery. H. influenzae and M. catarrhalis are important pathogens and therapy in clinical failures should be directed against them. The 7-valent protein conjugate polysaccharide vaccine (Prevnar) would have covered 73% of the serotypes of S. pneumoniae isolated in this study.

Context: Small-area variations in surgical rates raise concerns about access to care, treatment appropriateness, and the quality and cost of care., Objective: To measure small-area variations in rates of myringotomy with insertion of tympanostomy tubes (TTs) and to identify determinants of rate variation., Design and Setting: Retrospective analyses using hospital discharge data for patients who had undergone a myringotomy with insertion of TT by county in Ontario between April 1, 1996, and March 31, 1999. Information on possible determinants was taken from a survey of otolaryngologists and primary care physicians in 1996 and from the 1996 Canadian census and physician demographic databases for 1996-1999., Participants: A total of 75 358 hospitalizations for TT placement of children and adolescents (aged

Background: Otitis media is the most common medical problem in young children. The usual surgical treatment is myringotomy with insertion of tympanostomy tubes. There is debate about the usefulness of concomitant adenoidectomy or adenotonsillectomy. We examined the effects of these adjuvant procedures on the rates of reinsertion of tympanostomy tubes and rehospitalization for conditions related to otitis media., Methods: Using hospital discharge records for the period 1995 through 1997, we examined the results of surgery for all 37,316 children (defined as persons 19 years of age or younger) in Ontario, Canada, who received tympanostomy tubes as their first surgical treatment for otitis media. We determined the time to the first readmission for conditions related to otitis media and the time to the first reinsertion of tympanostomy tubes., Results: As compared with treatment involving the insertion of tympanostomy tubes alone, adjuvant adenoidectomy was associated with a reduction in the likelihood of reinsertion of tympanostomy tubes (relative risk, 0.5; 95 percent confidence interval, 0.5 to 0.6; P<0.001) and the likelihood of readmission for conditions related to otitis media (relative risk, 0.5; 95 percent confidence interval, 0.5 to 0.6; P<0.001). The risk of these outcomes was further reduced if an adjuvant adenotonsillectomy was performed. The effect was age-related. Children as young as one year appeared to benefit from adjuvant adenotonsillectomy; the benefit of an adjuvant adenoidectomy was apparent in two-year-olds and was greatest for children three years of age or older., Conclusions: Performing an adenoidectomy at the time of the initial insertion of tympanostomy tubes substantially reduces the likelihood of additional hospitalizations and operations related to otitis media among children two years of age or older.

We estimated the impact of alternative discharge strategies, following joint replacement (JR) surgery, on acute care readmission rates and the total cost of a continuum of care. Following surgery, patients were discharged to one of four destinations. Propensity scores were used to adjust costs and outcomes for potential bias in the assignment of discharge destinations. We demonstrated that the use of rehabilitation hospitals may lower readmission rates, but at a prohibitive incremental cost of each saved readmission, that patients discharged with home care had longer acute care stays than other patients, that the provision of home care services increased health system costs, and that acute care readmission rates were greatest among patients discharged with home care. Our study should be seen as one important stepping stone towards a full economic evaluation of the continuum of care for patients.

Objective: To determine factors influencing family physicians' and pediatricians' decisions to refer children with recurrent acute otitis media (RAOM) and otitis media with effusion (OME) to otolaryngologists for an opinion about tympanostomy tube insertion., Design: Mailed survey., Setting: Physicians' practices in Ontario., Participants: Random sample of 1459 family physicians and all 775 pediatricians in the province., Main Outcome Measures: Physicians' reports of the influence of 17 factors on decisions to refer (more likely, no influence, less likely to refer) and number of episodes of otitis media, months with effusion, level of hearing loss, or months of continuous antibiotics without improvement prompting referral., Results: Physicians agreed (> 80% concordance) on six out of 17 factors as indications for referring children with RAOM or OME. Opinions about the importance of other factors varied widely. Family physicians would refer children with otitis media after fewer episodes of illness, fewer months of effusion, lower levels of hearing loss, and fewer months of prophylactic antibiotic therapy than pediatricians (all P < .001). Pediatricians would prescribe continuous antibiotics longer (11.8 weeks) than family physicians (8.9 weeks, P < .0001), which correlated with lower referral thresholds for family physicians., Conclusion: Family physicians' and pediatricians' self-reported referral practices for surgical opinions on children with otitis media varied considerably. These observations raise questions about the consistency of care for children with otitis media and whether revised clinical guidelines would be helpful.

