The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein.

Conformational diseases, such as Alzheimer, Parkinson and Huntington diseases, are part of a common class of neurological disorders characterized by the aggregation and progressive accumulation of proteins bearing aberrant conformations. Huntington disease (HD) has autosomal dominant inheritance and is caused by mutations leading to an abnormal expansion in the polyglutamine (polyQ) tract of the huntingtin (HTT) protein, leading to the formation of HTT inclusion bodies in neurons of affected patients. Interestingly, recent experimental evidence is challenging the conventional view by which the disease pathogenesis is solely a consequence of the intracellular accumulation of mutant protein aggregates. These studies reveal that transcellular transfer of mutated huntingtin protein is able to seed oligomers involving even the wild-type (WT) forms of the protein. To date, there is still no successful strategy to treat HD. Here, we describe a novel functional role for the HSPB1-p62/SQSTM1 complex, which acts as a cargo loading platform, allowing the unconventional secretion of mutant HTT by extracellular vesicles. HSPB1 interacts preferentially with polyQ-expanded HTT compared with the WT protein and affects its aggregation. Furthermore, HSPB1 levels correlate with the rate of mutant HTT secretion, which is controlled by the activity of the PI3K/AKT/mTOR signalling pathway. Finally, we show that these HTT-containing vesicular structures are biologically active and able to be internalized by recipient cells, therefore providing an additional mechanism to explain the prion-like spreading properties of mutant HTT. These findings might also have implications for the turn-over of other disease-associated, aggregation-prone proteins.

Guiding individual decisions: a randomized, controlled trial of decision analysis.

In early 1983, all 1,280 faculty and resident physicians at one hospital who were eligible to be vaccinated against hepatitis B were divided randomly into three groups: Group 1 physicians received general information about the risks and benefits of alternative vaccine decisions; Group 2 physicians were additionally invited to provide personal information for an individualized decision analysis (12.6 percent responded); and Group 3 physicians, who served as controls, were not contacted. In one year's follow-up, 20 percent of physicians were screened for hepatitis B antibody or vaccinated. More Group 2 physicians whose decision analyses recommended screening or vaccination took these actions (39 percent) than any other group. Group assignment remained significantly associated with vaccine decisions after analyzing results by the "intention to treat" principle, and after adjusting for training status, exposure to blood and blood products, and pre-study intentions about the vaccine. Despite the low overall vaccine acceptance rate, it is concluded that individualized decision analysis can influence the clinical decisions taken by knowledgeable and interested patients.

Appearance of Ph negative recipient clones in chronic myeloid leukemia patients following bone marrow transplantation.

Seven patients were studied following bone marrow transplantation for chronic myeloid leukemia. Cytogenetic heteromorphisms were used to determine the origin of cells present post-BMT. Differences were found between results from blood and bone marrow samples, and between karyotype and interphase Y-body studies on the same samples. Philadelphia negative (Ph-) hematopoietic chimerism was found in 6 of 7 patients, all of whom had been Ph+ before BMT. One patient also demonstrated hematopoietic chimerism with Ph+ recipient cells following clinical evidence of relapse. In two patients who had received T-cell depleted grafts, cytogenetically rearranged Ph- clones of recipient cells were prominent in PHA-stimulated blood. In one case two clones had appeared only 1 month post BMT. The appearance of these clones so soon after transplant suggests very rapid clonal expansion, or that they were already present pre-BMT but at levels too low to have been detected. In the second patient, clones were not observed until more than 12 months post-BMT, after which four were found. These collectively expanded to occupy an increasing proportion of the total cells. These two patients with clones both remain in good health 44 and 51 months post-BMT. Further studies are needed to determine the true frequency and the significance of such findings.

A model of physicians' practice attributes determination.

This paper presents a conceptual framework for modelling physicians' styles of practice. It also develops and estimates a causal model of practice style determination. The method allows simultaneous analysis of different practice styles and their determinants. The paper provides new insights into physician decision-making and, in particular, the positive relationship between fees and the number of physicians.

Health maintenance organizations and hospital quality for coronary artery bypass surgery.

