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BACKGROUND: Multiple modern Indian hospitals operate at very low cost while meeting US-equivalent quality accreditation standards. Though US hospitals face intensifying pressure to lower their cost, including proposals to extend Medicare payment rates to all admissions, the transferability of Indian hospitals' cost advantages to US peers remains unclear. METHODS: Using time-driven activity-based costing methods, we estimate the average cost of personnel and space for an elective coronary artery bypass graft (CABG) surgery at two American hospitals and one Indian hospital (NH). All three hospitals are Joint Commission accredited and have reputations for use of modern performance management methods. Our case study applies several analytic steps to distinguish transferable from non-transferable sources of NH's cost savings. RESULTS: After removing non-transferable sources of efficiency, NH's residual cost advantage primarily rests on shifting tasks to less-credentialed and/or less-experienced personnel who are supervised by highly-skilled personnel when perceived risk of complications is low. NH's high annual CABG volume facilitates such supervised work "downshifting." The study is subject to limitations inherent in case studies, does not account for the younger age of NH's patients, or capture savings attributable to NH's negligible frequency of re-admission or post-acute care facility placement. CONCLUSIONS: Most transferable bases for a modern Indian hospital's cost advantage would require more flexible American states' hospital and health professional licensing regulations, greater family participation in inpatient care, and stronger support by hospital executives and clinicians for substantially lowering the cost of care via regionalization of complex surgeries and weekend use of costly operating rooms.
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Puente de Arteria Coronaria/economía , Enfermedad de la Arteria Coronaria/cirugía , Procedimientos Quirúrgicos Electivos/economía , Costos de Hospital , Medicare/economía , Transferencia de Pacientes/economía , Enfermedad de la Arteria Coronaria/economía , Femenino , Humanos , India , Masculino , Estados UnidosRESUMEN
BACKGROUND: Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of 'platinum-sensitive' ovarian cancer and has been shown to improve progression-free survival (PFS). PATIENTS AND METHODS: ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here. RESULTS: After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch-Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: -0.09 to 9.74 months). CONCLUSIONS: Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken.
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Neoplasias Ováricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Quinazolinas/uso terapéuticoRESUMEN
We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin-fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatin+capecitabine (Xelox, 41%), 102 received OxMdG+cetuximab (OxMdG+C, 13%) and 166 Xelox+cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdG+C and Xelox+C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xelox+cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P=0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P=0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Capecitabina , Cetuximab , Neoplasias Colorrectales/secundario , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Estudios de Seguimiento , Humanos , Leucovorina/administración & dosificación , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Oxaloacetatos , Pronóstico , Tasa de Supervivencia , Resultado del Tratamiento , Reino UnidoRESUMEN
Management accounting systems designed decades ago no longer provide timely, relevant information for companies in today's highly competitive environment. New operational control and performance measurement systems are recognizing the importance of direct measurement of quality, manufacturing lead times, flexibility, and customer responsiveness, as well as more accurate measures of the actual costs of consumed resources. Activity-based cost systems can assign the costs of indirect and support resources to the specific products and activities that benefit from these resources. Both operational control and activity-based systems represent new opportunities for improved managerial information in complex, technologically advanced environments.
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Dimethyl sulfoxide (DMSO) opens the blood-brain barrier of mice to the enzymatic tracer horseradish peroxidase. A single injection of horseradish peroxidase in 10 to 15 percent DMSO into the tail vein along with 10 to 15 percent DMSO delivered intraperitoneally allowed horseradish peroxidase to fill the extracellular clefts throughout the brain within 2 hours. In the absence of DMSO, peroxidase failed to enter brain parenchyma except through the circumventricular organs. Opening of the blood-brain barrier by DMSO is reversible. Dimethyl sulfoxide stimulated the pinocytosis of horseradish peroxidase by the cerebral endothelium; the peroxidase was then directed to lysosomal dense bodies for degradation. Vesicular transport of horseradish peroxidase from the luminal to the abluminal wall of the endothelial cell was not observed. Dimethyl sulfoxide did not alter the morphology of endothelial cells or brain parenchyma.