Hepatitis C virus (HCV) infection has recently been suggested to be a risk factor for the development of diabetes mellitus. The aim of our study was to investigate whether the prevalence of diabetes is increased among liver transplant recipients infected with HCV. We compared the prevalence of diabetes among 278 liver transplant recipients whose original cause of liver failure was HCV infection (110 patients), hepatitis B virus infection (HBV; 53 patients), and cholestatic liver disease (CLD; 115 patients). The pretransplantation prevalence of diabetes was higher in the HCV group (29%) compared with the HBV (6%) and CLD (4%) groups (P <.001). The prevalence of diabetes remained higher in the HCV group 1 year after transplantation: 37%, 10%, and 5% in the HCV, HBV, and CLD groups, respectively (P <.001). The cumulative steroid dose during the first year of transplantation was significantly lower in the HCV group compared with the CLD group. Multivariate analysis revealed that HCV-related liver failure (P =.002), pretransplantation diabetes (P <.0001), and male sex (P =.019) were independent predictors of the presence of diabetes 1 year after transplantation. The high prevalence of diabetes persisted in the HCV group, with 41% diabetic at 5 years. The majority of patients with diabetes mellitus (89%) required insulin therapy after transplantation. Patient and graft survival rates were similar among patients with and without diabetes. In conclusion, our study shows that there is a high prevalence of diabetes among liver transplant recipients infected with HCV both before and after transplantation.

Background: Bilateral myringotomy with insertion of tympanostomy tubes is the most common operation that children in Canada undergo. Area variations in surgical rates for this procedure have raised questions about indications used to decide about surgery. The objective of this study was to describe the factors that influence otolaryngologists to recommend tympanostomy tube insertion in children with otitis media and their level of agreement about indications for surgery., Methods: A survey was sent to all 227 otolaryngologists in Ontario in the fall of 1996. The influence of 17 clinical and social factors on recommendations to insert tympanostomy tubes were assessed. Case vignettes were used to determine the effect of multiple factors in decisions about the need for surgical management., Results: Surveys were returned by 138 (68.3%) of the 202 eligible otolaryngologists. There was agreement (more than 90% of respondents) about 6 indications for surgery: persistent effusion, a lack of improvement after 3 months of antibiotic therapy, a history of persistent effusion for 3 or more months per episode of otitis media, more than 7 episodes of otitis media in 6 months, a bilateral conductive hearing loss of 20 dB or more and a persistently abnormal tympanic membrane. Some respondents were more likely to recommend tube insertion if there were parental concerns about hearing problems or the frequency or severity of episodes of otitis media. Otolaryngologists agreed about the role of tympanostomy tubes in 1 of 4 case vignettes but disagreed about whether adenoidectomy should also be performed in that instance. Most viewed tympanostomy tube insertion as beneficial, with few adverse effects., Interpretation: There is a lack of consensus among practising otolaryngologists in Ontario as to which children with recurrent otitis media or persistent effusion should undergo bilateral myringotomy with tympanostomy tube insertion. These findings suggest the need to revisit clinical guidelines for this procedure.

