Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction.

PURPOSE: Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients. METHODS: For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance. RESULTS: In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant. CONCLUSIONS: It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance given that cognitive status did not interfere with patients' daily intellectual function. The computerized battery has methodological advantages (e.g., language options, objectivity, brevity, and ease of use) that make it well-suited for longitudinal studies, for long-term surveillance of substrate reduction therapy as well as for comparisons with other lysosomal storage disorders and other chronic diseases. These preliminary findings should allay fears of cognitive dysfunction due to short-term miglustat therapy.     

Self-selecting albino rats exhibit differential preferences for pure macronutrient diets: Characterization of three subpopulations

Analyses of natural feeding behavior in albino male Sprague-Dawley rats demonstrate that, when allowed to self-select from pure macronutrient diets (protein, carbohydrate and fat), these rats of the same genetic strain can be categorized into 3 subpopulations according to either their 24-h or their 12-h nocturnal patterns of nutrient intake. A majority of the animals (HC for high carbohydrate, 50% of the total population) consumed a diet rich in carbohydrate relative to protein or fat, while a smaller population of rats (HF, 30%) preferred the fat diet, and an even smaller population (HP, 20%) chose a high-protein diet. These 3 subpopulations, after a few weeks of maintenance on the diets, differed in their body weight, with the HF rats having a higher body weight than the HP animals, who tended to weigh more than the lightest HC rats. Whereas all subgroups exhibited a similar bimodal distribution of feeding during the nocturnal cycle, with peaks during the early and late dark periods, they were distinguishable on the basis of their nutrient consumption during specific phases of the dark cycle. This difference was most apparent in the early dark phase, when the 3 subgroups exhibited exaggerated preferences for the specific nutrient that was generally preferred over the 24-h cycle. This is in contrast to the middle dark phase, when diet preferences were attenuated or lost, and the late dark phase, when most rats were similar in showing an increased preference for protein and fat and a decreased preference for carbohydrate. The HF group was further distinguished by an unusually strong burst of feeding during the first 2 h of the dark period and an extra peak of feeding in the middle dark period (7th h), both of which were relatively high in fat content.     

Positive illusory bias and the self-protective hypothesis in children with learning disabilities.

We tested the hypothesis that overestimations of performance by children with learning disabilities (LD) are self-protective and will dissipate following positive feedback. Twenty-three boys and 17 girls with LD (ages 10.6 to 13.5 years) and a control group of non-LD matched children (22 boys and 17 girls) provided a prediction of their performance on a spelling test prior to completing the test. Subsequently, they were randomly assigned to either a positive feedback or a no-feedback condition. Finally, they provided a second prediction of performance on an equivalent spelling test. In children with LD, there was a positive bias in their predictions of performance, and, following positive feedback, their predictions became accurate. In children without LD, there was no positive bias and no effect of feedback. The results provide further support for the presence of a positive illusory bias and for the self-protective hypothesis in children with LD.     

Hospital and community health service costs: England and Scotland compared

In publications which have compared the health expenditure in the component parts of the United Kingdom by applying the Resource Allocation Working Party (RAWP) formula to the health budget of England, Scotland, Wales, and Northern Ireland it has been previously concluded that Scotland's hospital and community health services expenditure is more than 19% above what would be a fair distribution. It has also been implied that Scotland's allocation should be cut substantially to improve services in England. On the assumption that the purpose of examining the distribution of the health and community health service budget is to ensure "equal opportunity of access to health care for people at equal risk" it is concluded that simple RAWPing of the United Kingdom budget is flawed and a conclusion based on this is therefore untenable.     

Variable effects of obesity on access to total hip and knee arthroplasty

BackgroundObesity is an important comorbidity affecting outcomes after total joint arthroplasty. Consequently, surgeons may delay care of obese patients to first address obesity through different care pathways. The effect of obesity on patient wait times for total joint arthroplasty has not been explored. The purpose of this study was to evaluate the effect of obesity on access to total hip (THA) and knee (TKA) arthroplasty.MethodsThe study data set was constructed from the Nova Scotia Health Authority’s Horizon Patient Folder system and the Patient Access Registry Nova Scotia. Wait time was measured as days between the decision to treat and date of surgery. Body mass index (BMI) was calculated from a preoperative assessment, and patients were grouped into BMI categories. Multivariate log-linear regression was used to test for statistical differences, controlling for confounding factors.ResultsWe observed longer wait times for TKA with increasing BMI weight class. Patients with BMIs greater than 50 had 34% longer waits than reference weight patients. However, THA recipients showed no statistical difference in wait times across weight categories. Furthermore, there was variability among surgeons in the wait times experienced by patients.ConclusionThe finding of longer wait times for TKAs, but not THAs, among patients who were obese was unexpected. This shows the variable wait times for THA and TKA that patients who are obese can experience with different surgeons. It is important to understand the variability in wait times so that efforts to standardize the patient experience can be accomplished.     

