A population-based nested case-control study of the costs of hip and knee replacement surgery.

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.

Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature.

The novel aminosterol, squalamine, inhibits angiogenesis and tumor growth in multiple animal models. This effect is mediated, at least in part, by blocking mitogen-induced proliferation and migration of endothelial cells, thus preventing neovascularization of the tumor. Squalamine has no observable effect on unstimulated endothelial cells, is not directly cytotoxic to tumor cells, does not alter mitogen production by tumor cells, and has no obvious effects on the growth of newborn vertebrates. Squalamine was also found to have remarkable effects on the primitive vascular bed of the chick chorioallantoic membrane, which has striking similarities to tumor capillaries. Squalamine may thus be well suited for treatment of tumors and other diseases characterized by neovascularization in humans.

Removal of T4 endonuclease V-sensitive sites from SV40 DNA after exposure to ultraviolet light.

The induction and removal of sites sensitive to T4 endonuclease V from ultraviolet-irradiated Simian Virus 40 (SV40) Form I (supercoiled) DNA during a lytic infection of monkey CV-1 cells was investigated by agarose tube gel electrophoresis. Endonuclease-sensitive sites were induced at a rate of 0.049 sites/SV40 genome per J/m2, or 1.4 sites/1 . 10(8) daltons of DNA per J/m2. This value is similar to the yield of endonuclease-sensitive sites and pyrimidine dimers in uninfected host CV-1 cell DNA. Removal of endonuclease-sensitive sites was dose dependent and non-linear for at least 24 h after irradiation. These results suggest that SV40 DNA is subject to the excision repair mechanisms of the host cell, and that the excision of pyrimidine dimers may be one of the biochemical events underlying host cell reactivation.

A phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers.

PURPOSE: A Phase I study of squalamine, a novel antiangiogenic agent originally isolated from the dogfish shark Squalus acanthias, was conducted in patients with advanced cancers to: (a) determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of squalamine lactate when given as a 120-h continuous i.v. infusion every two weeks; and (b) to obtain information on prolonged (>120-h) continuous i.v. infusions in patients who have tolerated 120-h infusions. EXPERIMENTAL DESIGN: A rapid dose escalation scheme was used that permitted intrapatient dose escalation. Three or more patients were treated at each dose, of which at least one patient started treatment de novo at that dose. Once DLT was encountered, the dose was decreased by one dose level, and the duration of infusion was prolonged from 10 up to 30 days in 5-day increments. RESULTS: Nineteen patients were treated at eight squalamine dose levels; the number of patients/dose level who received 120-h infusions were [expressed as dose in mg/m(2)/day (number of patients initiated de novo at that dose/total number of patients treated at that dose)]: 6 (3/3), 12 (3/6), 24 (1/5), 48 (2/6), 96 (4/10), 192 (2/6), 384 (3/8), and 538 (1/5). DLT was encountered at 384 mg/m(2)/day (1/3 de novo patients, 5/8 total patients) and 538 mg/m(2)/day (1/1 de novo patients, 4/5 total patients) and consisted of hepatotoxicity, characterized by grade 3 transaminase elevations that resolved 3-11 days after ceasing squalamine infusion. Three patients did not experience hepatotoxicity when first treated at 384 mg/m(2)/day but developed DLT at the same dose when de-escalated from 538 mg/m(2)/day. Other toxicities included grade 1-3 fatigue, grade 1-2 nausea, anorexia, and neuromuscular symptoms. The maximum duration of continuous i.v. infusion was 20 days at a dose rate of 192 mg/m(2)/day in one patient without adverse effects. Pharmacokinetic calculations revealed a linear relationship between area under the curve or Cmax and squalamine dose rate up to 384 mg/m(2)/day, with a prolonged terminal squalamine persistence in patient plasma (median t(1/2) = 18 h; range, 8-48 h). Transient tumor responses were observed in a patient with synovial cell sarcoma and a patient with breast carcinoma with cutaneous metastases. CONCLUSIONS: The best tolerated dose rate of squalamine when administered as a 120-h continuous i.v. infusion was 192 mg/m(2)/day; however, patients without prior exposure to squalamine appeared to tolerate a dose rate of 384 mg/m(2)/day without DLT. On the basis of preclinical evidence of synergy with cytotoxic agents and demonstration of human safety from this trial, additional clinical trials have been initiated with squalamine in combination with chemotherapy for patients with late stage lung cancer and ovarian cancer.

Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies.

Squalamine, an antiangiogenic aminosterol, is presently undergoing Phase II clinical trials in cancer patients. To broaden our understanding of the clinical potential for squalamine, this agent was evaluated in nu/nu mouse xenograft models using the chemoresistant MV-522 human non-small cell lung carcinoma and the SD human neuroblastoma lines. Squalamine was studied alone and in combination with either cisplatin or paclitaxel plus carboplatin. Squalamine alone produced a modest MV-522 tumor growth inhibition (TGI) and yielded a TGI with cisplatin that was better than cisplatin alone. Squalamine also significantly enhanced the activity of paclitaxel/carboplatin combination therapy in the MV-522 tumor model. Squalamine similarly improved the effectiveness of cisplatin in producing TGI when screened against the SD human neuroblastoma xenograft. Xenograft tumor shrinkage was seen for the MV-522 tumor in combination treatments including squalamine, whereas no tumor shrinkage was seen when squalamine was omitted from the treatment regimen. To gain a greater understanding of the mechanism by which squalamine inhibited tumor growth in the xenograft studies, in vitro experiments were carried out with vascular endothelial growth factor-stimulated human umbilical vein endothelial cells in culture exposed to squalamine. Squalamine treatment was found to retard two cellular events necessary for angiogenesis, inducing disorganization of F-actin stress fibers and causing a concomitant reduction of detectable cell the surface molecular endothelial cadherin (VE-cadherin). We propose that the augmentation by squalamine of cytotoxicity from platinum-based therapies is attributable to interference by squalamine with the ability of stimuli to promote endothelial cell movement and cell-cell communication necessary for growth of new blood vessels in xenografts after chemotherapeutic injury to the tumor.

Chiropractic manipulation and stroke: a population-based case-control study.

BACKGROUND AND PURPOSE: Several reports have linked chiropractic manipulation of the neck to dissection or occlusion of the vertebral artery. However, previous studies linking such strokes to neck manipulation consist primarily of uncontrolled case series. We designed a population-based nested case-control study to test the association. METHODS: Hospitalization records were used to identify vertebrobasilar accidents (VBAs) in Ontario, Canada, during 1993-1998. Each of 582 cases was age and sex matched to 4 controls from the Ontario population with no history of stroke at the event date. Public health insurance billing records were used to document use of chiropractic services before the event date. RESULTS: Results for those aged <45 years showed VBA cases to be 5 times more likely than controls to have visited a chiropractor within 1 week of the VBA (95% CI from bootstrapping, 1.32 to 43.87). Additionally, in the younger age group, cases were 5 times as likely to have had >/=3 visits with a cervical diagnosis in the month before the case's VBA date (95% CI from bootstrapping, 1.34 to 18.57). No significant associations were found for those aged >/=45 years. CONCLUSIONS: While our analysis is consistent with a positive association in young adults, potential sources of bias are also discussed. The rarity of VBAs makes this association difficult to study despite high volumes of chiropractic treatment. Because of the popularity of spinal manipulation, high-quality research on both its risks and benefits is recommended.

Cloning and expression of a collagen-analog-encoding synthetic gene in Escherichia coli.

A family of totally synthetic genes coding for multiple tandem repeats of the amino acid sequence (Gly-Pro-Pro) has been prepared and inserted into the ClaI cloning site of the expression vector pJL6. A representative recombinant plasmid, pAC1, with an insert of about 340 bp was established in an Escherichia coli strain bearing a defective lambda prophage, to study expression of the CII-collagen analog fusion protein produced from pAC1 upon heat induction. Authentic fusion protein production was demonstrated by nucleotide sequencing, Northern-blot analysis, and in vivo synthesis. Conversion of a wild-type rpoH allele to the rpoH165 mutation was shown to suppress proteolysis of the unstable fusion protein.