Objective: To examine dental utilization following an adjustment to the provincial fee schedule in which preventive maintenance (recall) services were bundled at lower fees., Data Sources/study Setting: Blue Cross dental insurance claims for claimants associated with four major Ontario employers using a common insurance plan over the period 1987-1990., Study Design: This before-and-after design analyzes the dental claims experience over a four-year period for 4,455 individuals 18 years of age and older one year prior to the bundling of services, one year concurrent with the change, and two years after the introduction of bundling. The dependent variable is the annual adjusted payment per user., Data Collection/extraction Methods: The analysis was based on all claims submitted by adult users for services received at recall visits and who reported at least one visit of this type between 1987 and 1990. In these data, 26,177 services were provided by 1,214 dentists and represent 41 percent of all adult service claims submitted over the four years of observation., Principal Findings: Real per capita payment for adult recall services decreased by 0.3 percent in the year bundling was implemented (1988), but by the end of the study period such payments had increased 4.8 percent relative to pre-bundling levels. Multiple regression analysis assessed the role of patient and provider variables in the upward trend of per capita payments. The following variables were significant in explaining 37 percent of the variation in utilization over the period of observation: subscriber employment location; ever having received periodontal scaling or ever having received restorative services; regular user; dentist's school of graduation; and interactions involving year, service type, and regular user status., Conclusions: The volume and intensity of services received by adult patients increased when fee constraints were imposed on dentists. Future efforts to contain dental expenditures through fee schedule design will need to take this into consideration. Issues for future dental services research include provider billing practices, utilization among frequent attenders, and outcomes evaluation particularly with regard to periodontal care and replacement of restorations.

Background: Explanations for regional variation in the use of many medical and surgical treatments is controversial., Objectives: To identify factors that might be amenable to intervention, we investigated the determinants of regional variation in the use of knee replacement surgery., Research Design: We examined the effect of the following factors: characteristics and opinions of surgeons; family physicians and rheumatologists; patients' severity of disease before knee replacement; access to knee-replacement surgery; surgeons' use of other surgical treatment; and county population characteristics., Outcomes Measure: County utilization rates of knee replacement in Ontario, Canada., Results: Counties that had higher rates of knee replacement had older patients (P = 0.0001), higher percentage of medical school affiliated hospital beds (P = 0.04), with more male (P = 0.02) non-North American trained referring physicians (P = 0.002) and orthopedic surgeons who had higher propensities to operate and better perceptions of outcome (P = 0.0001)., Conclusions: After controlling for population characteristics and access to care (including the number of hospital beds, and the density of orthopaedic and referring physicians), orthopaedic surgeons' opinions or enthusiasm for the procedure was the dominant modifiable determinant of area variation. Thus, research needs to focus on the opinions of surgeons which may be important in reducing regional variation for knee replacement.

Background: The present study was designed to measure the longevity of knee replacements and to assess the determinants of revision knee replacements in order to enhance the potential for informed decision-making., Methods: Data on all hospitalizations for knee replacement that occurred in Ontario, Canada, between April 1, 1984, and March 31, 1991, were acquired. To calculate the rates of revision knee replacement, two algorithms were developed: one distinguished primary knee replacements from revision knee replacements, and the second linked revision knee replacements to primary knee replacements. The Kaplan-Meier method was used to assess survivorship (absence of a revision) for primary knee replacement. A proportional-hazards regression model was estimated to assess the role of independent variables on the survival of primary knee replacements., Results: During the period of the study, 7.0 percent (1301) of 18,530 knee replacements were classified as revisions. Significant differences were identified between hospitalizations for primary and revision knee replacements in terms of the patient and hospital characteristics. Patients who were more than fifty-five years old, lived in a rural area, or had a diagnosis of rheumatoid arthritis had a significantly (p < 0.05) longer duration before revision than did other patients. Primary knee replacements performed in a teaching or specialty hospital had a significantly (p < 0.05) shorter duration before revision than did those performed in a non-teaching hospital. The long-term rates of revision were uniformly low. Estimates of the proportion of knee replacements that would need to be revised within seven years ranged from a low of 4.3 percent, with use of the algorithm for the longest time to revision, to a high of 8.0 percent, with use of the algorithm for the shortest time to revision., Conclusions: Revision of a primary knee replacement was a rare event that depended on a patient's age, gender, and place of residence as well as on the hospital where the primary knee replacement was performed. Estimates of the rates of revision knee replacement after almost seven years ranged from a low of 4.3 percent to a high of 8.0 percent.

