Biomedical subjects
Publications and source records attributed to C L Bennett.
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BACKGROUND: Reporting of pharmaceutical-industry-sponsored randomised clinical trials often result in biased findings, either due to selective reporting of studies with non-equivalent arms or publication of low-quality papers, wherein unfavourable results are incompletely described. A randomised trial should be conducted only if there is substantial uncertainty about the relative value of one treatment versus another. Studies in which intervention and control are thought to be non-equivalent violates the uncertainty principle. METHODS: We examined the quality of 136 published randomised trials that focused on one disease category (multiple myeloma) and adherence to the uncertainty principle. To evaluate whether the uncertainty principle was upheld, we compared the number of studies favouring experimental treatments over standard ones. We analysed data according to the source of funding. FINDINGS: Trials funded solely or in part by 35 profit-making organisations had a trend toward higher quality scores (mean 2.94 [SD 1.3]; median 3) than randomised trials supported by 95 governmental or other non-profit organisations (2.4 [0.8]; 2; p=0.06). Overall, the uncertainty principle was upheld, with 44% of randomised trials favouring standard treatments and 56% innovative treatments (p=0.17); mean and median preference evaluation scores were 3.7 (1.0) and 4. However, when the analysis was done according to the source of funding, studies funded by non-profit organisations maintained equipoise favouring new therapies over standard ones (47% vs 53%; p=0.608) to a greater extent than randomised trials supported solely or in part by profit-making organisations (74% vs 26%; p=0.004). INTERPRETATION: The reported bias in research sponsored by the pharmaceutical industry may be a consequence of violations of the uncertainty principle. Sponsors of clinical trials should be encouraged to report all results and to choose appropriate comparative controls.
BACKGROUND: The antiplatelet drug clopidogrel is a new thienopyridine derivative whose mechanism of action and chemical structure are similar to those of ticlopidine. The estimated incidence of ticlopidine-associated thrombotic thrombocytopenic purpura is 1 per 1600 to 5000 patients treated, whereas no clopidogrel-associated cases were observed among 20,000 closely monitored patients treated in phase 3 clinical trials and cohort studies. Because of the association between ticlopidine use and thrombotic thrombocytopenic purpura and other adverse effects, clopidogrel has largely replaced ticlopidine in clinical practice. More than 3 million patients have received clopidogrel. We report the clinical and laboratory findings in 11 patients in whom thrombotic thrombocytopenic purpura developed during or soon after treatment with clopidogrel. METHODS: The 11 patients were identified by active surveillance by the medical directors of blood banks (3 patients), hematologists (6), and the manufacturer of clopidogrel (2). RESULTS: Ten of the 11 patients received clopidogrel for 14 days or less before the onset of thrombotic thrombocytopenic purpura. Although 10 of the 11 patients had a response to plasma exchange, 2 required 20 or more exchanges before clinical improvement occurred, and 2 had relapses while not receiving clopidogrel. One patient died despite undergoing plasma exchange soon after diagnosis. CONCLUSIONS: Thrombotic thrombocytopenic purpura can occur after the initiation of clopidogrel therapy, often within the first two weeks of treatment. Physicians should be aware of the possibility of this syndrome when initiating clopidogrel treatment.
BACKGROUND: A multidisciplinary panel representing various stakeholders in the health care delivery and oncology services marketplace was convened to develop specific criteria for healthcare purchasers to consider when evaluating the structures and processes of health plans. These rank ordered criteria also can be used by oncologic service providers and health plan designers as a yardstick for the services they offer. METHODS: A multidisciplinary 31-member Task Force was assembled by the Kerr L. White Institute and the American Cancer Society in March 1997. Task Force members were selected for their ability to offer expert insight as purchasers, suppliers, policymakers, consumers, or stakeholders in the health care marketplace. A preference-weighted majority voting rule was used to identify the three most important recommendations of the 10 that were generated through a modified Delphi technique. To test the practicality of the top three recommendations, leaders of large managed care organizations (MCOs) were surveyed; the results of this survey then were compared with the results of the Task Force survey. RESULTS: The three most important recommendations from the Task Force were that health plans provide access to: 1) comprehensive cancer care, 2) preventive and screening services, and 3) second opinions and treatment options supported by scientific evidence. The difference between the responses of the Task Force and the MCOs was that MCOs placed the highest importance on evidence-based decision-making, with their next three rankings coinciding with those identified by the Task Force. CONCLUSIONS: The value of these summary recommendations will be realized through their use by both purchasers and suppliers to influence the structure and content of the delivery of oncologic services.