Relative effects of drugs and diet on hyperactive behaviors: an experimental study.

In a test of Feingold's hypothesis that food additives trigger the hyperactive response, 26 hyperactive children were randomly assigned to treatment conditions whereby they were given active or placebo medications in combination with challenge cookies with artificial food colors or control cookies without the additives. The children were crossed over into each of the four treatment conditions and experimental procedures were employed, including double-blind assessments through the completion of behavior checklists, by teachers and parents. Stimulant medications were clearly more effective than diet in reducing hyperactive behavior. The parent ratings indicate strong drug effects and inconclusive diet effects. Drug effects are marked in teacher ratings as well. However, when the children were receiving placebos, their hyperactive behaviors in the classroom were greater when eating cookies with artificial colors than when eating cookies without artificial colors. According to the ratings, approximately seven children were no longer hyperactive. There is evidence to suggest that the behavior of three to eight children was diet-responsive, depending on the criteria used. There is evidence, particularly in teacher ratings, in support of Feingold's hypothesis if it is modified. Further research is required to specify which subtypes of hyperactive children respond to a diet free of artificial food colors.

Squalamine improves retinal neovascularization.

PURPOSE: Modalities for inhibiting neovascularization may be one avenue to the development of effective therapies for retinopathy. The effect of squalamine, an antiangiogenic amino sterol, on oxygen-induced retinopathy (OIR) was assessed in a mouse model. METHODS: OIR was induced in C57BL6 mice by a 5-day exposure to 75% oxygen from postnatal day (P)7 through P12. Squalamine (25 mg/kg, subcutaneous)treated animals received either daily doses for five days from P12 to P16 or one dose just after removal from oxygen on P12. Each set of animals was killed at P17 to P21. Retinopathy was assessed with a retinopathy scoring system evaluation of retinal wholemounts and by quantification of neovascular nuclei on retinal sections. RESULTS: Animals receiving 5 days of squalamine after a 5-day exposure to oxygen had total retinopathy scores (expressed as median score with 25th and 75th quartiles in parentheses) of 4(3, 5) versus oxygen-only-reared animals with scores of 8(7, 9; P < 0.001). Animals reared in room air and animals exposed to squalamine only had similar retinopathy scores: 1(1, 2) and 1(0, 2). Oxygen-reared animals receiving single-dose squalamine also showed improvement, with a median retinopathy score of 4(4, 6.75) versus oxygen-only-reared animals with median retinopathy score of 9(7, 10; P < 0.001). There was a decreased number of neovascular nuclei extending beyond the inner limiting membrane on retinal sections in animals treated with 5 days (P < 0.01) and 1 day (P < 0.001) of squalamine. CONCLUSIONS: Squalamine significantly improved retinopathy and may be a novel agent for effective treatment of ocular neovascularization.

Measuring the impact of trauma care on survival: rates of preventable death, effectiveness, and efficacy.

This paper focuses on the appropriateness of outcome measures to evaluate trauma care. The preventable death rate (PDR), based on the study of deceased patients only, has been the traditional measure of the impact of trauma care on improving the survival of patients with severe trauma. Another measure frequently used in other ares of evaluation research is the effectiveness rate--i.e. the survival rate in the total population of severe trauma patients. Because both the PDR and the effectiveness rate vary with the proportion of patients who would die even under conditions of optimal care, these two measures can be misleading. We illustrate their inadequacy by using published data on the impact of regionalization of trauma care. We propose the use of a third outcome measure of the impact of trauma care on survival, the efficacy rate--i.e. the survival rate among severe trauma patients with a potential for survival. Evaluation of trauma care should also measure outcomes other than survival and need not be restricted to patients with the most severe trauma. Evaluation of trauma care therefore requires outcome measures, such as the efficacy rate, which are based on the population at risk of manifesting the outcome of interest.

An integrative framework for health-related research.