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Barrera Hematoencefálica/efectos de los fármacos , Dimetilsulfóxido/farmacología , Animales , Química Encefálica , Dimetilsulfóxido/administración & dosificación , Endotelio/efectos de los fármacos , Espacio Extracelular/análisis , Femenino , Peroxidasa de Rábano Silvestre/análisis , Peroxidasa de Rábano Silvestre/metabolismo , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Ratones , Pinocitosis/efectos de los fármacosRESUMEN
BACKGROUND: The prostate-specific antigen test was approved by the U.S. Food and Drug Administration in 1986 to monitor the disease status in patients with prostate cancer and, in 1994, to aid in prostate cancer detection. However, after 1986, the test was performed on many men who had not been previously diagnosed with prostate cancer, apparently resulting in the diagnosis of a substantial number of early tumors. Our purpose is to provide insight into the effect of screening on prostate cancer rates. Detailed data are presented for whites because the size of the population allows for calculating statistically reliable rates; however, similar overall trends are seen for African-Americans and other races. METHODS: Prostate cancer incidence data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program and mortality data from the National Center for Health Statistics were analyzed. RESULTS/CONCLUSIONS: The following findings are consistent with a screening effect: 1) the recent decrease since 1991 in the incidence of distant stage disease, after not having been perturbed by screening; 2) the decline in the incidence of earlier stage disease beginning the following year (i.e., 1992); 3) the recent increases and decreases in prostate cancer incidence and mortality by age that appear to indicate a calendar period effect; and 4) trends in the incidence of distant stage disease by tumor grade and trends in the survival of patients with distant stage disease by calendar year that provide suggestive evidence of the tendency of screening to detect slower growing tumors. IMPLICATIONS: The decline in the incidence of distant stage disease holds the promise that testing for prostate-specific antigen may lead to a sustained decline in prostate cancer mortality. However, population data are complex, and it is difficult to confidently attribute relatively small changes in mortality to any one cause.
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Tamizaje Masivo , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/epidemiología , Negro o Afroamericano/estadística & datos numéricos , Distribución por Edad , Anciano , Anciano de 80 o más Años , Humanos , Incidencia , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Mortalidad/tendencias , Estadificación de Neoplasias , Vigilancia de la Población , Neoplasias de la Próstata/etnología , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Programa de VERF , Tasa de Supervivencia , Estados Unidos/epidemiología , Población Blanca/estadística & datos numéricosRESUMEN
BACKGROUND: During the 1980s, the incidence of primary malignant brain and other central nervous system tumors (hereafter called brain cancer) was reported to be increasing among all age groups in the United States, while mortality was declining for persons younger than 65 years. We analyzed these data to provide updates on incidence and mortality trends for brain cancer in the United States and to examine these patterns in search of their causes. METHODS: Data on incidence, overall and according to histology and anatomic site, and on relative survival were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute for 1975 through 1995. Mortality data were obtained from the National Center for Health Statistics. Medicare procedure claims from the National Cancer Institute's SEER-Medicare database were used for imaging trends. Statistically significant changes in incidence trends were identified, and annual percent changes were computed for log linear models. RESULTS/CONCLUSIONS: Rates stabilized for all age groups during the most recent period for which SEER data were available, except for the group containing individuals 85 years of age or older. Mortality trends continued to decline for the younger age groups, and the steep increases in mortality seen in the past for the elderly slowed substantially. Patterns differed by age group according to the site and grade of tumors between younger and older patients. During the last decade, use of computed tomography scans was relatively stable for those 65-74 years old but increased among those 85 years old or older. IMPLICATIONS: Improvements in diagnosis and changes in the diagnosis and treatment of elderly patients provide likely explanations for the observed patterns in brain cancer trends.
