Comparative value-based pricing of an Ebola vaccine in resource-constrained countries based on cost-effectiveness analysis.

OBJECTIVES: Pricing, affordability, and access are important deliberations around infectious disease interventions. Determining a fair price that not only incentivizes development but ensures value and access for patients is critical given the increasing global health crisis. Using Ebola virus disease (EVD) as an exemplar, we aim to elucidate the estimation of a jurisdiction-specific value-based price (VBP) for a vaccine package and to consider how prices compare across selected countries that have experienced EVD outbreaks. METHODS: Using a dynamic transmission model, we assessed the cost-effectiveness of a vaccine package - composed of the vaccine, storage, maintenance, and administration - for vaccination toward herd immunity in 4 countries affected with EVD (Democratic Republic of Congo, Liberia, Sierra Leone, Uganda). Based on the cost-effectiveness metrics and using willingness-to-pay thresholds equal to varying percentages of the Gross Domestic Product (GDP), we demonstrated how a VBP is calculated using a cost-effectiveness-based approach. RESULTS: The VBP for the vaccine is directly proportional to effectiveness (DALYs prevented), cost-effectiveness (ICER) and GDP per capita. Higher effectiveness, greater cost-effectiveness, and higher GDP per capita resulted in higher price ceilings compared to lower cost-effectiveness and lower GDP. CONCLUSION: Despite the concerns with the cost-effectiveness-based approach, we illustrated that it is an easily comprehensible method for determining the VBP of a vaccine using cost-effectiveness analysis. Choice of data, population characteristics, and disease dynamics are among the factors that need to be considered when comparisons are made across countries.

In infectious diseases, issues related to pricing, affordability and access to interventions are very important; particularly in low-income countries (LIC) because of the scarcity of resources coupled with several competing priorities. Pricing interventions fairly in LICs facilitates the prevention and management of infectious diseases, promotes innovation, and ensures patient access to valuable interventions. We were interested in determining a fair price of an intervention for an infectious disease (here, vaccination against Ebola virus disease) based on the cost-effectiveness (or value) of vaccination in four African countries.Using data from EVD outbreaks in Liberia, the Democratic Republic of Congo, Uganda, and Sierra Leone, we estimated the number of susceptible people who were exposed to the virus, became infected, recovered, or died. We did this for two scenarios: not vaccinating versus vaccinating to achieve herd immunity. We determined how many disability-adjusted life years (DALY; loss of the equivalent of a year of full health) would be prevented by vaccination; setting this as our value metric. Using this value metric and percentages of the gross domestic product (GDP) per capita as the willingness-to-pay (WTP) threshold (the price a payer might be prepared to pay for the intervention) we demonstrate how to calculate the maximum price for the vaccine package.The combination of greater effectiveness (DALYs averted), greater cost-effectiveness (value) and higher GDP per capita (WTP) resulted in different price ceilings in the four countries. The method proposed here is easy to understand and requires minimum data to determine a price for an intervention's price based on its value.

Cross-sectional associations between adipose tissue depots and areal bone mineral density in the UK Biobank imaging study.

The relationship between obesity and osteoporosis is poorly understood. In this study, we assessed the association between adiposity and bone. The fat-bone relationship was dependent on sex, body mass index classification, and menopausal status. Results highlight the importance of accounting for direct measures of adiposity (beyond BMI) and menopause status. INTRODUCTION: Assess the relationship between direct measures of adiposity (total body fat mass, visceral adipose tissue, and abdominal subcutaneous adipose tissue) with the whole body and clinically relevant bone sites of the lumbar spine, and femoral neck areal bone mineral density (aBMD) in men and women. METHODS: This cross-sectional analysis was conducted utilizing de-identified data from the UK Biobank on participants (n = 3674) with available dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) data. Sex-stratified multiple linear regression was used to assess the relationship between adiposity measures and aBMD outcomes, controlling for age, race, total body lean mass (DXA), height, BMI class, physical activity, smoking, menopausal status (women), and hormone use (women). RESULTS: In men, significant interactions were observed between measures of adiposity and BMI on aBMD for the whole body and lumbar spine. Interactions indicated a positive relationship between adiposity and aBMD in men classified as normal weight, but an inverse relationship in men with elevated BMI. In women, significant interactions between adiposity measures and menopausal status were observed primarily for the whole body and femoral neck aBMD bone outcomes which indicated a negative relationship between adiposity and aBMD in premenopausal women, but a positive relationship in postmenopausal women. CONCLUSION: Total body adiposity, abdominal subcutaneous adipose tissue, and visceral adipose tissue were all significantly associated with aBMD in both men and women. The strength and direction of association were dependent on sex, BMI classification, and menopausal status (women).

