Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Surrogate variables analysis”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

591 records · Page 33Linked to original sources
PubMedDate not supplied

Nutrition support in acute pancreatitis: a systematic review of the literature.

BACKGROUND: Failure to use the gastrointestinal (GI) tract in patients with acute pancreatitis may exacerbate the stress response and disease severity, leading to greater incidence of complications and prolonged hospitalization. The objectives of this study were to determine the optimum route for nutrition support, whether nutrition therapy is better than no artificial nutrition support, whether specific additives to enteral or parenteral therapy can further enhance their efficacy, and whether methodologic differences in delivery of enteral nutrition (EN) influence tolerance. METHODS: A computerized search was performed of MEDLINE, Cochrane database, EMBASE, and reference lists of pertinent review articles for prospective randomized trials in adult patients with acute pancreatitis that evaluated interventions with nutrition therapy. Primary outcome data and surrogate endpoint parameters (for nutrition indices, stress markers, and measures of the inflammatory/immune response) were extracted in duplicate independently. Where appropriate, meta-analysis was performed by random-effects model. RESULTS: From 119 articles screened, 27 randomized controlled trials were included and analyzed. In patients admitted for acute pancreatitis, meta-analysis of 7 trials showed that use of EN was associated with a significant reduction in infectious morbidity (risk ratio [RR] = 0.46; 95% confidence interval [CI], 0.29 - 0.74; p = .001) and hospital length of stay (LOS; weighted mean difference [WMD] = -3.94; 95% CI, -5.86 to -2.02; p < .0001), a trend toward reduced organ failure (RR = 0.59; 95% CI, 0.28-1.27; p = .18), with no effect on mortality (RR = 0.88; 95% CI, 0.43-1.79; p = .72) when compared with use of parenteral nutrition (PN). Results from individual studies suggest that EN in comparison to PN reduces oxidative stress, hastens resolution of the disease process, and costs less. Insufficient data exist to determine whether EN improves outcome over standard therapy (no artificial nutrition support) in patients admitted for acute pancreatitis. However, in those patients requiring surgery for complications of acute pancreatitis, meta-analysis of 2 trials indicates that provision of EN postoperatively may reduce mortality (RR = 0.26; 95% CI, 0.06 - 1.09; p = .06) compared with standard therapy. PN provided early within 24 hours of admission was shown to worsen outcome, whereas PN provided later after full-volume resuscitation appeared to improve outcome when compared with standard therapy. In early individual studies, specific supplements added to EN, such as arginine, glutamine, omega-3 polyunsaturated fatty acids, and probiotics, may be associated with a positive impact on patient outcome in acute pancreatitis, compared with EN alone without the supplements, but studies are too few to make strong treatment recommendations. Supplementation of PN with parenteral glutamine was shown to reduce oxidative stress and improve patient outcome (reduced duration of nutrition therapy and decreased hospital LOS) compared with PN alone in patients with acute pancreatis. A wide range of tolerance to EN exists, irrespective of known influences such as mode (continuous vs bolus) and level of infusion within the GI tract (gastric vs postpyloric). CONCLUSIONS: Patients with acute severe pancreatitis should begin EN early because such therapy modulates the stress response, promotes more rapid resolution of the disease process, and results in better outcome. In this sense, EN is the preferred route and has eclipsed PN as the new "gold standard" of nutrition therapy. When PN is used, it should be initiated after 5 days. The favorable effect of both EN and PN on patient outcome may be further enhanced by supplementation with modulators of inflammation and systemic immunity. Individual variability allows for a wide range of tolerance to EN, even in severe pancreatitis.

Acute Disease↗
PubMed2005

Ground reaction forces associated with an effective elementary school based jumping intervention.

BACKGROUND: Mechanical loading during childhood plays a critical role in normal growth and development of the skeleton. Ground reaction forces (GRFs) may provide a surrogate measure for the strain experienced by bone on landing and at take off. However, there appear to be no paediatric studies that assess GRFs across a variety of loading activities. OBJECTIVES: To measure biomechanical variables in commonly performed childhood activities used in an elementary physical education intervention study which augmented bone health in boys and girls. METHODS: Maximal GFR, maximal rates of force, and time to maximum force were measured for 12 different jumping activities on a force platform. The jumps measured were drop jumps from 10, 30, and 50 cm, all followed by a plyometric jump, submaximal and maximal jumping jacks, alternating feet jump, counter movement jumps, and side to side jumps over 10 and 20 cm foam barriers. The subjects were 70 children (36 boys and 34 girls), 8.3-11.7 years old. RESULTS: Subjects ranged in height from 128.4 to 172.6 cm and had a mass of 25.0-57.0 kg. Mean (SD) for vertical jump was 24.2 (5.5) cm and 135.2 (16.6) cm for standing long jump. The children engaged in loaded physical activity 5.7 (5.3) hours a week, on average. The highest mean maximal GRFs, normalised for body weight (BW), were generated from the plyometric portion of the drop jumps and the counter movement jump (about 5 times BW) compared with 3.5 times BW for jumping jacks. Similarly, the highest rates of change in force were 514 times BW/s for the drop jump from 10 cm and 493 times BW/s for the counter movement jump. CONCLUSIONS: Simple jumps requiring minimal equipment produce GRFs of 3.5-5 times BW and rates of force of around 500 times BW/s. As children appear to attenuate higher impact forces when jumping from increased heights, it cannot be assumed that merely increasing the height of the jump will necessarily "progress" the exercise intervention.