Research on the manifold aspects of health and health-care delivery, economics and administration has expanded rapidly in recent years and now engages a number of disciplines. The array of theories, methods, and analytical strategies derived from such diverse sources frequently impedes effective communication between investigators and sometimes renders it impossible. We propose a conceptual framework that encompasses all health-related research and demonstrates the relationships and interfaces between the various disciplines involved. The framework emerges from a classification of health-related research into studies of health states or health interventions followed by consideration of the level of analysis (e.g. cell, individual, community) employed and the purpose of each study (development, description, explanation, or evaluation).

The context of measuring disability: does it matter whether capability or performance is measured?

This study assesses the differences between two methods of conceptually framing physical disability questions, using two scenarios (capability and performance). The relationship between capability and performance was explored on the basis of the literature and empirically tested by administering two versions of the Activities Scale for Kids (ASK) to 28 physically disabled children. The capability version asked children what they "could do," whereas the performance version asked what they "did do." Capability was found to exceed performance (p < 0.001) by approximately 18%. The difference may relate to a difference in environmental contexts between the two versions, with performance reflecting abilities in usual (or real life) circumstances and capability reflecting abilities in a defined situation apart from real life. Researchers must, therefore, consider carefully the environmental circumstances in which they wish to evaluate outcomes, and use this information to decide whether to measure capability, performance, or both.

Measurement properties of the activities scale for kids.

The Activities Scale for Kids (ASK) is a self-report measure of childhood physical disability, that has excellent reliability (ICC = 0.97). The purpose of this study was to assess further the ASK's measurement properties. ASK questionnaires were completed by 200 children with musculoskeletal limitations (mean age, 10.1 years). Rasch analyses confirmed that all items measured the same construct and supported aggregation of a summary score. Validity of the ASK was demonstrated by a correlation of 0.81 (P<0.0001) with parent-reported Childhood Health Assessment Questionnaire scores; a significant difference in scores according to clinicians' global ratings of disability (P<0.0001), and a correlation of 0.92 (P<0.0001) with clinician-observation. The ASK showed minimal ceiling effects, no floor effects, and changed by 1.73 standard deviation units after clinically important change. The ASK is a valid and responsive outcome measure that permits 5- to 15-year-old children physical functioning in the community to be assessed accurately by mail. The quality of this measure will enable clinical studies to measure outcome not only in a way that is relevant to patients, but also in a way that is sensitive to small amounts of change and is practical and inexpensive.

Rasch analysis of the Western Ontario McMaster (WOMAC) Osteoarthritis Index: results from community and arthroplasty samples.

BACKGROUND AND OBJECTIVE: This study is based on secondary analysis of Western Ontario McMaster Osteoarthritis Index (WOMAC) data from a community sample over 55 years and total hip or knee arthroplasty samples presurgery and 1-year postoperative. METHODS: The WOMAC data were evaluated by Rasch analysis. Data were considered to fit the Rasch mathematical model for the pain and physical dimensions of the WOMAC if unidimensionality was confirmed by principle component analysis of the subscale and the residuals from the Rasch analysis, infit and outfit statistics were in the range of 0.80 to 1.20; if there was no differential item functioning based on gender or hip vs. knee subjects; and, if there was stability of the item logits across the three data samples. RESULTS: A three-item pain dimension (excluding night pain and pain on standing) and a 14-item physical dimension (excluding heavy domestic duties, getting in and out of the bath and getting on and off the toilet) fit the Rasch model based on these criteria. CONCLUSION: In evaluating existing health status questionnaires using Rasch methodology, it is important to evaluate relevant patient samples and longitudinal data when the measure is intended to evaluate change in status. By these criteria, a modified WOMAC questionnaire fits the Rasch model and has interval-level scaling properties.

The Quebec Back Pain Disability Scale: conceptualization and development.

The Quebec Back Pain Disability Scale is a new measure of functional disability for patients with back pain. Functional disability was operationalized in terms of perceived difficulty associated with simple physical activities. The content of the scale was developed in several stages, including a literature review, two studies seeking the opinions of patients and experts, pilot testing, and a large, longitudinal study of back pain patients. Forty-eight disability items were extensively studied using standard methods such as test-retest reliability, item-total correlations, and factor analysis, as well as modern techniques based on item response theory. Items that were highly effective in discriminating between different levels of disability were selected for the final, reduced scale. The scale has 20 items, representing six empirically derived categories of activities affected by back pain. Measurement properties of this instrument have been previously discussed.