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Neoplasias del Sistema Nervioso Central/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Biopsia con Aguja/métodos , Neoplasias Encefálicas/epidemiología , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/mortalidad , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mortalidad/tendencias , Técnicas Estereotáxicas , Tasa de Supervivencia , Tomografía Computarizada por Rayos XRESUMEN
Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.
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Antineoplásicos/uso terapéutico , Neoplasias/diagnóstico , Evaluación de Resultado en la Atención de Salud/métodos , Biomarcadores de Tumor , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Endoscopía , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Radiografía , Estudios Retrospectivos , Resultado del Tratamiento , UltrasonografíaRESUMEN
1. The use of 1,N6-ethenoadenosine 5'-triphosphate (epsilon-ATP), a synthetic, fluorescent analog of ATP, by whole rat liver mitochondria and by submitochondrial particles produced via sonication has been studied. 2. Direct [3H]adenine nucleotide uptake studies with isolated mitochondria, indicate the epsilon-[3H]ATP is not transported through the inner membrane by the adenine nucleotide carrier and is therefore not utilized by the 2,4-dinitrophenol-sensitive F1-ATPase (EC 3.6.1.3) that functions in oxidative phosphorylation. However, epsilon-ATP is hydrolyzed by a Mg2+-dependent, 2,4-dinitrophenol-insensitive ATPase that is characteristic of damaged mitochondria. 3. epsilon-ATP can be utilized quite well by the exposed F1-ATPase of sonic submitochondrial particles. This epsilon-ATP hydrolysis activity is inhibited by oligomycin and stimulated by 2,4-dinitrophenol. The particle F1-ATPase displays similar Km values for both ATP and epsilon-ATP; however, the V with ATP is approximately six times greater than with epsilon-ATP. 4. Since epsilon-ATP is a capable substrate for the submitochondrial particle F1-ATPase, it is proposed that the fluorescent properties of this ATP analog might be employed to study the submitochondrial particle F1-ATPase complex, and its response to various modifiers of oxidative phosphorylation.
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Adenosina Trifosfatasas/metabolismo , Adenosina Trifosfato/análogos & derivados , Etenoadenosina Trifosfato/metabolismo , Mitocondrias Hepáticas/metabolismo , Translocasas Mitocondriales de ADP y ATP/metabolismo , Nucleotidiltransferasas/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Transporte Biológico , Fraccionamiento Celular , Dinitrofenoles/farmacología , Masculino , Oligomicinas/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Ratas , Especificidad por SustratoRESUMEN
Twenty patients with extravasation of anthracyclines were treated on a single-arm pilot study with topical 99% dimethyl sulfoxide (DMSO) and observed for 3 months with regular examinations and photographs. DMSO was applied to approximately twice the area affected by the extravasation and allowed to air dry. This was repeated every six hours for 14 days. The initial signs of extravasation included swelling in 17 patients, erythema in 15, and pain in 12. The median area of damage was 8.25 cm2 and a median of 25 minutes elapsed between extravasation and application of DMSO with one patient not treated until seven days postextravasation. Sixteen patients were observed for 3 months, two died of disease earlier after receiving 2 weeks of DMSO and three days of DMSO, respectively, and two were lost to follow-up having received one day and five days of DMSO. In no patient did extravasation progress to ulceration or require surgical intervention, suggesting with 95% confidence a true ulceration rate of between 1% and 17%. At 3 months there was no sign of residual damage in six patients, while a pigmented indurated area remained in ten. Two patients had a recall reaction with increased pain at the extravasation site when further intravenous (IV) doxorubicin was administered. The only toxicities of DMSO included a burning feeling on application subsequently associated with itch, erythema, and mild scaling. Blisters occurred in four patients. Six patients reported a characteristic breath odor associated with DMSO. Topical DMSO appears to be a safe and effective treatment for anthracycline extravasation.