Biomechanical Phenomena↗
PubMedDate not supplied

Nasal nitric oxide: a comparison of measurement techniques.

Nasal nitric oxide measurement may be a surrogate marker of upper airway inflammation. There is, however, no standardized measurement technique; and this led us to examine measurement techniques for acceptability and reproducibility. In five subjects we examined the flow dependence of nasal NO. In 13 healthy volunteers, nasal NO was measured on-line by five methods: 1) Tidal nasal and oral breathing: NO sampling during exclusive nasal followed by exclusive oral tidal breathing; 2) Fixed flow exhalation: NO sampling during exclusive nasal followed by exclusive oral exhalation at 100 mL/second from total lung capacity; 3) Nasal-oral aspiration: air aspirated from the mouth via both nares at 100 mL/second with glottis closure; 4) Aspiration from one nares: air aspirated from one nares at 3.3 mL/second using nitric oxide analyzer sample line with velum closure; 5) Nasal Insufflation: NO sampled at one nares as air insufflated into the other nares at a flow of 100 mL/second with velum closure. Acceptability of all methods was assessed by subjects and technicians. Nasal NO concentration showed a significant inverse correlation with transnasal flow rate. All methods showed excellent reproducibility as assessed by the intraclass correlation coefficient except tidal breathing, which showed highly variable breath-to-breath NO levels, although mean breath values were reproducible. Mean nasal NO concentrations with methods 1, 2, 3, 4, and 5 were 32.1, 50.2, 62.8, 1381, and 60.0 ppb, respectively. Velum closure was not always achieved in methods 4 and 5, whereas methods 1 and 2 required separate nasal and oral procedures. Method 5 had reduced acceptability. NO concentrations were similar with methods that used the same airflow (2, 3, and 5). Nasal NO can be sampled in different ways with excellent reproducibility. In view of the flow dependence of nasal NO, it is vital to use a constant flow rate, and lower airway NO contribution must be excluded or subtracted. The fixed flow exhalation appears to be the preferred method as it is highly reproducible and acceptable.

Analysis of Variance↗
PubMed1997

Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study.

BACKGROUND: Plausible projections of future mortality and disability are a useful aid in decisions on priorities for health research, capital investment, and training. Rates and patterns of ill health are determined by factors such as socioeconomic development, educational attainment, technological developments, and their dispersion among populations, as well as exposure to hazards such as tobacco. As part of the Global Burden of Disease Study (GBD), we developed three scenarios of future mortality and disability for different age-sex groups, causes, and regions. METHODS: We used the most important disease and injury trends since 1950 in nine cause-of-death clusters. Regression equations for mortality rates for each cluster by region were developed from gross domestic product per person (in international dollars), average number of years of education, time (in years, as a surrogate for technological change), and smoking intensity, which shows the cumulative effects based on data for 47 countries in 1950-90. Optimistic, pessimistic, and baseline projections of the independent variables were made. We related mortality from detailed causes to mortality from a cause cluster to project more detailed causes. Based on projected numbers of deaths by cause, years of life lived with disability (YLDs) were projected from different relation models of YLDs to years of life lost (YLLs). Population projections were prepared from World Bank projections of fertility and the projected mortality rates. FINDINGS: Life expectancy at birth for women was projected to increase in all three scenarios; in established market economies to about 90 years by 2020. Far smaller gains in male life expectancy were projected than in females; in formerly socialist economies of Europe, male life expectancy may not increase at all. Worldwide mortality from communicable maternal, perinatal, and nutritional disorders was expected to decline in the baseline scenario from 17.2 million deaths in 1990 to 10.3 million in 2020. We projected that non-communicable disease mortality will increase from 28.1 million deaths in 1990 to 49.7 million in 2020. Deaths from injury may increase from 5.1 million to 8.4 million. Leading causes of disability-adjusted life years (DALYs) predicted by the baseline model were (in descending order): ischaemic heart disease, unipolar major depression, road-traffic accidents, cerebrovascular disease, chronic obstructive pulmonary disease, lower respiratory infections, tuberculosis, war injuries, diarrhoeal diseases, and HIV. Tobacco-attributable mortality is projected to increase from 3.0 million deaths in 1990 to 8.4 million deaths in 2020. INTERPRETATION: Health trends in the next 25 years will be determined mainly by the ageing of the world's population, the decline in age-specific mortality rates from communicable, maternal, perinatal, and nutritional disorders, the spread of HIV, and the increase in tobacco-related mortality and disability. Projections, by their nature, are highly uncertain, but we found some robust results with implications for health policy.