PURPOSE: To compare luteinizing hormone-releasing hormone (LHRH) agonists with orchiectomy or diethylstilbestrol, and to compare antiandrogens with any of these three alternatives. DATA SOURCES: A search of the MEDLINE, Cancerlit, EMBASE, and Cochrane Library databases from 1966 to March 1998 and Current Contents to 24 August 1998 for articles comparing the outcomes of the specified treatments. The search was limited to studies on prostatic neoplasms in humans. Total yield was 1477 studies. STUDY SELECTION: Reports of efficacy outcomes were limited to randomized, controlled trials. Twenty-four trials involving more than 6600 patients, phase II studies that reported on withdrawals from therapy (the most reliable indicator of adverse effects), and all studies reporting on quality of life were abstracted. DATA EXTRACTION: Two independent reviewers abstracted each article by following a prospectively designed protocol. The meta-analysis combined data on 2-year overall survival by using a random-effects model and; reported results as a hazard ratio relative to orchiectomy. DATA SYNTHESIS: Ten trials of LHRH agonists involving 1908 patients reported no significant difference in overall survival. The hazard ratio showed LHRH agonists to be essentially equivalent to orchiectomy (hazard ratio, 1.1262 [corrected] [95% CI, 0.915 to 1.386]). There was no evidence of difference in overall survival among the LHRH agonists, although CIs were wider for leuprolide (hazard ratio, 1.0994 [CI, 0.207 to 5.835]) and buserelin (hazard ratio, 1.1315 [CI, 0.533 to 2.404]) than for goserelin (hazard ratio, 1.1172 [CI, 0.898 to 1.390]). Evidence from 8 trials involving 2717 patients suggests that nonsteroidal antiandrogens were associated with lower overall survival. The CI for the hazard ratio approached statistical significance (hazard ratio, 1.2158 [CI, 0.988 to 1.496]). Treatment withdrawals were less frequent with LHRH agonists (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%). CONCLUSIONS: Survival after therapy with an LHRH agonist was equivalent to that after orchiectomy. No evidence shows a difference in effectiveness among the LHRH agonists. Survival rates may be somewhat lower if a nonsteroidal antiandrogen is used as monotherapy.
BACKGROUND: Growth factor use has been shown to ameliorate chemotherapy-induced neutropenia, leading to shorter hospital stays and lower use of parenteral antibiotics, two costly areas of cancer treatment. Prior reports on pediatric patients have shown evidence of cost savings in some studies, but no such evidence in others. In this study a retrospective analysis compared the costs of inpatient supportive care for pediatric patients with T-cell leukemia and advanced lymphoblastic lymphoma enrolled in a Pediatric Oncology Group trial. PROCEDURE: Patients 1-22 years of age were randomized to receive either granulocyte colony-stimulating factor (G-CSF; n = 45) or no G-CSF (n = 43) following induction and two cycles of maintenance therapy. There were no significant differences in neutropenia-related outcomes during the induction phase. During maintenance therapy, G-CSF patients had significantly fewer days to an ANC >500 cells/microl and a trend towards fewer days of hospitalization. Data on resource utilization were tabulated from case report forms. Costs were imputed from national data on hospitalization costs, average wholesale prices of pharmaceuticals, and patient billing information from a single institution. RESULTS: Total median costs of supportive care were $34,190 for patients receiving G-CSF and $28,653 for patients not receiving G-CSF (P > 0. 05 for the cost difference). Sensitivity analyses demonstrated that the total cost difference was not statistically significant, even in scenarios that included reasonable variations in estimates of the range of the length of stay, antibiotic regimen, and dosage and cost of G-CSF. CONCLUSIONS: In the setting of pediatric leukemia, the cost of growth factor may offset potential savings from shorter hospital stays or lower antibiotic use, a finding consistent with that from the Children's Cancer Study Group.
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Amyotrophic lateral sclerosis (ALS) denotes a heterogeneous group of neurodegenerative disorders affecting upper and lower motor neurons. ALS4 is a juvenile-onset, autosomal dominant form of ALS that is characterized by slow progression, distal limb weakness and amyotrophy, and pyramidal signs associated with severe loss of motor neurons in the brain and spinal cord. The ALS4 locus was recently mapped by linkage analysis to a large genetic interval on chromosome 9q34. By undertaking extensive genetic linkage analysis, we have significantly refined the ALS4 locus to a critical interval of less than 3 cM, flanked by D9S149 and D9S1198. Previous physical mapping in this region has indicated that this critical interval spans approximately 500 kb. Seventeen putative transcripts have been localized within this interval including 7 characterized genes, 2 partially characterized genes, and 8 "anonymous" expressed sequence tags . These are therefore positional candidate genes for the ALS4 locus. We have also undertaken mutation analysis and genetic mapping to investigate and exclude candidate genes, including RING3L/ORFX and RALGDS, from a pathogenic role in ALS4.