The hallmark of chronic myelogenous leukaemia (CML) is the presence of the Philadelphia chromosome and its resultant fusion message, BCR-ABL, and fusion protein, p210. Patients with CML in blast crisis, or with Philadelphia positive acute lymphoblastic leukaemia (ALL), can have a smaller BCR-ABL fusion transcript possessing only the first exon of BCR fused to ABL. This smaller transcript encodes a 190 kD protein which is more strongly transforming than the p210 protein derived from the larger CML-associated transcript. We performed RT-PCR on samples from CML patients in chronic phase to determine the frequency and mechanism of p190 and p210 co-expression and to see if this correlated with clinical indices. We examined the peripheral blood or marrow of 67 patients with CML and found that 35 of them expressed both transcripts whereas the remainder expressed the p210-encoding transcript exclusively. Additional PCR products of an intermediate size were also frequently detected and have been isolated and sequenced. Data from two of these products indicate that they are the result of alternative splicing and include variable combinations of BCR exons. We believe that the expression of the p190-encoding transcript in the chronic phase of CML is also due to alternative splicing. A comparison of patients co-expressing the p190- and p210-encoding transcripts with those patients who expressed only the p210-encoding transcript detected significantly higher white blood cell (WBC) counts and blast cell counts at time of testing as well as significantly higher white blood cell counts at diagnosis.

Objective: This study estimated the total cost of musculoskeletal disorders for Canadians in 1994 and assessed the sensitivity of these cost estimates to variations in the definition of musculoskeletal disorders., Methods: Disease-related costs, from a societal perspective, were measured using a prevalence-based analysis. First, direct treatment costs, including expenditures on hospitals and other institutions, physicians and other health professionals, drugs, research, and other items were assessed. Second, indirect costs associated with lost (or foregone) productivity due to disability and premature mortality were evaluated using the human capital approach., Results: The total cost of musculoskeletal disorders in Canada was $25.6 billion (in 1994 Canadian dollars, $1.00 CDN approximately $0.75 US) or 3.4% of the gross domestic product. Direct and indirect costs were estimated at $7.5 billion and $18.1 billion, respectively. Lower and upper bound estimates of the total cost of musculoskeletal disorders, derived from the sensitivity analysis, were $19.9 billion and $30.8 billion, respectively. Wide variations were reported in the total cost of various musculoskeletal disorder subcategories, with the highest costs reported for injuries ($10.7 billion), back and spine disorders ($8.1 billion), and arthritis and rheumatism ($5.9 billion)., Conclusions: The economic cost of musculoskeletal disorders was substantial and was sensitive to the definition of musculoskeletal disorders and other underlying assumptions. The hallmark of this study was the variation between subcategories in their cost, pattern of health resource use, and sequelae. The cost estimates may provide guidance in setting priorities for research and prevention activities.

A cross-sectional, community-based survey of a random sample of 1750 of 242,311 Medicare recipients was performed. The patients were at least sixty-five years old and had had a primary or revision knee replacement (either unilaterally or bilaterally) between 1985 and 1989. Three samples were surveyed separately: a national sample (to reflect the United States as a whole) and samples from Indiana and the western part of Pennsylvania (sites chosen for convenience to assess the validity of the findings for the national sample on a regional level). Each sample was stratified by race, age, residence (urban or rural), and the year of the procedure. Valid and reliable questionnaires were used to elicit the participants' assessments of pain, physical function, and satisfaction two to seven years after the knee replacement. Of the 1486 patients who were eligible for inclusion in the survey, 1193 (80.3 per cent) responded. The mean age of the respondents was 72.6 years. Eight hundred and forty-nine respondents (71.2 per cent) were white, and 849 (71.2 per cent) were women. The participants reported that they had little or no pain in the knee at the time of the survey, regardless of the age at the time of the knee replacement, the body-mass index, or the length of time since the knee replacement. After adjustment for potential confounding variables, predictors of better physical function after the replacement were an absence of problems with the contralateral knee, primary knee replacement (rather than revision) (Indiana sample only), and a lower body-mass index (Indiana and western Pennsylvania samples). Four hundred and fifteen (85.2 per cent) of the 487 patients in the national sample were satisfied with the result of the knee replacement. In what we believe to be the first community-based study of the outcome of knee replacement, patients reported having significant (p = 0.0001) and persistent relief of pain, improved physical function, and satisfaction with the result two to seven years postoperatively. The findings of the present study suggest that age and obesity do not have a negative impact on patient-relevant outcomes (pain and physical function). Dissemination of these findings has the potential to increase appropriate referrals for knee replacement and thereby reduce the pain and functional disability due to osteoarthrosis of the knee.