Adolescent↗
PubMed2006

Performance of a novel collimator for high-sensitivity brain SPECT.

We assessed improvements in performance in detection and estimation tasks due to a novel brain single photon computed tomography collimator. Data were acquired on the CeraSPECT scanner using both new and standard collimators. The new variable focusing collimator SensOgrade samples the projections unequally, with central regions more heavily represented, to compensate for attenuation of counts from central brain structures. Furthermore, it utilizes more of the cylindrical crystal surface. Two phantom studies were performed. The first phantom was a 21-cm-diameter cylindrical background containing nine spheres ranging from 0.5 to 5 cm3 in volume. 99mTc sphere to background activity ratio was 10:1. Twenty-nine 10-min datasets were acquired with each collimator. The second phantom was the Radiology Support Devices (Long Beach, CA) striatal phantom with striatal-background ratios of 10:1 on the left and 5:1 on the right. Twenty-nine 4-min datasets were acquired with each collimator. Perfusion imaging using 99mTc-HMPAO was also performed in three healthy volunteers using both collimators under identical simulations. Projections were reconstructed by filtered backprojection with an unwindowed ramp filter. The nonprewhitening matched filter signal-to-noise ratio (NPW-SNR) was computed as a surrogate for human performance in detecting spherical lesions. Sphere activity concentration, radius, and location coordinates were simultaneously estimated by fitting images to an assumed model using an iterative nonlinear algorithm. Resolution recovery was implicit in the estimation procedure, as the point spread function was incorporated into the model. NPW-SNR for sphere detection was 1.5 to 2 times greater with the new collimator; for the striatal phantom the improvement in SNR was 54%. The SNR for estimating sphere activity concentration improved by 46 to 89% for spheres located more than 5 cm from the phantom center. Images acquired with the standard collimator were too noisy in the central regions to allow estimation of sphere activity. In 99mTc-HMPAO human studies, SNR was improved by 21 to 41% in the cortex, 66% in the basal ganglia, and 74% in the thalamus. The new collimator leads to substantially improved detection and estimation performance throughout the brain. The higher sensitivity will be particularly important for dynamic imaging.

Brain↗
PubMed2003

Anthropometric measures, cytokines and survival in haemodialysis patients.

BACKGROUND: Lower serum albumin concentration (sAlb) and higher levels of pro-inflammatory cytokines have been reported to predict death in patients treated with haemodialysis (HD). SAlb, along with anthropometric measures, has been used as a surrogate marker for nutritional status in patients with chronic disease. Though adequate nutrition has been considered an important factor for patients treated with HD, it has not been established if any nutritional markers other than lower serum albumin and lower body mass index (BMI) predict death. Furthermore, it has not been shown whether anthropometric measures other than BMI are associated with predictors of mortality. METHODS: At the outset of the study, patients were assessed using demographic and anthropometric indices including arm fat area (AFA), arm muscle area (AMA), BMI, per cent ideal weight (PIW), pre-dialysis sAlb, and circulating levels of tumour necrosis factor-alpha (TNF-alpha), IL-1 and IL-6. A severity index, previously demonstrated to be a mortality marker, was used to grade medical co-morbidity. RESULTS: Two-hundred and forty patients entered the study. The mean age was 55.1+/-14.3 years, mean sAlb 3.76+/-0.60 mg/dl, mean AFA 1742+/-1225 mm(2), mean AMA 5464+/-1817 mm(2), mean PIW 101.0+/-21.3% and mean BMI 24.9+/-5.6 kg/m(2). PIW, BMI, AFA and AMA were, as expected, all highly correlated with one another. SAlb correlated with serum transferrin; however, neither sAlb nor serum transferrin concentration correlated with circulating cytokine levels. Circulating cytokines and sAlb did not correlate with PIW, BMI, AFA or AMA. In Cox regression analyses using multiple control variables, IL-6 predicted survival, while the anthropometric measures did not. CONCLUSIONS: Pro-inflammatory cytokines and sAlb are robust predictors of death in patients treated with HD. PIW and BMI correlate well with other anthropometric measures in patients treated with HD, but these measures do not correlate with markers of inflammation. Anthropometric measures are poor predictors of survival compared with measures linked to the acute-phase response.