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder affecting both children and adults that can be manifested by severe bleeding episodes. Adult ITP patients have a low rate of spontaneous remission, and symptomatic patients commonly undergo splenectomy; however, maintenance therapy may increase the rate of remission, allowing splenectomy to be avoided. Anti-D is a recently licensed treatment for ITP that has the potential to delay, and possibly avoid, the need for splenectomy. We used preliminary data from an ongoing clinical trial to evaluate the costs involved in using anti-D therapy for 1 year with the intent of avoiding the need for splenectomy. We accounted for different possible outcomes at the completion of the clinical trial. An economic model with a theoretical cohort of 100 patients was developed using the model of an ongoing clinical trial. The average wholesale price was used to determine the cost of an infusion of anti-D based on an average dose ($1,213 per infusion). The cost of splenectomy was determined by a literature review ($16,000). Costs were calculated for all known patient outcomes; where outcomes were unknown and likely to vary, all possible outcomes were accounted for (splenectomy or no splenectomy). In our theoretical cohort, 31 of 100 patients were taken off anti-D and received splenectomy, 32 of 100 were stable after receiving anti-D and would not need splenectomy, and 37 of 100 had Indeterminate outcomes after receiving anti-D. When compared with the cost of the hypothetical scenario of initially giving all 100 patients splenectomy ($1.6 million), a minimum of 47 patients would have to avoid splenectomy to result in a cost savings for our cohort of 100 patients. The group of 47 patients avoiding splenectomy would be composed of the 32 patients comprising the stable group and at least 15 of the 37 patients comprising the group with indeterminate outcomes. If all 37 of the patients in the group with indeterminate outcomes avoid splenectomy, $363,000 and 69 spleens would be saved. Our data suggest that in the phase III trial of maintenance anti-D therapy versus immediate splenectomy, anti-D therapy will be a cost-effective option if 47% or more of patients avoid splenectomy.
Hong Kong and Mainland China are undertaking health reform following recent economic fluctuations and Hong Kong's transformation to a Special Administrative Region of China in 1997. Despite spending only 4.7% of its Gross Domestic Product on health care, one third as much as in the United States, Hong Kong has developed health statistics comparable to those in leading western nations. In contrast, Mainland China's 3.6% of GDP expenditure on health is associated with health statistics and expenditures similar to those found in most developing countries. Hong Kong has adopted health care financing and organizational health systems that are commonly seen in centrally planned economies, while its economy functions as a highly capitalistic enterprise. In contrast, mainland China has integrated many features of health care systems associated with market economies, while its overall economy is largely centrally planned. In this paper we examine the policy factors associated with these disparate health systems and investigate whether they can be maintained according to the 'one country, two systems' approach that has been adopted by Chinese policy makers.
We describe genetic analysis of a large pedigree with an X-linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea (XPID), which frequently results in death during infancy or childhood. Linkage analysis mapped the XPID gene to a 17-cM interval defined by markers DXS8083 and DXS8107 on the X chromosome, at Xp11. 23-Xq13.3. The maximum LOD score was 3.99 (recombination fraction0) at DXS1235. Because this interval also harbors the gene for Wiskott-Aldrich syndrome (WAS), we investigated mutations in the WASP gene, as the molecular basis of XPID. Northern blot analysis detected the same relative amount and the same-sized WASP message in patients with XPID and in a control. Analysis of the WASP coding sequence, an alternate promoter, and an untranslated upstream first exon was carried out, and no mutations were found in patients with XPID. A C-->T transition within the alternate translation start site cosegregated with the XPID phenotype in this family; however, the same transition site was detected in a normal control male. We conclude that XPID maps to Xp11.23-Xq13.3 and that mutations of WASP are not associated with XPID.