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Antibióticos Antineoplásicos , Dimetilsulfóxido/uso terapéutico , Extravasación de Materiales Terapéuticos y Diagnósticos/tratamiento farmacológico , Administración Tópica , Dimetilsulfóxido/administración & dosificación , Humanos , Proyectos Piloto , Estudios ProspectivosRESUMEN
Preclinical data suggest that some new anticancer agents directed at novel targets demonstrate tumor growth inhibition but not tumor shrinkage. Such cytostatic agents may offer clinical benefits for patients in the absence of tumor shrinkage. In addition, lower doses of some of these agents may be just as effective as higher doses, implying that toxicity may not be an ideal end point for dose finding. Because of these factors, the sequence and design of traditional phase I, II, and III trials used for cytotoxic agents (which typically shrink tumors and in a dose-dependent manner) may not be appropriate for cytostatic agents. This article discusses options for modifying trial designs to accommodate cytostatic agents. Examples are given where these options have been tried or are currently being tried. Recommendations given for choosing among the trial designs depend on what is known preclinically about the agents (eg, does one have a validated and reproducible biologic end point that can be used to guide a dose escalation?), what is known about the patient population being studied (eg, does one have a well-documented historical progression-free survival rate at 1 year for comparison with the experience of the new agent?), and the numbers of agents and patients available for participation in trials. Planned and ongoing trials will test the utility of some of these new approaches.
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Antineoplásicos , Evaluación de Medicamentos/métodos , Proyectos de Investigación , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Humanos , Tamaño de la MuestraRESUMEN
PURPOSE: To develop evidence-based guidelines for (1) prostate re-biopsy after radiation and (2) radiation therapy with rising prostate-specific antigen (PSA) levels after radical prostatectomy in the management of patients with localized prostatic cancer. DESIGN: The American Society of Therapeutic Radiology and Oncology (ASTRO) challenged a multidisciplinary consensus panel to address consensus on specific issues in each of the two topics. Four well-analyzed patient data sets were presented for review and questioning by the panel. The panel sought criteria that would be valid for patients in standard clinical practice as well as for patients enrolled in clinical trials. Subsequent to an executive session that followed these presentations, the panel presented its consensus guidelines. RESULTS AND CONCLUSIONS: Based on the data presented, the prostate re-biopsy negative rates ranged from 62% to 80% for patients with stage T1-2 tumors. The panel judged that prostate re-biopsy is not necessary as standard follow-up care and that the absence of a rising PSA level after radiation therapy is the most rigorous end point of total tumor eradication. Further, the panel judged that re-biopsy may be an important research tool. Based on the data presented, the long-term (5 years or more) PSA remission rate after salvage radiation therapy ranges from 27% to 45%. The panel requested results from prospective randomized trials to evaluate optimally this information. The panel judged that the total dose of radiation should be 64 Gy or slightly higher and that, in patients with or without radiation therapy, there is no standard role for androgen suppressant therapy for rising PSA values after prostatectomy.
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Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/radioterapia , Biopsia , Medicina Basada en la Evidencia , Humanos , Masculino , Prostatectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Dosificación Radioterapéutica , RetratamientoRESUMEN
Ninety-three stage III and IV patients with non-Hodgkin's lymphoma were randomized to either high dose CVP (cyclophosphamide 1500 mg/m2 i.v. day 1, vincristine 1.4 mg/m2 day 1, and prednisone 40 mg/m2 orally days 1-10) or high dose CAVP (cyclophosphamide 1000 mg/m2 i.v. day 1, doxorubicin 45 mg/m2 i.v. day 1, vincristine and prednisone as above). Overall, the complete response (CR) rates were similar (CVP 51%, CAVP 51%). Patients with the International Working Formulation diffuse large cell lymphoma had significantly higher CR with CAVP. No difference in CR duration was detected between the two regimens. CRs were durable with 68% of diffuse and 86% of diffuse large cell complete responders alive and disease free at 7 years. Survival was similar with both regimens except for patients with diffuse large cell lymphoma who survived longer with CAVP. Both regimens were equitoxic with neutropenia less than 1.0 x 10(9)/liter in 36% of courses, infections in 15% of courses, and fatal infections in three patients. These intermittent high dose cyclophosphamide equitoxic regimens produced durable responses. However, the doxorubicin-containing regimen is superior in diffuse large cell lymphoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma no Hodgkin/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Estudios de Seguimiento , Hematopoyesis/efectos de los fármacos , Humanos , Prednisona/administración & dosificación , Prednisona/efectos adversos , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