Adipose Tissue↗
PubMed2005

Adsorption, oxidation, and bioaccessibility of As(III) in soils.

At As-contaminated sites, where the ingestion of soil by children is typically the critical human-health exposure pathway, information on the bioavailability of soil-bound As is often limited. The influence of various soil physical and chemical properties (iron and manganese oxides, pH, cation exchange capacity, total inorganic and organic carbon, and particle size) on As(III) adsorption, sequestration, bioaccessibility (as a surrogate for oral bioavailability), and oxidation was investigated in 36 well-characterized soils by use of a physiologically based extraction test (PBET). These results were compared to an earlier published study with As(V) on the same set of soils. The properties of the soils were able to explain >80% of the variability in the adsorption and sequestration (as measured by the reduction in bioaccessibility over time) of As(III) in these soils. The initial bioaccessibility of As(III) was significantly higher than the initial bioaccessibility of As(V) on the same set of soils. However, over a 6-month period of aerobic aging, a significant portion of the solid-phase As(III) on these soils was oxidized to As(V), decreasing its bioaccessibility markedly. A multivariable linear regression model previously developed to predict the steady-state bioaccessibility of As(V) in soils was able to predict the bioaccessibility in As(III)-spiked soils within a root-mean-square error (RMSE) of 16.8%. Generally, soils having a higher iron oxide content and lower soil pH exhibited lower bioaccessibility. This model was also able to predict the in vivo bioavailability of As in contaminated soils previously used in an independent juvenile swine dosing trial within an RMSE of 15.5%, providing a greatly improved yet conservative estimate of bioavailability relative to the typical default assumption of 100%. However, the model was not able to accurately predict the bioavailability of As in a different set of contaminated soils previously used in an independent Cebus monkey dosing trial, consistently overpredicting the bioavailability, resulting in an RMSE of 42.7%. This model can be used to provide an initial estimate of As bioavailability in soil to aid in screening sites and justifying expensive site-specific animal feeding studies. Further, as the model is based on major soil properties, the resulting estimates are valid as long as the major soil properties do not change, thus providing some confidence in the long-term applicability of the estimates.

Adsorption↗
PubMed2003

Biochemical failure as a determinant of distant metastasis and death in prostate cancer treated with radiotherapy.

PURPOSE: Biochemical failure (BF), defined by a rising prostate-specific antigen (PSA) profile, is an early surrogate of treatment failure. However, little evidence is available to show that BF is associated with death for patents with prostate cancer treated with radiotherapy. We examined the relationship between BF and death from prostate cancer. METHODS AND MATERIALS: A total of 942 patients were treated between 1987 and 1998 with external beam radiotherapy who had sufficient PSA determinations in follow-up for the analyses described. The median radiation dose was 72 Gy, median PSA was 9.9 ng/mL, and median follow-up was 73 months. The American Society for Therapeutic Radiology and Oncology consensus definition was used to define BF. Kaplan-Meier calculations were from the start of radiotherapy. Cox proportional hazards regression multivariate analyses were used to investigate the association of BF (time-dependent variable) and other factors to distant metastasis (DM), cause-specific death (CSD), and overall death (OD). The year of treatment was included in some of the multivariate analyses to correct for potential unknown factors that may have occurred during the years of the study, such as stage migration. RESULTS: BF was observed in 316 patients (34%), and 66 (7%) experienced DM, 32 (3%) died of prostate cancer, and 230 (24%) died overall during the study period. The Kaplan-Meier 5-year rate estimates from the start of treatment for BF, DM, CSD, and OD were 38%, 6%, 3%, and 13%, respectively. All patients with DM had BF. In multivariate analyses, BF was associated with DM and CSD, but not OD. The inclusion of the year of treatment did not alter these relationships. CONCLUSION: BF, as a time-dependent covariate, was the strongest determinant of DM and was also very significantly related to CSD. The inclusion of the year of treatment had little effect on these associations. Longer follow-up is needed to determine conclusively the relationship of BF to OD.

Aged↗
PubMedDate not supplied

The use of data loggers to determine the energetics and physiology of aquatic birds and mammals.