Physical activity, sedentary time, and longitudinal bone strength in adolescent girls.

The association between baseline physical activity and sedentary time with 2-year longitudinal bone strength was evaluated. The effect of physical activity on bone depended on maturity status. Sedentary time did not negatively impact bone outcomes, regardless of maturity. Maturity should be considered when developing exercise interventions to improve bone outcomes. INTRODUCTION: Physical activity during adolescence is important to obtain peak bone mass; however, adolescents are increasingly sedentary, potentially increasing risk for osteoporosis later in life. The aim of this study was to assess the association of physical activity and sedentary time with 2-year longitudinal bone outcomes in adolescent females (69% Hispanic/31% non-Hispanic). METHODS: Bone strength was assessed at the 66% tibia, 20% femur, and 66% radius of 9- to 12-year-old girls (n = 131) using peripheral quantitative computed tomography at baseline and 2-year follow-up. Physical activity and sedentary time were assessed via accelerometry. Linear regression analyses were used to assess whether baseline vigorous physical activity (VPA), moderate physical activity (MPA), light physical activity (LPA), or sedentary time predict longitudinal bone outcomes, adjusting for relevant confounders. RESULTS: Significant interactions were found between maturity offset and physical activity. In weight-bearing bones, significant interactions were primarily identified between VPA and maturity offset. Interactions indicated that VPA was associated with favorable bone outcomes at the tibia and femur in girls further past the age of PHV. However, this favorable effect was not observed in girls closer to the age of PHV. At the radius, interactions were primarily observed between LPA and maturity offset. Again, LPA was more beneficial for girls further past the age of PHV. Sedentary time did not significantly influence bone outcomes. CONCLUSION: The effects of physical activity on bone may be dependent on maturity. Therefore, physical activity interventions, with attention to maturity status, may be required to optimize bone strength in girls.

Immunosuppressant therapy adherence and graft failure among pediatric renal transplant recipients.

The study objective was to determine the association between immunosuppressant therapy (IST) adherence and graft failure among pediatric renal transplant recipients (RTRs) using data reported in the United States Renal Data System (USRDS), which contains Medicare prescription claims. RTRs (

Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults.

Risk factors for non-melanoma skin cancer among populations with evidence of precursor damage are not well described. We examined and compared risk factors associated with the development of cutaneous basal-cell (BCC) or squamous-cell (SCC) carcinoma among a group of 918 adults with significant sun damage (> or = 10 clinically assessable actinic keratoses) but no prior history of skin cancer. These adults were participants in a 5-year skin chemoprevention trial between 1985 and 1992, who had been randomized to the placebo group and followed for occurrence of skin cancer. During the study, a total of 129 first SCC and 164 first BCC lesions were diagnosed. The overall BCC and SCC incidence rates for this group of men and women, mean age 61 years, were 4,106 and 3,198 per 100,000 person-years, respectively. Different constitutional and exposure factors were independently associated with BCC compared to SCC. Only increased age independently predicted BCC occurrence among this population. In contrast, older age along with male gender, natural red hair color and adult residence in Arizona for 10 or more years independently predicted SCC occurrence. The substantial incidence of skin cancer found among this population confirms the need for active dermatological monitoring among individuals with multiple visible actinic lesions.

Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos.

BACKGROUND: The use of automated external defibrillators by persons other than paramedics and emergency medical technicians is advocated by the American Heart Association and other organizations. However, there are few data on the outcomes when the devices are used by nonmedical personnel for out-of-hospital cardiac arrest. METHODS: We studied a prospective series of cases of sudden cardiac arrest in casinos. Casino security officers were instructed in the use of automated external defibrillators. The locations where the defibrillators were stored in the casinos were chosen to make possible a target interval of three minutes or less from collapse to the first defibrillation. Our protocol called for a defibrillation first (if feasible), followed by manual cardiopulmonary resuscitation. The primary outcome was survival to discharge from the hospital. RESULTS: Automated external defibrillators were used, 105 patients whose initial cardiac rhythm was ventricular fibrillation. Fifty-six of the patients 153 percent) survived to discharge from the hospital. Among the 90 patients whose collapse was witnessed (86 percent), the clinically relevant time intervals were a mean (+/-SD) of 3.5+/-2.9 minutes from collapse to attachment of the defibrillator, 4.4+/-2.9 minutes from collapse to the delivery of the first defibrillation shock, and 9.8+/-4.3 minutes from collapse to The arrival of the paramedics. The survival rate was 74 percent for those who received their first defibrillation no later than three minutes after a witnessed collapse and 49 percent for those who received their first defibrillation after more than three minutes. CONCLUSIONS: Rapid defibrillation by nonmedical personnel using an automated external defibrillator can improve survival after out-of-hospital cardiac arrest due to ventricular fibrillation. Intervals of no more than three minutes from collapse to defibrillation are necessary to achieve the highest survival rates.

Efficacy of transdermal nicotine in reducing post-cessation weight gain in a Hispanic sample.

This study examined nicotine replacement effects and pre-quit smoking characteristics with respect to post-cessation weight gain in a primarily Mexican-American sample of Hispanic smokers. Hispanic smokers (108) were randomly assigned to receive either nicotine transdermal patch or placebo patch for 10 weeks, during which time smoking status and weight change were measured. The overall weight gain experienced by the successful quitters was greater than that experienced by non-quitters. Differences between quitters and non-quitters were significant for both females (2.0 vs. 0.86 kg; p < 0.05) and for males (2.3 vs. 1.2 kg; p < 0.05) at 6 weeks post-randomization. At the end of the 10-week treatment, only the females showed a significant difference in weight gain between the quitters and non-quitters (2.8 vs. 1.1; p < 0.01). Results of the random effects regression models for quitters indicated that the active group gained weight at a significantly lower rate than the placebo group (p = 0.047) for females, but not for males (p = 0.87). Years of smoking (p = 0.001) but not baseline cigarettes (p = 0.13) were significant predictors of weight for females, but not for males (p = 0.24 and 0.72, respectively). The use of nicotine patch treatment for smoking cessation effectively attenuated weight gain for successful female quitters compared with placebo-treated quitters. Identification of pre-quit smoking characteristics may prove useful in predicting who is most likely to gain weight when quitting smoking.

Effect of subacute ibuprofen dosing on rectal mucosal prostaglandin E2 levels in healthy subjects with a history of resected polyps.