INTRODUCTION: Coronary artery bypass graft (CABG) surgery is a well-established, commonly performed treatment for coronary artery disease--a disease that affects over 10% of US adults and is a major cause of morbidity and mortality. In 2005, the mean cost for a CABG procedure among Medicare beneficiaries in the USA was $32, 201 ± $23,059. The same operation reportedly costs less than $2000 to produce in India. The goals of the proposed study are to (1) identify the difference in the costs incurred to perform CABG surgery by three Joint Commission accredited hospitals with reputations for high quality and efficiency and (2) characterise the opportunity to reduce the cost of performing CABG surgery. METHODS AND ANALYSIS: We use time-driven activity-based costing (TDABC) to quantify the hospitals' costs of producing elective, multivessel CABG. TDABC estimates the costs of a given clinical service by combining information about the process of patient care delivery (specifically, the time and quantity of labour and non-labour resources utilised to perform each activity) with the unit cost of each resource used to provide the care. Resource utilisation was estimated by constructing CABG process maps for each site based on observation of care and staff interviews. Unit costs were calculated as a capacity cost rate, measured as a $/min, for each resource consumed in CABG production. Multiplying together the unit costs and resource quantities and summing across all resources used will produce the average cost of CABG production at each site. We will conclude by conducting a variance analysis of labour costs to reveal opportunities to bend the cost curve for CABG production in the USA. ETHICS AND DISSEMINATION: All our methods were exempted from review by the Stanford Institutional Review Board. Results will be published in peer-reviewed journals and presented at scientific meetings.
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Puente de Arteria Coronaria/economía , Enfermedad de la Arteria Coronaria/cirugía , Costos y Análisis de Costo/métodos , Costos de Hospital , Protocolos Clínicos , Humanos , India , Estados UnidosRESUMEN
Plasma and cerebrospinal fluid (CSF) kinetics of diaziquone, 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ), were evaluated after intravenous injection in patients with implanted Ommaya reservoirs. After a 30-min infusion plasma disappearance was very rapid, with a disposition half-life of 2 to 6 min and on elimination half-life of 25 to 35 min. Area under the concentration-time curve for CSF was 22% to 42% of the corresponding plasma area. Based upon total plasma AZQ concentration, volume of distribution for AZQ was 2.0 to 10.0 l/m2. Plasma binding of AZQ was 79% in one normal subject. When the effect of plasma binding is considered, distribution volumes are more plausible and it appears that free plasma AZQ is completely available to the CSF.
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Antineoplásicos/metabolismo , Aziridinas/metabolismo , Azirinas/metabolismo , Benzoquinonas , Adulto , Antineoplásicos/sangre , Antineoplásicos/líquido cefalorraquídeo , Aziridinas/sangre , Aziridinas/líquido cefalorraquídeo , Femenino , Humanos , Cinética , Masculino , Unión ProteicaRESUMEN
Ten patients with brain tumors and indwelling ventricular reservoirs were pretreated with 5% to 10% dimethyl sulfoxide (DMSO) (intravenous, oral, or both) and were then treated with 1.0 to 1.25 gm/m2 cyclophosphamide (CYC). All patients were also on anticonvulsants and dexamethasone. CYC and alkylating activity (alk act) in plasma and concomitant ventricular cerebrospinal fluid (CSF) were measured by gas chromatography and p-nitrobenzyl pyridine assay. CYC entered the CSF without difficulty and was lost from CSF more slowly than from plasma. Alk act did not enter CSF as well as did CYC. DMSO did not alter any measured aspect of CYC or alk act disposition. Specifically, it did not alter the CYC plasma half-life (t1/2), CSF t1/2, peak CSF: peak plasma CYC concentration ratio, or the urinary excretion of CYC. DMSO did not alter the plasma t1/2 or urinary excretion of alk act or the peak CSF:peak plasma concentration ratio of alk act. Our data show reduced plasma t1/2 of CYC and increased plasma and urinary alk act. This may reflect tht effect of long-term therapy with anticonvulsants or steroids.