By deploying a data logger specifically designed for the purpose, it was possible to record heart rate, fH (beats/min), from free-ranging gentoo penguins, Pygoscelis papua, and Antarctic fur seals, Arctocephalus gazella, at the British Antarctic Survey Base at Bird Island. The heart rate data were then converted into oxygen consumption (VO2, mlO2 min-1 kg-1) and/or energy expenditure (W/kg) using equations that had been derived from calibration experiments. In these experiments the relationships between fH and VO2 were determined in animals at rest and while exercising at different levels on a treadmill or in a static water channel (penguins) and in a variable speed flume (California sea lions, Zalophus californianus, as surrogate fur seals) or in a static water channel (fur seals). The validity of using these relationships was tested by recording simultaneously fH, VO2 by direct respirometry and VCO2 by the doubly labelled water (DLW) technique in six penguins and in six California sea lions during 72 h and 24 h, respectively, at various levels of activity. For the penguins, both indirect methods gave mean algebraic errors within 2% of the measured VO2, whereas for the sea lions, the mean algebraic errors were 36.4% for the DLW method and 2.7% for the fH method. The range of errors was greater for the DLW method, in both species. Field data from 15 penguins indicate that the fH method provides data that are comparable to those obtained using the DLW method, but with the added advantage that they can be broken down into the energy costs for specific types of behaviour. The implanted data loggers also recorded the temperature of the abdominal cavity (T(ab)) and it was evident that this routinely decreased by approximately 2 degrees C during diving bouts and by a maximum of almost 5 degrees C. Such temperature decreases, particularly if representative of similar decreases in other tissues, may at least partly explain why the energy costs of travelling to and from the foraging site and of foraging itself are similar to those for penguins resting in water at 5 degrees C. Field data from 15 female fur seals indicate that, when the animals are ashore, there is good agreement between the values for mean energy expenditure obtained by the fH and DLW methods. However, when the animals are at sea, the values obtained by DLW are substantially greater than those obtained by fH. When the at-sea values are corrected for the apparent overestimations referred to above, there is good agreement between the data obtained using the two methods. The data derived from fH indicate that, as with the penguins, the energy expenditures during travelling to and from the foraging site and during foraging are similar to those of fur seals resting in water at 7 degrees C.

Animals↗
PubMed2004

Contribution of insulin-stimulated glucose uptake and basal hepatic insulin sensitivity to surrogate measures of insulin sensitivity.

OBJECTIVE: The goal of this study was to evaluate the performance of surrogate measures of insulin sensitivity and insulin secretion. RESEARCH DESIGN AND METHODS: The homeostasis model assessment (HOMA) of insulin resistance (IR) and the insulin sensitivity index (S(i)) from oral glucose tolerance test (OGTT) were compared with the M value from a hyperinsulinemic-euglycemic clamp in 467 subjects with various degrees of glucose tolerance. Endogenous glucose production (EGP) and hepatic insulin sensitivity were determined in a subset (n = 143). Insulin secretion was estimated as the HOMA beta-cell index and as the insulinogenic index from the first 30 min of the OGTT (I/G30) and compared with the first-phase insulin response (FPIR) to an intravenous glucose tolerance test (n = 218). RESULTS: The M value correlated with the HOMA-IR (r = -0.591, P < 0.0001) and the S(i) (r = 0.533, P < 0.0001) indexes in the total study group. HOMA-IR correlated with basal EGP in the total study group (r = 0.378, P < 0.0005) and in subjects with diabetes (r = 0.330, P = 0.01). However, neither HOMA-IR nor S(i) correlated significantly with the M value in subjects with impaired fasting glucose (IFG) (r = -0.108, P = 0.5; r = 0.01, P = 0.9) or IFG/impaired glucose tolerance (IGT) (r = -0.167, P = 0.4; r = 0.09, P = 0.6). The HOMA-IR correlated with hepatic insulin sensitivity in the whole study group (r = -0.395, P < 0.005) as well as in the IFG/IGT subgroup (r = -0.634, P = 0.002) and in the diabetic subgroup (r = -0.348, P = 0.008). In subjects with IFG/IGT, hepatic insulin sensitivity was the most important determinant of HOMA-IR, explaining 40% of its variation. The HOMA beta-cell index showed a weak correlation with FPIR in the whole study group (r = 0.294, P = 0.001) but not in the subgroups. In contrast, the I/G30 correlated with FPIR in the whole study group (r = 0.472, P < 0.0005) and in the IFG/IGT subgroup (r = 0.493, P < 0.005). CONCLUSIONS: HOMA-IR is dependent upon both peripheral and hepatic insulin sensitivity, the contribution of which differs between subjects with normal and elevated fasting glucose concentrations. These discrepancies develop as a consequence of a nonparallel deterioration of the variables included in the equations with worsening of glucose tolerance.

Blood Glucose↗
PubMed2000

Prediction of survival for older hospitalized patients: the HELP survival model. Hospitalized Elderly Longitudinal Project.