Nonsteroidal antiinflammatory drugs are among the most promising chemopreventive agents for colorectal cancer. Although the mechanism by which nonsteroidal antiinflammatory drugs exert such effects remains to be further characterized, their best known pharmacological effect is inhibition of prostaglandin synthetase, which leads to decreases in tissue prostaglandin levels. We conducted a randomized, double-blind, controlled study to examine the effect of daily ibuprofen treatment on the rectal mucosal prostaglandin E2 (PGE2) levels in healthy subjects with a history of resected polyps. Study participants (n = 27) completed a 2-week run-in period and were then randomized to take a single, daily dose of ibuprofen (300 or 600 mg) or of a placebo for 4 weeks. Rectal biopsy specimens were taken before and after the run-in period and at 2 and 4 weeks after the ibuprofen/placebo treatment. Notably large between- and within-subject variability in the rectal mucosal PGE2 content was seen. The changes in PGE2 levels after ibuprofen/placebo treatment correlated with the baseline PGE2 content. After adjustment of the baseline values, 2 weeks of 300 mg/day of ibuprofen treatment resulted in significantly more suppression of PGE2 levels than that observed after the placebo treatment (55% versus 22% suppression from baseline; P = 0.033). Although other ibuprofen treatment schedules and doses appeared to result in suppression in the PGE2 levels, the suppression was not statistically significant because of the large variability in this measurement. Because lower doses are associated with fewer adverse effects, a dose of 300 mg of ibuprofen/day should be considered for future Phase II chemoprevention studies. Stratifying study participants, based on their baseline PGE2 levels and inclusion of a larger number of study subjects, are recommended for future trials where the rectal mucosal PGE2 level is to be used as a surrogate end point biomarker.

Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians' Network.

BACKGROUND: The risks of colorectal cancer and adenoma, the precursor lesion, are believed to be influenced by dietary factors. Epidemiologic evidence that cereal fiber protects against colorectal cancer is equivocal. We conducted a randomized trial to determine whether dietary supplementation with wheat-bran fiber reduces the rate of recurrence of colorectal adenomas. METHODS: We randomly assigned 1429 men and women who were 40 to 80 years of age and who had had one or more histologically confirmed colorectal adenomas removed within three months before recruitment began to a supervised program of dietary supplementation with either high amounts (13.5 g per day) or low amounts (2 g per day) of wheat-bran fiber. The primary end point was the presence or absence of new adenomas at the time of follow-up colonoscopy. Subjects and physicians, including colonoscopists, were unaware of the group assignments. RESULTS: Of the 1303 subjects who completed the study, 719 had been randomly assigned to the high-fiber group and 584 to the low-fiber group. The median times from randomization to the last follow-up colonoscopy were 34 months in the high-fiber group and 36 months in the low-fiber group. By the time of the last follow-up colonoscopy, at least one adenoma had been identified in 338 subjects in the high-fiber group (47.0 percent) and in 299 subjects in the low-fiber group (51.2 percent). The multivariate adjusted odds ratio for recurrent adenoma in tile high-fiber group, as compared with the low-fiber group, was 0.88 (95 percent confidence interval, 0.70 to 1.11; P=0.28), and the relative risk of recurrence according to the number of adenomas, in the high-fiber group as compared with the low-fiber group, was 0.99 (95 percent confidence interval, 0.71 to 1.36; P=0.93). CONCLUSIONS: As used in this study, a dietary supplement of wheat-bran fiber does not protect against recurrent colorectal adenomas.

Chemoprevention of human actinic keratoses by topical 2-(difluoromethyl)-dl-ornithine.

Alpha-2-(Difluoromethyl)-dl-ornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, has been shown to suppress skin carcinogenesis in murine models after oral or topical administration. We designed a randomized, placebo-controlled study using a topical hydrophilic ointment formulation with or without 10% (w/w) DFMO. Forty-eight participants with moderate-severe actinic keratoses (AKs) on their forearms (i.e., at least 10 well-circumscribed lesions on the lateral surface) completed a 1-month run-in on placebo ointment. Before randomization, all lateral forearm AKs were circled, counted, photographed, and skin biopsies were obtained for DFMO and polyamine levels. Then participants were randomized to receive DFMO ointment on the right versus the left forearm and placebo hydrophilic ointment on the contralateral forearm twice daily for 6 months. DFMO was not detected in the blood of any subject, and there were no systemic toxicities. None of a subsample of 17 placebo forearms had measurable concentrations of DFMO, whereas 13 of the corresponding DFMO-treated forearms had high DFMO skin levels. As compared with placebo, the 6-month DFMO treatment caused a 23.5% reduction in the number of AKs (P = 0.001) as well as significant suppression of AK biopsy spermidine levels (26%; P = 0.04). Seven of the 48 (14.6%) participants experienced severe (2; 4.2%) or moderate (5; 10.4%) inflammatory reactions on their DFMO-treated arms which required dosing modification. Topical DFMO for 6 months can reduce the number of AK lesions and skin spermidine concentrations in high-risk participants and deserves additional study as a skin cancer chemopreventive agent.