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Neoplasias Encefálicas/tratamiento farmacológico , Ciclofosfamida/metabolismo , Dimetilsulfóxido/uso terapéutico , Adulto , Anciano , Ciclofosfamida/líquido cefalorraquídeo , Ciclofosfamida/uso terapéutico , Dimetilsulfóxido/administración & dosificación , Dimetilsulfóxido/efectos adversos , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Cinética , Masculino , Persona de Mediana EdadRESUMEN
We have compared the regulation of adenylate cyclase activity in membrane fractions from C6 glioma cells and in monolayer cultures of C6 cells that had been permeabilized with saponin. Guanine nucleotides (GTP and GTP gamma S) and isoproterenol increase adenylate cyclase activity in C6 membranes and in permeabilized C6 cells. In C6 membranes, guanine nucleotides activate adenylate cyclase in the presence or absence of isoproterenol; in permeabilized cells, however, guanine nucleotides increase adenylate cyclase activity only in the presence of isoproterenol. We suggest that the properties of the permeabilized cells more closely resemble those of intact cells, and that some component which is present in permeabilized cells but is lost following cell disruption may be important for the normal regulation of adenylate cyclase activity.
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Adenilil Ciclasas/metabolismo , Permeabilidad de la Membrana Celular , Glioma/enzimología , Nucleótidos de Guanina/farmacología , Línea Celular , Permeabilidad de la Membrana Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Guanosina 5'-O-(3-Tiotrifosfato) , Guanosina Trifosfato/análogos & derivados , Guanosina Trifosfato/farmacología , Isoproterenol/farmacología , Saponinas/farmacología , Tionucleótidos/farmacologíaRESUMEN
Back supports are often used to minimize or prevent complications of osteoporosis. Nevertheless, the few related studies to date reveal that the currently available thoracolumbar and lumbosacral supports have substantial limitations, including (1) poor compliance because of discomfort or restricted motion, (2) expense, (3) unacceptable cosmetic and aesthetic appearance, and (4) medical contraindications to the use of rigid supports. We report the initial results of a clinical trial of the Posture Training Support (a thoracolumbar support) in 29 women and 1 man with osteoporosis or osteopenia of the spine (ages 37 to 87 years), who were referred because of back pain or kyphosis. We hypothesize that this inexpensive, unobtrusive device promotes improvement in posture and reduces back pain either by acting as a proprioceptive reinforcer or by producing a force posteriorly below the inferior angles of the scapulae and thus decreasing the anterior compressive forces that are commonly exerted on the spine. Among the 23 patients who reported substantial back pain before use of the support, relief of the pain was "significant" in 17 and minimal in 6. Nineteen patients noted improvement in their posture. No patient reported worsening of back pain or posture, nor did any patient discontinue use of the device for cosmetic reasons, discomfort, or other complaints. Four patients previously could not tolerate other back supports, and 14 had previously used other supports without substantial improvement. These preliminary results suggests that the Posture Training Support may be of considerable symptomatic and prophylactic value to patients with osteoporosis who cannot tolerate conventional back supports.