OBJECTIVE: To develop and validate a model estimating the survival time of hospitalized persons aged 80 years and older. DESIGN: A prospective cohort study with mortality follow-up using the National Death Index. SETTING: Four teaching hospitals in the US. PARTICIPANTS: Hospitalized patients enrolled between January 1993 and November 1994 in the Hospitalized Elderly Longitudinal Project (HELP). Patients were excluded if their length of hospital stay was 48 hours or less or if admitted electively for planned surgery. MEASUREMENTS: A log-normal model of survival time up to 711 days was developed with the following variables: patient demographics, disease category, nursing home residence, severity of physiologic imbalance, chart documentation of weight loss, current quality of life, exercise capacity, and functional status. We assessed whether model accuracy could be improved by including symptoms of depression or history of recent fall, serum albumin, physician's subjective estimate of prognosis, and physician and patient preferences for general approach to care. RESULTS: A total of 1266 patients were enrolled over a 10-month period, (median age 84.9, 61% female, 68% with one or more dependency), and 505 (40%) died during an average follow-up of more than 2 years. Important prognostic factors included the Acute Physiology Score of APACHE III collected on the third hospital day, modified Glasgow coma score, major diagnosis (ICU categories together, congestive heart failure, cancer, orthopedic, and all other), age, activities of daily living, exercise capacity, chart documentation of weight loss, and global quality of life. The Somers' Dxy for a model including these factors was 0.48 (equivalent to a receiver-operator curve (ROC) area of 0.74, suggesting good discrimination). Bootstrap estimation indicated good model validation (corrected Dxy of 0.46, ROC of 0.73). A nomogram based on this log-normal model is presented to facilitate calculation of median survival time and 10th and 90th percentile of survival time. A count of geriatric syndromes or comorbidities did not add explanatory power to the model, nor did the hospital of patient recruitment, depression, or the patient preferences for general approach to care. The physician's perception of the patient's preferences and the physician's subjective estimate of the patient's prognosis improved the estimate of survival time significantly. CONCLUSIONS: Accurate estimation of length of life for older hospitalized persons may be calculated using a limited amount of clinical information available from the medical chart plus a brief interview with the patient or surrogate. The accuracy of this model can be improved by including measures of the physician's perception of the patient's preferences for care and the physician's subjective estimate of prognosis.

Activities of Daily Living↗
PubMed2006

Mathematical modelling of survival of glioblastoma patients suggests a role for radiotherapy dose escalation and predicts poorer outcome after delay to start treatment.

AIMS: The outcome of patients with glioblastoma (GBM) remains extremely poor. We have developed a mathematical model, using pathological and radiation biology concepts, to assess the detrimental effect of delay to start radiotherapy, the possible benefit from dose escalation, and to extract biological data from clinical data. MATERIALS AND METHODS: Survival data were available for 154 adult patients with GBM treated in our centre with curative intent to a dose of 60 Gy in 30 fractions between 1996 and 2002. Survival data for 129 patients from the 60 Gy arm of the MRC BR02 randomised trial of radiotherapy dose were obtained for comparison. The model generates the equivalent of individual patients with a brain tumour, and produces an explicit outcome, either death or survival. The tumour, assumed to be growing exponentially, causes normal cell damage in the brain, and death occurs when the number of normal brain cells falls below a critical level. The outcome for an individual patient is determined by values of the variables assigned by the model. Parameters for the single patient include tumour doubling time, surviving fraction of tumour cells after each fraction of radiotherapy, and a waiting time from presentation to the start of radiotherapy. A surrogate for performance status is implemented, using a rule that rejects patients whose tumours are too advanced at presentation to be suitable for radical radiotherapy. Values for the parameters that determine individual patient outcome are randomly assigned from a set of probability distributions, using Monte Carlo simulation. The simulation constructs survival results for a population, typically 2000 individuals. The descriptors of the probability distributions that are used to determine the parameters that define the patient characteristics are adjusted to optimise the fit of the modelled population to real clinical data, using a combination of folding polygon and simulated annealing techniques. RESULTS: The model fits the clinical data well. The results suggest that the surviving fraction of tumour cells after a radiation dose of 2 Gy (SF2) does influence patient outcome. The mean in vivo SF2 for the Addenbrooke's data is 0.80, implying that hypoxia is a serious problem in radiotherapy for GBM. The Addenbrooke's data suggest a mean tumour doubling time of 24 days, so that a delay to start radiotherapy would be expected to have an adverse effect. Considering patients by treatment intent, median survival plummets as delay increases, and almost no patients survive long term after a 70-day delay. Radiotherapy dose escalation has an important predicted effect on survival. Assuming that the treatment could be delivered safely, a dose of 74 Gy, given at 2 Gy/fraction, would extend the survival of all patients. The proportion of long-term survivors would increase, from 2.4% with 60 Gy, to 6.4% with 74 Gy. The model can be used to derive gamma50, which has a value of 0.42, lower than the typical value of 1-2. CONCLUSION: Using the model, we have extracted biological information from clinical data. The model could be used to assess the potential benefit, or lack of benefit, from a proposed radiotherapy trial, and to estimate the necessary size. It shows that a single modality is unlikely to achieve a major improvement in long-term survival, although radiotherapy dose escalation should have a role, provided it can be given safely. The model could be extended to include chemotherapy, bio-reductive drugs, or gene therapy.