A bile acid-induced apoptosis assay for colon cancer risk and associated quality control studies.

Bile acids are important in the etiology of colorectal cancer. Bile acids induce apoptosis in colonic goblet cells at concentrations comparable to those found in fecal water after high-fat meals. Preliminary evidence indicated that cells of the normal-appearing (nontumorous) portion of the colon epithelium of colon cancer patients are more resistant to bile salt-induced apoptosis than are cells from normal individuals. In the present study, 68 patients were examined, and biopsies were taken at 20 cm from the anal verge, cecum, and descending colon. The patients included 17 individuals with a history of colorectal cancer, 37 individuals with adenomas, and 14 individuals who were neoplasia free. The mean bile salt-induced apoptotic index among normal individuals was 57.6 +/- 3.47 (SE), which differed significantly (P < 0.05) from the mean value of 36.41 +/- 3.12 in individuals with a history of colon cancer. The correlation between independent observers was 0.89 (P < 0.001), indicating good interobserver reliability. Components of variance comparing interindividual versus intraindividual sources of variation suggested that site-to-site variability, both between regions of the colon and for adjacent biopsies, was larger than the interpatient variability for individuals with a history of neoplasia. Therefore, there was "patchiness" of the susceptibility of regions of the colon to bile acid-induced apoptosis in individuals with a history of neoplasia (a patchy field effect). There was no obvious correlation of low-apoptotic index regions with regions in which previous neoplasias had been found and removed. On the other hand, for normal, i.e., neoplasia-free, individuals, there was relatively less intraindividual variation compared to interindividual variation. Our assay shows an association between resistance to bile acid-induced apoptosis, measured at 20 cm from the anal verge, and colon cancer risk. Thus, this assay may prove useful as a biomarker of colon cancer risk.

Progress report: the Arizona phase III study of the effect of wheat bran fiber on recurrence of adenomatous colon polyps.

A double-blind, placebo-controlled Phase III cancer prevention trial in subjects with previous resection of adenomatous colon polyps is nearing completion. The study's primary objective is to evaluate the effects of daily dietary supplementation with large (13.5 g/day) versus small (2.0 g/day) doses of wheat bran fiber for 3 years. A summary of the study design and a progress report are presented.

Concentrations of carotenoids, tocopherols, and retinol in paired plasma and cervical tissue of patients with cervical cancer, precancer, and noncancerous diseases.

Paired blood (collected after an overnight fast) and cervical tissue (cancerous, precancerous, and noncancerous) samples were obtained from 87 patients (age, 21-86 years) who had a hysterectomy or biopsy due to cervical cancer, precancer (cervical intraepithelial neoplasia I, II, and III), or noncancerous diseases. The samples were analyzed using high-performance liquid chromatography for 10 micronutrients (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, cis-beta-carotene, alpha-tocopherol, gamma-tocopherol, and retinol). The results indicated that: (a) among the three patient groups, the mean plasma concentrations of all micronutrients except gamma-tocopherol were lowest in the cancer patients; however, the mean tissue concentrations of the two tocopherols and certain carotenoids were highest in the cancerous tissue; and (b) among the 10 micronutrients, only the concentrations of beta-carotene and cis-beta-carotene were lower in both the plasma and tissue of cancer and precancer patients than in those of noncancer controls. These results suggest that: (a) not all of the micronutrient concentrations in plasma reflect the micronutrient concentrations in cervical tissue; thus, in some cases, it may be necessary to measure the tissue micronutrient concentrations to define the role of the micronutrients in cervical carcinogenesis; and (b) maintaining an adequate plasma and tissue concentration of beta-carotene may be necessary for the prevention of cervical cancer and precancer.

