Strip-plot designs, mixed models, and comparisons between linear and non-linear models for microtitre plate bioassays.

By paying careful attention to the experimental units and, randomizing where it is reasonable, we are able to devise designs for cell culture bioassay which are statistically legitimate and practical in the laboratory. These designs, strip-plot layouts, can accommodate linear or non-linear models, fixed or mixed models, and can provide good protection from location effects. Non-linear mixed models using these designs can be extended to address serial dilution error. A statistically based approach which includes randomization and proper design is a powerful tool for identifying subtle effects of factors within and outside bioassays; this attention to statistical detail is a necessary first step towards continuous improvement of biological assays.

A layered tin(II) phosphonate, [Sn(C6H5O3P)]n.

Poly[tin(II)-mu-phenylphosphonato], [Sn(C(6)H(5)O(3)P)](n), was synthesized solvothermally at 423 K and crystallized in the monoclinic system, space group Cc. The inorganic layers consist of alternating pyramidal Sn and tetrahedral P centers, joined by doubly bridging O atoms. The corner-sharing SnO(3) and PO(3)C(6)H(5) polyhedra define a corrugated layer of six-membered rings. The layers are connected along the unique b axis by interdigitated phenyl rings of the phenylphosphonate groups.

Validity of the pain anxiety symptoms scale (PASS): prediction of physical capacity variables.

Anxious responses to pain may lead to avoidance of behavior expected to produce pain. McCracken et al. (1992) developed the Pain Anxiety Symptoms Scale (PASS) to assess anxiety related specifically to pain. Efforts to validate the scale, however, have been confined mostly to examining associations between the PASS and other self-report instruments. This study tested whether PASS scores were related to behavioral performance variables recorded by therapists during a physical capacity evaluation. Participants were 98 male patients with persistent pain referred to two industrial rehabilitation centers. PASS scores were correlated negatively with amount of weight lifted and carried, and results of hierarchical regressions showed that PASS scores accounted for additional variance in these variables when measures of trait anxiety, depression and pain severity were controlled. However, we did not replicate the findings of McCracken et al. (1992) that PASS scores accounted for variance in self-reported disability with trait anxiety, depression or pain severity controlled. Results extend the validity of the PASS and are consistent with models of fear of pain: patients with high PASS scores may avoid potentially painful physical exertion to reduce their fear.

Validation of bioassays for quality control.

For a biological assay to be useful for quality control it should fail bad lots, pass good lots, and estimate relative potency with high accuracy and precision. To fail a lot we rely most heavily on the test for parallelism. For the parallelism test and other preliminary tests as well as for inference, appropriate estimates of assay variation are crucial. Location effects on 96 well plates and serial dilution of samples using multichannel pipettes make it difficult to obtain good estimates of assay variation. This paper develops the use of a split-block design and analysis where blocks are reasonably consistent regions of a plate; this approach removes some location effects, allows other location effects to be treated as assay variation and provides appropriate measures of assay variation. Randomization, even within the split-block design, is difficult without robots to reduce the likelihood of procedural errors. There are hardware, software, and validation obstacles to implementation of robots in the bioassay laboratory. More generally, validation of a bioassay should be reported on log relative potency and must address between- and within-assay variation. When between assay variation is not small, the usual weighted approach to combining relative potency estimates (which ignores between-assay variation) is inappropriate; a simple sampling average and standard deviation is a better solution.

Relationships among patient hostility, anger expression, depression, and the working alliance in a work hardening program.

Hostility, anger expression, and depression may adversely affect the response of chronic pain patients to pain or functional restoration programs by hampering the development of good working alliances between patients and physical or occupational therapists. Measures of hostility, anger expression, and depression and the Working Alliance Inventory (WAI) were completed by 71 patients with chronic pain (stemming from work-related injuries) prior to starting a "work hardening" program. The physical or occupational therapist acting as any given patient's "program manager" completed the WAI, as well. Hostility and anger expression were correlated negatively only with patient ratings of the working alliance. Therapist ratings were predicted by the interaction of patient anger expression and depression, such that therapists reported their poorest alliances with patients who were both depressed and expressed anger. Results imply that hostility and the propensity to express anger may diminish a pain patient's capacity to foster a collaborative relationship with physical or occupational therapists, while therapists may readily become alienated from depressed and irritable patients.