Brain Neoplasms↗
PubMedDate not supplied

Serum anti-ganglioside IgM antibodies in soft tissue sarcoma: clinical prognostic implications.

PURPOSE: Gangliosides are tumor-associated antigens with many biologic functions, including complex interactions with cytokines and other modulators of the immune system. Serum total ganglioside level may be an ideal surrogate marker to predict tumor burden and response to treatment. Antibodies produced against tumor gangliosides may help predict survival. The purpose of this study is to determine whether the serum total ganglioside levels might predict the tumor burden in patients with soft tissue sarcoma, and whether the augmented anti-ganglioside immunoglobulin M (IgM) response might reflect the clinical outcome of these patients. METHODS: Serum TG levels were measured in the cryopreserved sera by estimating lipid-associated sialic acids from 97 patients before surgical resection of soft tissue sarcoma and from 39 age- and gender-matched healthy volunteers. All sera were analyzed for IgM titers (expressed natural log) by enzyme-linked immunosorbent assay against eight gangliosides (GM1, GM2, GM3, GD3, GD2, GD1a, GD1b, and GT1b). Cox regression was used for univariate and multivariate analyses of the variables affecting progression-free and overall survival. RESULTS: Serum TG levels were higher in soft tissue sarcoma patients than in healthy individuals (21.8 + 7.7 vs 16.1 + 2.7 mg/dL; P = 0.001). Larger tumors, high histologic grade, and more advanced stage of disease correlated with higher serum total ganglioside levels (P < 0.05). Anti-ganglioside titers to GM3, GD2, and GT1b were significantly higher in patients with soft tissue sarcoma, whereas anti-GD1a and GD1b titers were significantly higher in healthy subjects. The titers of antibodies against GM1, GM2, and GD3 in patients with soft tissue sarcoma were comparable to those of the healthy individuals. When compared with healthy controls, patients with low-grade tumors had higher titers of anti-GT1b, anti-GM3, and anti-GD2 antibodies, and patients with high-grade tumors had higher titers of anti-GT1b and anti-GD2 antibodies. These data suggest that the predominant gangliosides expressed by sarcomas may include GT1b and GD2. In addition, low-grade tumors may express an immunogenic species of GM3. On both univariate and multivariate analyses, augmented anti-GD1a IgM titers, age > 50 years, and retroperitoneal location were predictive of decreased overall survival, whereas augmented anti-GT1b titers were predictive of improved overall survival. CONCLUSIONS: Serum TG level may be a useful marker of tumor burden and response to treatment for soft tissue sarcoma. Anti-GD1a and anti-GT1b IgM titers predicted survival and may be of therapeutic and prognostic value in the management of soft tissue sarcoma.

Adolescent↗
PubMed2004

Placement changes and emergency department visits in the first year of foster care.

OBJECTIVES: Despite great needs, many children in foster care do not receive adequate medical care. Suboptimal care may be attributable in part to placement changes, which disrupt continuity of care by both a consistent surrogate parent and potentially a primary care physician. These disruptions in turn may lead to increased use of the emergency department (ED) for outpatient care. The primary aim of this study was to test whether a greater rate of placement changes was associated with increasing use of the ED among children in their first year of foster care. The secondary aim was to compare ED visit rates with rates of visits to other ambulatory care settings among children in foster care and other Medicaid-eligible children not in foster care. METHODS: Using Medicaid claims linked to foster care administrative data, we assembled a retrospective cohort of foster children in a large urban municipality from 1993 to 1996. Eligible children spent at least 9 months in a new episode of foster care and were continuously eligible for Medicaid during a 1-year follow-up period. A comparison cohort was drawn from Medicaid-eligible children not in foster care during fiscal year 1995. The dependent variable was the rate of visits to the ED or other ambulatory care settings during a 1-year follow-up period. A negative binomial model estimated visit rates to the ED and other ambulatory care settings as the number of foster care placements increased. Potential interactions were considered between age and location of service use (ED or ambulatory care setting), between age and foster care placements, and between location of service use and number of foster care placements. RESULTS: The 2358 children in the sample accounted for 1206 ED visits during the follow-up period; 38% experienced >or=2 placement changes. Children of all ages exhibited increasing reliance on the ED for ambulatory care services as the number of placements increased, with the rates of ED use more than doubling for all age groups beyond infancy. However, other ambulatory care service use increased by only 41% to 53%; there was much less utilization in these nonemergency settings for all children but particularly toddlers and infants, compared with their Medicaid-eligible peers. Although the absolute rates of all visits for younger foster children (<6 years of age) were low, older foster children had increasingly greater ED use than did their Medicaid-eligible peers, with nearly double the rate of ED visits in the adolescent age group. A temporal relationship between placements and ED visits was also identified; 75% of ED visits occurring within 3 weeks of a placement change occurred in the period after a placement change. CONCLUSIONS: Foster children received fewer overall outpatient services than did their Medicaid-eligible peers, but with age and increasing numbers of placements, had higher visit rates and received a greater proportion of their overall outpatient care in the ED. These results suggest that poor access to nonemergent ambulatory care settings might have contributed to an increasing reliance on ED settings as foster care placements increased. The temporal relationship between ED visits and placement changes underscores the need for better health care management for foster children, particularly in the period after placement changes.