Objective: To assess agreement among rheumatologists and family physicians (FP) about the indications for knee replacement (KR) referral, use of nonsurgical management options, and perceived outcomes of KR, and to determine the relationship between these opinions and the number of patients seen with severe osteoarthritis (OA) of the knee., Methods: 98 adult rheumatologists and a random sample of 250 FP in Ontario, Canada were surveyed. Of the practising and traceable rheumatologists and FP, 70.0 and 5.16% responded, respectively., Results: FP disagreed on how 28 of 32 patient factors affected their KR referral decision, while rheumatologists disagreed on 26 of these 32 factors (p = 0.03). Rheumatologists and FP consistently disagreed on the use of 8 of 10 treatments for knee OA (p = 0.37). While rheumatologists and FP reported similar KR outcomes, FP were less in agreement (p = 0.03). Clinical disagreement for the indications for KR (p < 0.0001) and KR outcomes (p < 0.0001) were greater among FP than among orthopedic surgeons who were surveyed in a prior study. Clinical disagreement about the indications for KR was greater among rheumatologists than among surgeons (p = 0.04), but there was no difference in perceived KR incomes (p = 0.18)., Conclusion: Referring physicians disagreed on the indications for KR referral an on the treatments for knee arthritis, but were in general agreement regarding KR outcomes. Clinical disagreement was greater among FP than among rheumatologists, who in turn reported more disagreement than orthopedic surgeons. Explanations for these difference in perceptions should be the focus of research, but guidelines specifically tailored for each physician specialty may be required to reduce clinical uncertainty.

Background: Familial adenomatous polyposis (FAP) patients often develop periampullary adenomas that may progress to periampullary cancer, a common cause of death in this population. The risk of periampullary cancer in FAP is unclear, and variables that predict the occurrence and severity of periampullary tumors are not well understood. The specific aim of this study was to determine whether the risk of periampullary neoplasia segregates in specific FAP families., Materials and Methods: A total of 144 FAP patients from 74 families were either screened by gastroduodenoscopy (n = 132) or information was obtained from surgical or autopsy reports (n = 12). The severity of periampullary neoplasia was recorded for each patient and graded based on maximum polyp size and histology. Linear regression was used to determine the significance of a number of variables with respect to periampullary neoplasia. A blood sample was available from at least one member of 50 unrelated families and used to detect germline mutations in codons 686 through 1693 of the adenomatous polyposis coli (APC) gene., Results: Statistically significant familial segregation was found for the incidence and severity of periampullary neoplasia (P < 0.02). Age was also a statistically significant variable (P < 0.01). No correlation was observed between specific APC germline mutations and periampullary polyp frequency and severity., Conclusions: The occurrence and severity of periampullary neoplasms in patients with FAP segregates in families. This familial association may be related to as yet unidentified modifier genes or perhaps common environmental factors. These results should prove useful in developing upper gastrointestinal screening protocols for FAP patients at risk for periampullary neoplasia.

Background: Most cholecystectomies can be performed using a laparoscopic approach. However, 3 to 10 percent of laparoscopic cholecystectomies (LC) must be converted to open cholecystectomies (OC) and preoperative factors that predict risk for conversion are still not defined., Study Design: Preoperative and intraoperative data were collected and analyzed from 628 patients who were scheduled for elective LC by two surgeons in an academic institution. Logistic regression was performed on data from two groups of patients: LC completed, 596 patients (95 percent) and LC converted, 32 patients (5 percent)., Results: Elective LC was accomplished with no common bile duct injuries, low morbidity rate (7.3 percent), and zero mortality rate. Both patient and surgeon factors predicted conversion from LC to OC. Older patients (65 years of age or older, (p < 0.01), males (p < 0.01), and patients with multiple attacks (ten or more) of biliary colic (p < 0.01), or a documented history of acute cholecystitis (p < 0.01) had a greater risk for conversion. Both surgeons had higher rates of conversion (p < 0.05) during the learning phase (fewer than 50 LC) of their experience., Conclusions: Risk factors for conversion may be predicted and awareness of these factors should help in the selection of the appropriate procedure for patients and in selection of cases for resident training.