Squamous cells as predictors of bacterial contamination in urine samples.

STUDY OBJECTIVE: To determine whether squamous cells in urine indicate bacterial contamination. METHODS: We prospectively studied 105 consecutive women who presented to the emergency department with symptoms suggestive of a urinary tract infection. Two urine samples were collected from each woman, a midstream clean-catch (MSCC) sample and a catheterized (CATH) sample. Microscopic urinalyses to assess for squamous cells and urine cultures to assess for bacterial contamination were performed on all samples. Bacterial contamination was defined as growth of fewer than 10,000 colonies of a single species per milliliter or growth of three or more species of commensal bacteria (mixed flora) in a urine sample. RESULTS: Squamous cells were found in 99 of 105 CATH samples (94%); however, no CATH samples had bacterial contamination. Squamous cells were found in 101 of 105 MSCC samples (96%); however, only 22 MSCC samples (21%) had bacterial contamination. CONCLUSION: The presence of squamous cells in CATH urine samples obtained from women is not indicative of bacterial contamination. The presence of squamous cells in MSCC urine samples obtained from women also is not a good indicator, with an overall predictive value for bacterial contamination of 21%.

Estimating effectiveness of cardiac arrest interventions: a logistic regression survival model.

BACKGROUND: The study objective was to develop a simple, generalizable predictive model for survival after out-of-hospital cardiac arrest due to ventricular fibrillation. METHODS AND RESULTS: Logistic regression analysis of two retrospective series (n=205 and n=1667, respectively) of out-of-hospital cardiac arrests was performed on data sets from a Southwestern city (population, 415,000; area, 406 km2) and a Northwestern county (population, 1,038,000; area, 1399 km2). Both are served by similar two-tiered emergency response systems. All arrests were witnessed and occurred before the arrival of emergency responders, and the initial cardiac rhythm observed was ventricular fibrillation. The main outcome measure was survival to hospital discharge. Patient age, initiation of CPR by bystanders, interval from collapse to CPR, interval from collapse to defibrillation, bystander CPR/collapse-to-CPR interval interaction, and collapse-to-CPR/collapse-to-defibrillation interval interaction were significantly associated with survival. There was not a significant difference between observed survival rates at the two sites after control for significant predictors. A simplified predictive model retaining only collapse to CPR and collapse to defibrillation intervals performed comparably to the more complicated explanatory model. CONCLUSIONS: The effectiveness of prehospital interventions for out-of-hospital cardiac arrest may be estimated from their influence on collapse to CPR and collapse to defibrillation intervals. A model derived from combined data from two geographically distinct populations did not identify site as a predictor of survival if clinically relevant predictor variables were controlled for. This model can be generalized to other US populations and used to project the local effectiveness of interventions to improve cardiac arrest survival.

Application of neural networks to population pharmacokinetic data analysis.

This research examined the applicability of using a neural network approach to analyze population pharmacokinetic data. Such data were collected retrospectively from pediatric patients who had received tobramycin for the treatment of bacterial infection. The information collected included patient-related demographic variables (age, weight, gender, and other underlying illness), the individual's dosing regimens (dose and dosing interval), time of blood drawn, and the resulting tobramycin concentration. Neural networks were trained with this information to capture the relationships between the plasma tobramycin levels and the following factors: patient-related demographic factors, dosing regimens, and time of blood drawn. The data were also analyzed using a standard population pharmacokinetic modeling program, NON-MEM. The observed vs predicted concentration relationships obtained from the neural network approach were similar to those from NONMEM. The residuals of the predictions from neural network analyses showed a positive correlation with that from NONMEM. Average absolute errors were 33.9 and 37.3% for neural networks and 39.9% for NONMEM. Average prediction errors were found to be 2.59 and -5.01% for neural networks and 17.7% for NONMEM. We concluded that neural networks were capable of capturing the relationships between plasma drug levels and patient-related prognostic factors from routinely collected sparse within-patient pharmacokinetic data. Neural networks can therefore be considered to have potential to become a useful analytical tool for population pharmacokinetic data analysis.