Asunto(s)
Dolor de Espalda/terapia , Tirantes , Osteoporosis/rehabilitación , Postura , Adulto , Anciano , Anciano de 80 o más Años , Dolor de Espalda/etiología , Diseño de Equipo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/complicaciones , Osteoporosis Posmenopáusica/complicaciones , Osteoporosis Posmenopáusica/rehabilitación , Cooperación del Paciente , Estudios ProspectivosRESUMEN
OBJECTIVE: To determine the effect of application of back supports on back strength in subjects with osteoporosis. DESIGN: In a prospective, randomized, controlled study, we compared compliance and evaluated changes in back strength in 45 women with osteoporosis who were older than 40 years of age and were randomly assigned to one of three groups: (1) postural exercise only, (2) postural exercise and a conventional thoracolumbar support, or (3) postural exercise and a Posture Training Support (PTS) (a weighted kypho-orthosis). MATERIAL AND METHODS: Of the 45 study participants, 15 were assigned to a PTS group, 15 to conventional thoracolumbar support, and 15 to no orthosis. All subjects were instructed in basic body mechanics and postural exercises. Back extensor strength, grip strength, and patient's physical activity were measured at baseline and at subsequent 8-week intervals for a 16-week period. Each patient's compliance during the study period was also recorded. RESULTS: compliance was poor among the thoracolumbar group; only 5 of the 15 subjects completed the study (P<0.001), in comparison with 11 of the 15 patients in the control group and all 15 in the PTS group. Analysis revealed statistically significant mean increases in back strength in the PTS group (23%) and the control group (13%) and a nonsignificant increase in the thoracolumbar group (15%), although poor compliance in the thoracolumbar group yielded insufficient power to detect a significant difference in this group. No statistically significant difference was found between the improvements in the PTS and control groups, possibly because of the small sample size in this pilot study. One patient who wore the PTS for only 4 hours a day rather than 8 hours had the largest percentage increase in back extensor strength of this group (78%). At 16 weeks, decreases in back strength of more than 5% below the initial measurements were noted in 1 of 11 subjects (9%) who completed the control arm of the study, 2 of 14 (14%) who completed the PTS arm, and 2 of 5 (40%) who completed the thoracolumbar arm. CONCLUSION: Compliance with use of the PTS was better than that with the thoracolumbar support. Back extensor strength may increase in patients who comply with the PTS and postural exercise program. We caution, however, that this pilot study requires replication in a larger series to determine the clinical and statistical generalizability of these findings to a wider population.
Asunto(s)
Dorso/fisiopatología , Tirantes , Músculo Esquelético/fisiopatología , Osteoporosis/fisiopatología , Osteoporosis/terapia , Anciano , Anciano de 80 o más Años , Terapia por Ejercicio , Femenino , Humanos , Persona de Mediana Edad , Proyectos Piloto , Estudios ProspectivosRESUMEN
Glioblastoma multiforme is composed of multiple cellular compartments with different morphologic, kinetic, metabolic, vascular, and genetic properties. Optimal therapy may consist of a variety of therapeutic strategies designed for individual compartments, administered in close temporal relation. These concepts may turn out to be valid for other solid tumors as well. Microwave-induced hyperthermia can be used to treat metabolically quiescent, relatively hypoxic, nondividing cells (Go) otherwise resistant to radiation and chemotherapy. Similarly, polychemotherapy can treat a broad spectrum of cell types if the blood-brain barrier can be circumvented. Radical surgery, repetitively applied, can be safely used to "set up" experimental agents if the operation microscope and laser are employed. A consecutive series of 74 adult patients with malignant astrocytoma were treated with primary resection, radiation therapy, and 1,3,-bis(2 chloroethyl) 1 nitrosourea chemotherapy. At recurrence, all patients were offered reoperation with the microscope and the laser prior to administration of phase-I agents--hyperthermia via an implantable miniature microwave antenna (6 cases); aziridinylbenzoquinone chemotherapy (13 cases); and blood-brain barrier reversal with dimethyl sulfoxide (DMSO) and polychemotherapy (9 cases). It was concluded that temperatures of 45 degrees C could be safely achieved and human tumors could not efficiently dissipate heat; that DMSO plus drug therapy could be tolerated but blood-brain barrier reversal demonstrated by us in animals could not be shown in humans; and that aggressive multimodality therapy and reoperation could produce a 40% 2-year survival rate for patients younger than 40 years.