Objective: This study defined negative outcomes of solid organ transplantation, proposed a new classification of complications by severity, and applied the classification to evaluate the results of orthotopic liver transplantation (OLT)., Summary and Background Data: The lack of uniform reporting of negative outcomes has made reports of transplantation procedures difficult to interpret and compare. In fact, only mortality is well reported; morbidity rates and severity of complications have been poorly described., Methods: Based on previous definition and classification of complications for general surgery, a new classification for transplantation in four grades is proposed. Results including risk factors of the first 215 OLTs performed at the University of Toronto have been evaluated using the classification., Results: All but two patients (99%) had at least one complication of any kind, 92% of patients surviving more than 3 months had grade 1 (minor) complications, 74% had grade 2 (life-threatening) complications, and 30% had grade 3 (residual disability or cancer) complications. Twenty-nine per cent of patients had grade 4 complications (retransplantation or death). The most common grade 1 complications were steroid responsive rejection (69% of patients) and infection that did not require antibiotics or invasive procedures (23%). Grade 2 complications primarily were infection requiring antibiotics or invasive procedures (64%), postoperative bleeding requiring > 3 units of packed red cells (35%), primary dysfunction (26%), and biliary disease treated with antibiotics or requiring invasive procedures (18%). The most frequent grade 3 complication was renal failure, which is defined as a permanent rise in serum creatinine levels > or = twice the pretransplantation values (11%). Grade 4 complications (retransplantation or death) mainly were infection (14%) and primary dysfunction (11%). Comparison between the first and last 50 OLTs of the series indicates a significant decrease in the mean number of grade 1 and 2 complications. This was partially a result of better medical status of patients at the time of transplantation. Using univariate and multivariate analyses of risk factors, the best predictor of grade 1 complications was donor obesity; for grade 2 complications, the best predictor was a donor liver rewarming time of > 90 minutes, and for grade 3 and 4 complications, the best predictor was the APACHE II scoring system and donor cardiac arrest., Conclusions: Standardized definitions and classifications of complications of transplantation will allow us to better evaluate and compare results of transplantation among centers and over time, and better compare effectiveness of new therapies. Orthotopic liver transplantation still is a procedure with high morbidity that requires careful analysis of risk factors to optimize selection of patients and organ sharing.

A cell suspension containing more than 90% lactotrophs can be prepared from enzymically dispersed adenohypophyses obtained from male rats pretreated with estradiol. The lactotrophs are separated from the mixed cell population by centrifugation on a discontinuous density gradient prepared from a commercial preparation of colloidal silica (Percoll, Pharmacia). The method allows isopycnic separation of these delicate cells under very mild conditions; normal ionic strength and normal pH were maintained throughout the gradient, centrifugal acceleration did not exceed 1600 X g, and all procedures were done at room temperature. Histological verification that at least 90% of the cells were lactotrophs was done using specific immunoperoxidase staining. The functional capability of the lactotrophs was established by measuring the dose--response to the dopamine agonist bromocriptine and to thyrotropin-releasing hormone (TRH). Bromocriptine decreased spontaneous release in a dose-related way over the concentration range of 10(-10) to 10(-8) M. TRH, which causes an in vivo release of prolactin (PRL) in estrogen-primed rats, produced a dose-related increase in the release of PRL over the concentration range of 3 X 10(-10) to 3 X 10(-8) M after the high spontaneous release had been previously reduced by bromocriptine (3 X 10(-8) M).

This study was carried out to determine whether heroin-dependent persons, having completed methadone detoxification, can be maintained on an inert substance which has previously been associated with methadone. Forty heroin-dependent men and women were randomly allocated to either a "standard detoxification" group or a cordial substitution group. Results showed that subjects administered methadone-associated cordial after methadone detoxification could not be retained at the clinic for a time significantly beyond that of subjects in the standard detoxification group despite the inability of the subjects to accurately estimate methadone dosage. The role of cognitive factors is discussed.