A short formal synthesis of squalamine from a microbial metabolite.

A short formal synthesis of squalamine is described, utilizing the biotransformation product 2, which is available in one step from commercially available 3-keto-23,24-bisnorchol-4-en-22-ol (1). Regioselective C-22 oxidation and C-24 sulfation of the corresponding alcohols in the presence of a free C-7 alcohol make for an efficient preparation of squalamine intermediate 11.

Determinants of preventive practices in fee-for-service primary care.

A study of primary care physicians was conducted in the provinces of Quebec and New Brunswick, Canada, to ascertain their patterns of preventive practice with respect to cancer in four anatomic sites: breast, cervix, colon-rectum, and lung. The determinants of preventive practices among 552 fee-for-service physicians in both provinces are explored. Scales were created for the practice behaviors related to each type of cancer (dependent variables) and for knowledge and belief (independent variables). The content of these scales was delineated through factor analysis and their reliability assessed using Cronbach's alpha. Other variables were considered in the analysis, including continuing education activities, perceived barriers to prevention, and other sociodemographic and professional variables. Bivariate analysis and multivariate techniques were used. The explanatory factors were regrouped into cognitive, sociodemographic, and organizational determinants. Particular patterns were delineated for each cancer type. In a fee-for-service reimbursement setting without specific incentives for preventive practices, the creation of favorable organizational environments and the conveying of agreed-upon information to physicians are important ways of enhancing the integration of preventive activities into clinical practice. Identification of the sociodemographic determinants of preventive practices reveals the complexity of physicians' behaviors.

Determinants of preventive practices of general practitioners in Torino, Italy.

We conducted a study of general practitioners in Torino, Italy, to determine their patterns of preventive practice. We examined a set of primary and secondary preventive interventions and their determinants. We explored the determinants of primary preventive interventions (antismoking and alcohol abuse counseling, counseling for prevention of accidents at home among the elderly, flu vaccination for the elderly, and counseling on contraceptive use) and cancer early detection techniques (chest x rays and sputum cytology for lung cancer; mammography, physical examination, teaching of breast self-examination, and Papanicolaou [Pap] smear for gynecological cancers). Grouping determinants in cognitive, sociodemographic, and organization factors, we found different patterns for each maneuver. Cognitive factors played an important role, but their importance varied for each intervention. We found that smoking behavior of physicians predicted antismoking counseling. Further, the availability of other primary care services is an important factor in the early detection of gynecological cancers.

Enthusiasm or uncertainty: small area variations in the use of mammography services in Ontario, Canada.

STUDY OBJECTIVE: To examine the variation in mammography utilisation in relation to age group and indication across health planning regions in Ontario, Canada. DESIGN: This study includes all women aged 30 and over in Ontario who received a mammogram between July 1, 1990 and December 31, 1991. Data from a sample of 10,000 women aged 50-69 were used to assign mammogram indication as "screening", "possible diagnostic", or "probable diagnostic" based on previous health care utilisation patterns. Age specific rates and age adjusted rates in relation to age group (30-39, 40-49, 50-69, and 70 + years) and region were derived. MAIN RESULTS: Overall, 572,762 women received one or more mammograms. Rates increased from 30-54 years and decreased thereafter. Similar variations were seen in the 40-49 and 50-69 age groups. The ranking in the area specific rates remained consistent for all ages except the 30-39 year range. In relation to indication, the largest variation across regions occurred in the screening group. CONCLUSIONS: Mammography utilisation varies across age groups. The greatest variability is for screening, probably because of physician referral patterns, patient uptake, and perhaps access to mammography. The extent of variation was similar when compared between groups where recommendations were consistent (ages 50-59) and where they were inconsistent (ages 40-49) suggesting that perhaps enthusiasm rather than uncertainty is related to regional variation for this procedure.