Correlation between health outcome and length of hospital stay in lumbar microdiscectomy.

STUDY DESIGN: Prospective observational trial in a community hospital setting. OBJECTIVES: To examine the effect on patient-reported outcome of a clinical practice, namely, decrease in hospital length of stay for single-level lumbar microdiscectomy. SUMMARY OF BACKGROUND DATA: Health care reform and the economic demands of managed care have created increasing pressure to manage health care resources more effectively. Spine surgery is one of the most common surgeries. METHODS: Starting in October 1993, length of stay for patients undergoing lumbar microdiscectomy was decreased at the study institution. Patients completed questionnaires (SF-36) before surgery and 3 months after surgery that assessed health status, back-related functional status, and treatment satisfaction. Comparisons were made between the intervention group and a historical control group and between 1-day and 2-day patients. RESULTS: SF-36 scores 3 months after surgery approximated age and sex norms of five of the eight SF-36 scales and improved significantly on the remaining three scales. The physical functioning and general health scores were significantly better for the 1-day than the 2-day patients. Patient satisfaction was similar in all groups. Hospital charges for the 1-day patients were $781 less per patient than for the 2-day patients. CONCLUSIONS: Hospital length of stay for lumbar microdiscectomy can be decreased without adverse effect on short-term patient self-reported health status or satisfaction and with lower hospital charges. This model assesses the effect of efficient management of health care resources on patient-perceived quality and satisfaction.

Treatment of chronic hepadnavirus infection in a woodchuck animal model with an inhibitor of protein folding and trafficking.

A novel strategy for anti-viral intervention of hepatitis B virus (HBV) through the disruption of the proper folding and transport of the hepadnavirus glycoproteins is described. Laboratory reared woodchucks chronically infected with woodchuck hepatitis virus (WHV) were treated with N-nonyl-deoxynojirimycin (N-nonyl-DNJ), an inhibitor of the endoplasmic reticulum (ER) alpha-glucosidases. The woodchucks experienced significant dose dependent decreases in enveloped WHV, resulting in undetectable amounts in some cases. The reduction in viremia correlated with the levels of hyperglucosylated glycan in the serum of treated animals. This correlation supports the mechanism of action associated with the drug and highlights the extreme sensitivity of the virus to this type of glycan inhibitor. At N-nonyl-DNJ concentrations that prevented WHV secretion, the glycosylation of most serum glycoproteins appeared unaffected, suggesting great selectivity for this class of therapeutics. Indeed, this may account for the low toxicity of the compound over the treatment period. We provide the first evidence that glucosidase inhibitors can be used in vivo to alter specific steps in the N-linked glycosylation pathway and that this inhibition has anti-viral effects.

Assessment of platelet function assays.

Optical aggregometry, traditionally used to assess platelet function, is highly dependent on sample preparation and technical procedure; as a result, data from various laboratories can be quite variable. In a study designed to assess the sources of variation, it was determined that the total standard deviation ranged from 3.6% to 7.7%. The assay variation by one analyst on one aggregometer on a single day ranged from 1.7 to 4.6. Day-to-day variation contributed 42% to 63% of the total variation, between-operator variation contributed 1% to 33% of the total variation, and within [between repeat measurements for a given sample by a given operator on a single day] variation contributed 22% to 36% of the total variation. Because of the disadvantages associated with optical aggregometry, alternate platelet function assays were considered and their correspondence to optical aggregometry was evaluated: activated clotting time, whole blood aggregometry, platelet count ratio, Platelet Function Analyzer (PFA-100, Dade), and Rapid Platelet function Assay (Accumetrics). Of those assays evaluated, activated clotting time and PFA-100 are assays that measure aspects of coagulation and hemostasis, whereas whole blood aggregometry, platelet count ratio, and RPFA are more closely related to platelet function. Each assay has value in monitoring various aspects of the coagulation process. The best method for monitoring safety and efficacy of various inhibitors of platelet function will ultimately be determined by clinical trials.

Overview: performance measures--the next generation.

Can our existing quality toolkit respond adequately to the unprecedented changes in the health care system? The guest editor highlights the lessons offered by the articles in the issue and reflects on the challenges in identifying performance measures and using the data for quality improvement.

Clinical practice evaluation at Providence Health System.