This study uses hospital discharge data for 1992-1994 to assess differences between HMO and insured non-HMO patients in California and Florida with regard to the quality of the hospitals used for coronary artery bypass graft (CABG) surgery. The authors found that commercially insured HMO patients in California used higher quality hospitals than commercially insured non-HMO patients, controlling for patient distance to the hospital. In contrast, commercially insured HMO and non-HMO patients in Florida were similarly distributed across hospitals of different quality levels, whereas Medicare HMO patients in Florida used lower quality hospitals than patients in the standard Medicare program. The authors conclude that the association between HMO coverage and hospital quality may differ across geographic areas and patient populations, possibly related to the maturity and structure of managed care markets.

Comparing aggregate estimates of derived thresholds for clinical decisions.

Thresholds for medical decision making are the probabilities of disease at which clinicians choose to initiate testing or therapy. A descriptive analysis of clinicians' decision making can derive their test and test-treatment thresholds and has the potential to explain variations in test utilization. A previously described method summarizes thresholds for a group of clinicians by determining the range of probability which includes the maximum number of clinicians' individual thresholds. However, there is no statistical procedure to compare the summary measure of thresholds that is derived from the distribution of clinicians' thresholds. We describe two alternative methods of developing a summary measure of the thresholds for a group of clinicians. These alternative methods enable the analyst to apply standard statistical tests when analyzing the decision-making behavior of groups of clinicians. For the "Unweighted Mean of the Midpoints" method, confidence limits of means and standard t-tests can be used to compare different groups. For the "Weighted Mean of the Midpoints" method, a weighted standard error of the mean can be calculated to determine confidence intervals, and a weighted t-test or weighted regression can be used to compare weighted means of the midpoints of threshold ranges.

Development of function-related groups version 2.0: a classification system for medical rehabilitation.

OBJECTIVE: To present a new version (2.0) of the Functional Independence Measure-Function Related Group (FIM-FRG) case-mix measure. DATA SOURCE/STUDY SETTING: 85,447 patient discharges from 252 freestanding facilities and hospital units contained in the 1992 Uniform Data System for Medical Rehabilitation. STUDY DESIGN: Patient impairment category, functional status at admission to rehabilitation, and patient age were used to develop groups that were homogeneous with respect to length of stay. Within each impairment category patients were randomly assigned to one data set to create the system (through recursive partitioning) or a second set for validation. Clinical and statistical criteria were used to increase the percentage of patients classified, expand the impairment categories of FIM-FRGs Version 1.1, and evaluate the incremental predictive ability of coexisting medical diagnoses. Predictive stability over time was evaluated using 1990 discharges. PRINCIPAL FINDINGS: In Version 2.0, the percentage of patients classified was increased to 92 percent. Version 2.0 includes two new impairment categories and separate groups for patients admitted to rehabilitation for evaluation only. Coexisting medical diagnoses did not improve LOS prediction. The system explains 31.7 percent of the variance in the logarithm of LOS in the 1992 validation sample, and 31.0 percent in 1990 discharges. CONCLUSIONS: FIM-FRGs Version 2.0 includes more specific impairment categories, classifies a higher percentage of patient discharges, and appears sufficiently stable over time to form the basis of a payment system for inpatient medical rehabilitation.

Unrecognized redistributions of revenue in diagnosis-related group-based prospective payment systems.

The Medicare prospective payment system, which is based on the diagnosis-related group patient-classification system, identifies previously unrecognized redistributions of revenue among diagnosis-related groups and hospitals. The redistributions are caused by two artifacts. One artifact results from the use of labor market indexes to adjust costs for the different prices paid by hospitals in different labor markets. The other artifact results from the use of averages that are based on the number of hospitals, not the number of patients, to calculate payment rates from average costs. The effects of these artifacts in a sample data set have been measured, and it was concluded that they lead to discrepancies between costs and payments that may affect hospital incentives--the overall payment for each diagnosis-related group--and Medicare's total payment.

The impact of DRG-based prospective payment on clinical decision making.

The Medicare Prospective Payment System (PPS) and the financial incentives it creates are likely to influence physician practices, as well as to offer new opportunities for research into clinical decision making. Hospital managers and physicians alike will need to look increasingly to decision analysis for answers regarding technology assessment and the cost-effectiveness of clinical practices. Areas of research in which decision analysis might contribute significantly include: the compromise between cost and quality, the comparative advantages of outpatient versus inpatient procedures, and the appropriate timing of patient discharge or transfer.

The importance of considering single testing when two tests are available.