Ambulatory Care↗
PubMed2003

Markers and meaning of primary treatment failure.

BCR is the most clinically used endpoint for identification of treatment failure. Approximately 15% to 53% of patients undergoing primary curative therapy will develop BCR. BCR often precedes clinically detectable recurrence by years. It does not necessarily translate directly into PCa morbidity and mortality, nor does it always reflect the desired endpoint. Furthermore, it has not been validated as a surrogate endpoint, in that interventions that have been shown to alter the PSA level have not been shown to also alter survival. The utility of PSA level as a surrogate endpoint is brought into question by the knowledge that the overall survival rate of patients at 10 years is similar in patients with and without BCR, and that in a significant proportion of men, the only evidence of disease during their lifetime will be a detectable PSA level. The likelihood of developing BCR post-therapy can be predicted by using multiple clinical and pathologic variables. With the development of nomograms that incorporate several markers, the accuracy of prediction has improved. Until recently, the natural history of BCR post-RRP has not been well understood. Pound et al showed the heterogenous and prolonged natural history of BCR. In this large series of men with BCR following RRP, only 34% of men developed metastatic disease. The median time from development of BCR to identification of metastases was 8 years, and the median time from the development of metastatic disease to death was just under 5 years. These data highlight the extremely variable and potentially indolent nature of BCR. The risk of metastatic disease following BCR has been relatively well defined and relates to PSADT and time to PSA recurrence. It generally is accepted that a PSADT of less than 6 to 10 months and a time to PSA recurrence of less than 1 to 2 years relates to a higher risk of developing metastatic disease. Local recurrence, however, remains poorly understood with respect to its true incidence, clinical significance, and natural history. The significance of BCR post-RT remains unclear due to the lack of data on its natural history. Attempts have been made to identify patients at high risk for metastatic progression by looking at time to PSA recurrence and PSADT. A PSADT of less than 6 to 12 months and a time to PSA recurrence of less than 12 months reflects a higher risk of developing metastatic disease. Accurate risk stratification by means of an algorithm similar to that produced by Pound et al has not been performed on a large cohort, thus making risk assessment for an individual patient difficult. The major dilemma for clinicians in the management of BCR is the identification of the site of disease recurrence, which ultimately guides therapy decisions. Clinicopathologic features allow for risk stratification for recurrence, and multiple investigations have attempted to localize the site of recurrence. Time to biochemical progression, Gleason score, and PSADT are predictive of the probability and time to development of metastatic disease, and allow for stratification of patients into different risk groups (see Table 2). TRUS, CT, PET, and DRE all have limited utility in the identification of local recurrence. ProstaScint and MRI have demonstrated encouraging initial results: however, they require further investigation. Bone scintigraphy is of little value for the initial investigation of BCR. In patients with a PSA level of less than 10 ng/mL, the risk of having a positive bone scan is less than 1% and, until the PSA level rises above 40 ng/mL, the risk of having a positive bone scan is less than 5%. Therefore, bone scintigraphy should be reserved for patients with a PSA level greater than 10 to 20 ng/mL or patients with a rapidly rising PSA level. Using new MRI sequences, there is some evidence that MRI is better for the detection of bony metastatic disease; however, this technique requires further investigation. BCR causes anxiety for the patient and the treating doctor, because the best way to manage patients with PSA-only progression is unknown. Currently, there are no validated treatment recommendations for the management of BCR. The information in this review provides the framework for assignment of patients into clinical trials based on different risk categories. Patients at high risk for metastatic progression could be identified early and thus entered into appropriate clinical trials for systemic therapies. Similarly, patients with a low risk of progression could be placed into observation protocols, potentially sparing them from exhaustive and inappropriate investigations.

Biomarkers↗