Over the past seven years, Providence Health System (PHS) in Portland, Oregon, has used an outcomes research paradigm to study treatment of back pain, coronary artery disease, total joint replacement, and cancer. In presenting case studies of each of these areas, the authors chronicle the evolution of clinical practice evaluation at PHS, beginning with early studies in the 1960s, to the establishment of the Center for Outcomes Research and Education (CORE), to the formation of a new systemwide strategy that is responsive to the evolving health care marketplace.

SC-52151, a novel inhibitor of the human immunodeficiency virus protease.

SC-52151 is a potent, selective, tight-binding human immunodeficiency virus (HIV) protease inhibitor containing the novel (R)-(hydroxyethyl) urea isostere. The mean 50% effective concentration for lymphotropic, monocytotropic strains and field isolates of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus is 26 ng/ml (43 nM). The combination of SC-52151 and nucleoside reverse transcriptase inhibitors synergistically inhibited HIV-1 replication without additive toxicity. An extended postantiviral effect correlates with inhibition of gag and gag-pol polyprotein processing. SC-52151 is highly protein bound ( >90%) in human plasma, and the level of partitioning into erythrocytes is low. Physiological concentrations of alpha-1-acid glycoprotein, but not albumin, substantially affect the antiviral potency of SC-52151. The oral bioavailability of [14C]SC-52151 is 17% when it is administered as an elixir to the rat, dog, or monkey. Oxidation of the t-butyl moiety is the major route of biotransformation, and elimination is mainly by biliary excretion. No toxicologically significant effects have been observed in animals. Pharmacokinetic and metabolism studies in multiple animal species predict 20 to 30% systemic bioavailability, an elimination half-life of 1 to 2 h, and a volume of distribution of greater than 3 liters/kg in humans.

Self-report measures for assessing treatment outcomes in cardiac surgery patients.

Patient self-report measures are increasingly valued as outcome variables in health services research studies. In this article, the authors describe the Functional Status, Health Related Quality of Life, Life Satisfaction, and Patient Satisfaction scales included in the Processes, Structures, and Outcomes of Cardiac Surgery (PSOCS) cooperative study underway within the Department of Veterans Affairs health care system. In addition to reporting on the baseline psychometric characteristics of these instruments, the authors compared preoperative Medical Outcomes Study SF-36 data from the study patients with survey data from a probability sample of the US population and with preoperative data on cardiac surgery patients from a high volume private sector surgical practice. Descriptive analyses indicate that the SF-36 profiles for all of the cardiac patients are highly similar. The Veterans Affairs and private sector patients report diminished physical functioning, physical role functioning, and emotional role functioning as well as reduced energy relative to an age-matched comparison sample. At the same time, however, the Veterans Affairs patients evidenced lower levels of capacity on most of the SF-36 dimensions relative to the private sector patients.

Measuring the success of treatment in patient terms.

Measuring the success of major surgeries such as total hip and total knee replacement is important for both case selection and public policy. Patients, purchasers, and practitioners must choose among clinical scoring systems, health status measures, and patient satisfaction ratings to monitor performance and ensure appropriate use of costly procedures. The present study compares results from the Medical Outcomes Study Short Form 36 (SF-36) Health Status Survey and clinical scoring systems to direct patient ratings of success. Data come from a study of 128 total knee-replacement procedure and 211 total hip replacements. Analyses indicate that for both hip and knee patients, success is related closely to posttreatment physical function and bodily pain. Patient ratings of success also are related to the clinical scores used by physicians. Success is related less to change from pretreatment function for knee patients than for hip patients. Although patient ratings of success are generally consistent with other outcome measures, their relationship to patient expectations, satisfaction, and attributions need to be understood before they can become a useful tool for performance monitoring and case selection.

Public accountability for health: new standards for health system performance.

This article reviews the failure of contemporary quality oversight organizations to respond to the changing health care environment and suggests an overhaul of quality measurement and assurance functions. The authors examine the factors that have limited public accountability for health care, emphasizing the limited agreement that exists on the purpose of American health care, standards for evaluating care, or the appropriate locus of responsibility for quality of care. A five-part quality oversight system is proposed including development of quality measures, promulgation of national standards, validation and accreditation, use of data for purchasing and provider selection, and use of data for quality improvement.