Pediatric Femoral Shaft Fracture: An Age-Based Treatment Algorithm

PurposeFractures of the femoral shaft in children are common. The rates of bone growth and remodeling in children vary according to their ages, which affect their respective management. MethodsThis paper evaluates the incidence and patterns of pediatric femoral shaft fracture and the current concepts of treatments available.ResultsThe type of fracture—closed or open; stable or unstable—needs to be taken into account. Child abuse should be suspected in fractures sustained by infants. For younger children, non-surgical management is preferred, which include Pavlik harness (< 6 months old) and early spica casting (6 months to 6 years old). Older children (> 6 years old) usually benefit from surgical treatments as outcomes of non-surgical alternatives are worse and are associated with prolonged recovery times. These operative measures for older children that are 6–12 years old include elastic stable intramedullary nailing and submuscular plating. Factors to be considered when devising an appropriate intervention include body mass, location of injury, and nature of fracture. For adolescent and skeletally mature teenagers (> 12 years old), rigid antegrade entry intramedullary fixation is indicated. In the event of open fractures or polytrauma, external fixation should be considered as a temporary treatment method for initial fracture stabilization.ConclusionAn age-based and evidence-based algorithm has been proposed to guide surgeons in the process of evaluating an appropriate treatment.     

Clinical prediction models to predict the risk of multiple binary outcomes: a comparison of approaches

Clinical prediction models (CPMs) can predict clinically relevant outcomes or events. Typically, prognostic CPMs are derived to predict the risk of a single future outcome. However, there are many medical applications where two or more outcomes are of interest, meaning this should be more widely reflected in CPMs so they can accurately estimate the joint risk of multiple outcomes simultaneously. A potentially naïve approach to multi‐outcome risk prediction is to derive a CPM for each outcome separately, then multiply the predicted risks. This approach is only valid if the outcomes are conditionally independent given the covariates, and it fails to exploit the potential relationships between the outcomes. This paper outlines several approaches that could be used to develop CPMs for multiple binary outcomes. We consider four methods, ranging in complexity and conditional independence assumptions: namely, probabilistic classifier chain, multinomial logistic regression, multivariate logistic regression, and a Bayesian probit model. These are compared with methods that rely on conditional independence: separate univariate CPMs and stacked regression. Employing a simulation study and real‐world example, we illustrate that CPMs for joint risk prediction of multiple outcomes should only be derived using methods that model the residual correlation between outcomes. In such a situation, our results suggest that probabilistic classification chains, multinomial logistic regression or the Bayesian probit model are all appropriate choices. We call into question the development of CPMs for each outcome in isolation when multiple correlated or structurally related outcomes are of interest and recommend more multivariate approaches to risk prediction.     

The effect of glycogen depletion and supercompensation on the physical working capacity at the fatigue threshold

Summary The purpose of this investigation was to determine the effect of glycogen depletion and super-compensation on the physical working capacity at the fatigue threshold (PWC_FT). Ten adult males (mean age 23 years, SD 3) volunteered as subjects for this study. During the first laboratory visit the subjects performed a maximal bicycle ergometer test for the determination of maximum oxygen consumption . Between 48 and 72 h later, the subjects pedaled to exhaustion at a power output which corresponded to a mean of 76% of (range, 72–80%) for the purpose of glycogen depletion. For the next 3 days, the subjects were fed a 10.5 MJ · day^–1 low carbohydrate diet which consisted of 7.5% carbohydrates, 22.0% protein and 70.5% fat. The subjects then performed an incremental cycle ergometer test to the onset of fatigue or PWC_FT, which was estimated from integrated electromyographic voltages of the vastus lateralis muscle. For the next 3 days the subjects were fed a 10.5 MJ high carbohydrate diet which consisted of 72.2% carbohydrates, 12.4% protein and 15.4% fats for the purpose of glycogen supercompensation. The subjects then performed a second PWC_FT test. A paired t-test indicated that there was no significant (p > 0.05) difference between the means of the PWC_FT values (depletion 246 W, SD 30; supercompensation 265 W, SD 28) and they were highly correlated atr=0.884. The results of this investigation suggested that the methods commonly used to affect glycogen depletion or supercompensation had no effect on PWC_FT.     

Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4

Risperidone is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses. Formation of 9-hydroxyrisperidone, an active metabolite, is the most important metabolic pathway of risperidone in human. In the present study, in vitro metabolism of risperidone (100 μM) was investigated using the recombinant human cytochrome P450 (CYP) enzymes CYP1A1, CYP1A2, CYP2C8, CYP2C9-arg₁₄₄, CYP2C9-cys₁₄₄, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 supplemented with an NADPH-generating system. 9-Hydroxyrisperidone was determined by a new HPLC method with an Hypersil CN column and a UV detector. Of these enzymes, CYPs 2D6, 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone, with activities of 7.5, 0.4 and 0.2 pmol pmol^–1 CYP min^–1, respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities. Thus, both CYP2D6 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study. This observation is confirmed by the findings that both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone. Furthermore, inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat. The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6β-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat. Received: 4 May 1998 / Accepted: 26 October 1998