PURPOSE: We examined the knowledge and understanding of male teenagers of the necessity for genital examination, and signs and symptoms of serious testicular pathology. Furthermore, current national guidelines for health education were reviewed to understand better the curriculum used by the educational system and to assess its effectiveness. MATERIALS AND METHODS: In 1998, a 5-question survey was administered privately and confidentially to male athletes before a sports physical examination. The athletes were 12 to 18 years old, attended middle or high school, and were sampled randomly. The National Health Education Standards benchmark for grades 9 through 11 was examined with specific attention to male self-health education standards. RESULTS: A total of 318 athletes responded revealing that 54% did not know why the genitals were examined on a sports physical examination, 45% did not use appropriate testicular protection and the majority did not respond appropriately to symptoms of serious testicular pathology. Despite the fact that 46% of respondents answered that checking for a hernia is reason for a genital examination there was no mention of tumor, infection or varicocele. Review of the benchmarks revealed no standards referring to a minimum understanding of anatomy or physiology. Generalized guidelines for high risk behaviors were provided without specific mention of testicular torsion, cancer, varicocele or sexually transmitted diseases. CONCLUSIONS: Young males are at higher risk for testicular torsion, cancer and varicocele than other age groups, and yet our population was universally unaware of these as a reason for genital examination. Furthermore, the majority did not respond appropriately to questions regarding serious testicular pathology. Review of national guidelines reveals poorly defined, nonspecific provisions for male self-health care. Therefore, we have developed a curriculum for male self-health to address this problem.
A common severe complication of human immunodeficiency virus (HIV) infection has been Pneumocystis carinii pneumonia (PCP). Recently, with increasing use of PCP prophylaxis and multidrug antiretroviral therapy, the clinical manifestations of HIV infection have changed dramatically and the predictors of inpatient mortality for PCP may have also changed. We developed a new staging system for predicting inpatient mortality for patients with HIV-associated PCP admitted between 1995 and 1997. Trained abstractors performed chart reviews of 1,660 patients hospitalized with HIV-associated PCP between 1995 and 1997 at 78 hospitals in seven metropolitan areas in the United States. The overall inpatient mortality rate was 11.3%. Hierarchically optimal classification tree analysis identified an ordered five-category staging system based on three predictors: wasting, alveolar-arterial oxygen gradient (AaPO(2)), and serum albumin level. The mortality rate increased with stage: 3.7% for Stage 1, 8.5% for Stage 2, 16.1% for Stage 3, 23.3% for Stage 4, and 49.1% for Stage 5. This new staging system may be useful for severity of illness adjustment in the current era while exploring current variation in HIV-associated PCP inpatient mortality rates among hospitals and across cities.
In the early 1990s, hospital survival among patients with human immunodeficiency virus (HIV)-related Pneumocystis carinii pneumonia (PCP) and respiratory failure was poor, approximately 20%. We examined ICU use and outcomes for patients with acute respiratory failure from PCP from 1995 to 1997. We conducted a retrospective medical record review using a random sample of 71 hospitals in seven regions of the United States. Among 1,660 patients with confirmed or presumed PCP, 155 (9%) received mechanical ventilation for respiratory failure. Factors that predicted use of mechanical ventilation, independent of severity of illness on hospital admission, included African-American ethnicity and geographic location (p </= 0.002). Hospital survival for patients receiving mechanical ventilation was 38% (95% CI 30, 46). Controlling for severity of illness, patients who were on PCP prophylaxis prior to developing PCP were less likely to survive to hospital discharge (p </= 0.02). There were no significant differences in hospital survival regardless of whether patients had received less than or more than 5 d of PCP treatment prior to respiratory failure (39 versus 29%; p = 0.5). In conclusion, from 1995 to 1997, hospital survival after PCP requiring mechanical ventilation was approximately 40%. Physicians caring for patients with severe HIV-related PCP should be aware of the improvements in outcomes for this disease before making recommendations about withholding or withdrawing ventilatory support for respiratory failure.