When considering two dichotomous tests in combination for reaching a treatment decision, the choice between single and multiple testing depends, in part, on the pretest probability of disease. The authors show that two tests are never preferred to a single test for all disease probabilities, regardless of whether the two tests are performed in parallel or in series.

Clinical guidelines for using two dichotomous tests.

Building on the threshold model developed by Pauker and Kassirer for a single test, the authors describe a decision analytic model for two tests with dichotomous outcomes. The model includes ten decision strategies that differ depending on which tests are performed, whether the tests are performed together or in sequence, and the definition of a positivity criterion used to make the treatment decision when the test results disagree. Formulas derived from the model are used to compute the preferred option as a function of disease probability and to calculate test and test-treatment thresholds. General guidelines developed from the model can be used without calculation to identify relative preferences for alternative options and to predict threshold effects.

Multiple test analyzer (MTA): a microcomputer program for determining preferred strategies with two diagnostic tests.

There are ten distinct management strategies in clinical situations that involve two diagnostic tests with dichotomous outcomes. The authors describe a microcomputer program, based on a previously described model, that can be used to identify test and test-treatment thresholds and to compute preferred strategies. The program provides tables and graphs of the results, which can be viewed or printed, and there is an optimization routine that facilitates comprehensive analysis. It can be used by decision-analytic researchers and policy analysts, medical educators who teach decision analysis, and clinicians who use decision analysis in their practices.

The single-cutoff trap: implications for Bayesian analysis of stress electrocardiograms.

Quantitative analysis of exercise electrocardiograms has been emphasized by many investigators. Specific problems have been found when a single cutoff is used to define a positive or a negative test: a single cutoff does not distinguish stress electrocardiography results that are slightly positive from those that are markedly positive. This may lead clinicians to underweigh strong evidence for or against coronary artery disease. This study evaluated clinicians' quantitative analysis of stress electrocardiograms. Two hundred and thirty-five physicians interpreted the results of mildly positive (1.2 mm ST-segment depression) and strongly positive (2.2 mm ST-segment depression) stress electrocardiograms. Their posttest probability estimates were too high for a mildly positive test (0.62 +/- 0.02 versus actual of 0.38; p less than 0.001) and too low for a strongly positive test (0.77 +/- 0.01 versus actual of 0.98; p less than 0.001). Physicians should understand decision aids and should use multiple rather than single cutoffs to interpret the results of stress electrocardiography.

A course in clinical decision making adaptable to diverse audiences.

Faculty at the University of Pennsylvania have developed a prototype course in clinical decision making that can be adapted to the diverse backgrounds of a variety of medical audiences. The course was offered in its entirety to third and fourth-year medical students and in abbreviated form to two postgraduate audiences (community and university-based physicians) during 1982. Methods were developed for content, process, and outcome evaluation for the courses; the latter consisted of pretest and posttest comparisons of performance on a written examination. Ninety-four individuals attended one or more sessions of the three courses. All courses were very favorably received, although the postgraduate audiences perceived less clinical relevance than educational relevance in the material (p less than 0.05). The medical students performed better on the pretest than either group of physicians, with the student-university physician difference reaching statistical significance (p less than 0.01). Nevertheless, all groups performed better on the posttest than on the pretest (p less than 0.001) and the degree of improvement was no different among the groups (p greater than 0.29). We conclude that our course's concepts and skills can be effectively adapted to and assimilated by physicians at all levels of training and experience.

Assessing physicians' estimates of the probability of coronary artery disease: the influence of patient characteristics.

The authors assessed physicians' probability estimates of coronary artery disease (CAD) in 250 patients undergoing a screening exercise stress test. True likelihood of disease (prevalence) was derived from the literature. Discrimination and calibration were assessed by comparing physicians' probability estimates and prevalence using pairwise comparisons, rank correlation, and linear regression. There were differences in the discriminative abilities of the physicians based on patient characteristics. For example, the physicians had better discriminative ability for patients with typical cardiac chest pain compared with atypical chest pain. The physicians were able to predict the prevalence of CAD in broad groups of patients. However, they overestimated probabilities for patients with low prevalence of disease and underestimated probabilities for patients with high prevalence of disease. The authors conclude that physicians make consistent errors in the use of probability estimates. The quality of these estimates depends on patient characteristics such as type of chest pain and true likelihood of disease.

The characteristics of stat laboratory tests.

We studied the use of stat (ie, statim--as soon as possible) laboratory tests at a university teaching hospital. For the 20 most frequently performed tests, 35.7% of the determinations were performed on a stat basis. The frequency with which a test was ordered on a stat basis ranged from 6.0% (for ESR) to 61.5% (amylase level). The proportion of laboratory test requests from a hospital service that were ordered stat ranged from 3.8% (orthopedic surgery) to 100% (emergency services). The daily number of regular laboratory test requests decreased significantly over the weekend, but the daily number of stat requests fell less sharply. The number of requests for routine tests decreased after 6 pm, but the number of requests for stat tests remained relatively constant until about midnight.

Morphine-augmented hepatobiliary scintigraphy: a meta-analysis.

The aim of this study was to compare the sensitivity and specificity of morphine-augmented hepatobiliary scintigraphy (MA-HBS) with that of conventional hepatobiliary scintigraphy (C-HBS) for acute cholecystitis. The results of most MA-HBS studies cannot be compared with C-HBS estimates, since articles describing C-HBS often include non-candidates for MA-HBS. However, using meta-analytic techniques to combine data from eligible studies (4 for C-HBS and 5 for MA-HBS), the specificity of MA-HBS (0.84; 95% CI = 0.75-0.94) was significantly greater (P = 0.008) than that of C-HBS (0.68; 95% CI = 0.61-0.75); there were no differences in sensitivity (MA-HBS; 0.96, 95% CI = 0.92-0.99; C-HBS: 0.97, 95% CI = 0.97-0.99).

Measuring hospital outcomes from a buyer's perspective.

This study reports lessons learned from a project to develop a flexible, generalizable, and valid method for corporate buyers of hospital care that would permit them to use available secondary data to rate the outcomes quality of all hospitals in a local market area. As hospitalization insurance has moved from coverage that applied equally to all licensed hospitals to arrangements which selected a certain preferred hospital or hospitals and rejected others, the need to determine the quality of different hospitals (as well as what they would cost the insurer or buyer) has become apparent. The product of this project was the development and demonstration of a set of rating methods that build on the strengths available in large hospital discharge data bases, such as (but by no means limited to) that of the Pennsylvania Health Care Cost Containment Council (PHC4). These measures, or others developed using these methods, deal with uncertainty in the data--its diagnosis and treatment--in a conceptually valid and practically useful way, illustrate a process that might be used in the general development of quality measures, and provide a useful critique of some other measures.

Blood lead in children and its determinants in Nagpur, India.

In a community-based cross-sectional study of 297 children aged 6 months to 6 years in an Indian city, the authors assessed the prevalence of elevated (> or = 10 microg/dL) blood lead (PbB) levels, their risk factors, and the lead contents in potential environmental sources. Mean PbB was 18.4 microg/dL +/- 16.5. The prevalence of elevated PbB was 67%. Anticipated risk factors for elevated PbB were living in houses painted with lead-based paint, odds ratio (OR) 6.42 (1.75, 23.6; p = 0.005), recent exposures to lead-based paint, OR 2.61 (1.07, 6.66; p = 0.03), and the use of the eye cosmetic ma," OR 2.63 (1.24, 5.56; p = 0.01). Unanticipated results were effect of upper caste as a risk factor, OR (adjusted) 1.85 (95% CI = 0.96, 3.57; p = 0.06), and the lack of effect of traffic, parental occupational exposure, or nutritional status. Analysis of various environmental sources such as paint, pencils, crayons, and clay revealed high lead levels. These results demonstrate the existence of a major environmental health problem in Indian children, with risk factors that differ from those in other countries.

Health insurance under competition: would people choose what is expected?

To determine relative preferences for different cost-sharing options, we asked a 17% random sample of 2,754 nonunion employees to compare health insurance policies that differed in the level of 1) deductible amount, 2) coinsurance rate, 3) coinsurance limit, 4) maximum liability, and 5) price. Using conjoint analysis, we derived preference curves for each of the five components and measured preferences for the compromise between more coverage and the corresponding price increase. In contrast to other studies, our findings suggest that under fair market prices, respondents would choose policies with greater coverage for catastrophic illness, and they would as likely choose cost-sharing policies that contain incentives to reduce utilization as they would choose policies without these incentives.