PURPOSE: Medical care for clinical trials is often not reimbursed by insurers, primarily because of concern that medical care as part of clinical trials is expensive and not part of standard medical practice. In June 2000, President Clinton ordered Medicare to reimburse for medical care expenses incurred as part of cancer clinical trials, although many private insurers are concerned about the expense of this effort. To inform this policy debate, the costs and charges of care for patients on clinical trials are being evaluated. In this Association of American Cancer Institutes (AACI) Clinical Trials Costs and Charges pilot study, we describe the results and operational considerations of one of the first completed multisite economic analyses of clinical trials. METHODS: Our pilot effort included assessment of total direct medical charges for 6 months of care for 35 case patients who received care on phase II clinical trials and for 35 matched controls (based on age, sex, disease, stage, and treatment period) at five AACI member cancer centers. Charge data were obtained for hospital and ancillary services from automated claims files at individual study institutions. The analyses were based on the perspective of a third-party payer. RESULTS: The mean age of the phase II clinical trial patients was 58.3 years versus 57.3 years for control patients. The study population included persons with cancer of the breast (n = 24), lung (n = 18), colon (n = 16), prostate (n = 4), and lymphoma (n = 8). The ratio of male-to-female patients was 3:4, with greater than 75% of patients having stage III to IV disease. Total mean charges for treatment from the time of study enrollment through 6 months were similar: $57,542 for clinical trial patients and $63,721 for control patients (1998 US$; P =.4) CONCLUSION: Multisite economic analyses of oncology clinical trials are in progress. Strategies that are not likely to overburden data managers and clinicians are possible to devise. However, these studies require careful planning and coordination among cancer center directors, finance department personnel, economists, and health services researchers.
BACKGROUND: Despite awareness of HIV-related tuberculosis (TB), nosocomial outbreaks of multidrug-resistant TB among HIV-infected individuals occur. OBJECTIVE: To investigate delays in TB isolation and suspicion among HIV-infected inpatients discharged with TB or Pneumocystis carinii pneumonia (PCP), common HIV-related pneumonias. DESIGN: Cohort study during 1995 to 1997. SETTING: For PCP, 1,227 persons who received care at 44 New York City, Chicago, and Los Angeles hospitals. For TB, 89 patients who received care at five Chicago hospitals. MEASUREMENTS: Two-day rates of TB isolation/suspicion. RESULTS: For HIV-related PCP, Los Angeles hospitals had the lowest 2-day rates of isolation/suspicion of TB (24.3%/26.6% vs 65.5%/66.4% for New York City and 62.8%/58.3% for Chicago, respectively; p < 0.001 for overall comparison by chi(2) test for each outcome measure). Within cities, hospital isolation/suspicion rates varied from < 35 to > 70% (p < 0.001 for interhospital comparisons in each city). The Chicago hospital with a nosocomial outbreak of multidrug-resistant TB from 1994 to 1995 isolated 60% of HIV-infected individuals who were discharged with a diagnosis of HIV-related TB and 52% discharged with HIV-related PCP, rates that were among the lowest of all Chicago hospitals in both data sets. CONCLUSION: Low 2-day rates of TB isolation/suspicion among HIV-related PCP patients were frequent. One Chicago hospital with low 2-day rates of TB isolation/suspicion among persons with HIV-related PCP also had low 2-day rates of isolation/suspicion among confirmed TB patients. That hospital experienced a nosocomial multidrug-resistant TB outbreak. Educational efforts on the benefits of early TB suspicion/isolation among HIV-infected pneumonia patients are needed.
OBJECTIVE: To compare trends in nosocomial tuberculosis (TB) prevention measures and health-care worker (HCW) tuberculin skin test (TST) conversion of hospitals with HIV-related Pneumocystis carinii pneumonia (PCP) patients and other US hospitals from 1992 through 1996. DESIGN AND SETTING: Surveys in 1992 and 1996 of 38 hospitals with PCP patients in four high-HIV-incidence cities and 136 other US hospitals from the American Hospital Association membership list. PARTICIPANTS: Twenty-seven hospitals with PCP patients and 103 other US hospitals. RESULTS: In 1992, 63% of PCP hospitals and other US hospitals had rooms meeting Centers for Disease Control and Prevention (CDC) criteria (ie, negative air pressure, six or more air exchanges per hour, and air directly vented to the outside) for acid-fast bacilli isolation; in 1996, almost 100% had such isolation rooms. Similarly, in 1992, nonfitted surgical masks were used by HCWs at 60% of PCP hospitals and 68% at other US hospitals, while N95 respirators were used at 90% of PCP hospitals and 83% of other US hospitals in 1996. There was a significant decreasing trend in TST conversion rates among HCWs at both PCP and other US hospitals; however, this trend varied among all hospitals. HCWs at PCP hospitals had a higher risk of TST conversion than those at other US hospitals (relative risk, 1.71; p < 0.0001). CONCLUSION: From 1992 through 1996, PCP and other US hospitals have made similar improvements in their nosocomial TB prevention measures and decreased their HCW TST conversion rate. These data show that most hospitals are compliant with CDC TB guidelines even before the enactment of an Occupational Safety and Health Administration TB standard.