Comparison of population pharmacokinetic modeling methods using simulated data: results from the Population Modeling Workgroup.

Statistical modeling methods have had increasing use in drug disposition studies, both to estimate pharmacokinetic parameters and to develop regression models that relate these parameter estimates to patient characteristics. These methods are particularly flexible as they allow non-linearity and sparse within-patient information. In the past few years, multiple analysis methods have become available, but there is a lack of systematic comparisons of their estimates on the same data sets. Two simulated data sets were therefore developed by the Population Modeling Workgroup of the Biopharmaceutical Section of the American Statistical Association. We analysed these data sets using seven population modeling programs, some of which contain multiple analysis methods. Although each data set represents a single replicate from a given model and data collection design, the results suggest that the behaviour of some methods differs from that of the others.

Averaging pharmacokinetic parameter estimates from experimental studies: statistical theory and application.

In most experimental pharmacokinetic studies, parameter estimates are computed separately for each subject, then averaged across subjects. Average estimators for ratios and functions of parameters are often of interest; examples include half-life and clearance. For these parameters, recommendations regarding averaging using the arithmetic versus the harmonic mean have been based on computer simulations.1-3 The goal in this paper was to demonstrate that these empirically generated results can be derived using approximations for the expected values of reciprocals and ratios. We first consider estimating the reciprocal of a parameter, and predict the earlier simulation results for half-life. We additionally predict results for clearance when computed as dose divided by area under the curve. Next we consider estimating the ratio of two parameters, and predict the earlier simulation results for clearance in a first-order exponential model. As a further example, we predict results for the mean residence time in noncompartmental analysis. These approximations provide a unifying approach that can be used to determine optimal summary estimators, without the need for extensive computer simulations.

Score for neonatal acute physiology and phlebotomy blood loss predict erythrocyte transfusions in premature infants.

OBJECTIVE: To test the hypothesis that utilization of a previously described measure of acuity (ie, the score for neonatal acute physiology [SNAP]) during the first 7 postnatal days predicts which infants with a birth weight of 1500 g or less received erythrocyte transfusion during the initial hospitalization. DESIGN: Retrospective chart review. SETTING: A regional tertiary care newborn intensive care unit at the Arizona Health Sciences Center, University Medical Center, Tucson. MATERIALS: Medical records of premature infants (birth weight, < or = 1500 g) who were admitted from October 1993 to January 1995. MAIN OUTCOME MEASURES: Occurrence or nonoccurrence of erythrocyte transfusion was determined in 47 infants who were compared for demographic information, phlebotomy blood loss, diagnoses, medications, and the SNAP at 0, 1, 2, and 7 days of life. RESULTS: Infants with a birth weight of 1500 g or less received a mean +/- SD of 1.9 +/- 2.9 transfusions with 22 (47%) of the infants given transfusions Infants who were given transfusions vs those who were not given transfusions were of a lower mean +/- SD birth weight (971 +/- 238 g vs 1272 +/- 144 g; P < .001) and a lower gestational age (27.7 +/- 1.6 weeks vs 30.7 +/- 2.8 weeks; P < .001), and they had a greater mean phlebotomy blood loss (3.3 +/- 1.6 mL/kg per day vs 1.4 +/- 0.5 mL/kg per day; P < .001) during the first postnatal week. The SNAP indexes in those who received transfusions were higher at 1, 2, and 7 days of life (P = .03, P = .001, and P < .001, respectively). Using stepwise logistic regression, phlebotomy blood loss and the SNAP at 7 days of life were significant predictors of the number of transfusions. The logistic model predicted which infants had been administered transfusions with 86% sensitivity and 88% specificity. CONCLUSIONS: The efficacy and cost-effectiveness of recombinant human erythropoietin therapy in premature infants remain under study. As earlier treatment with recombinant human erythropoietin may be more efficacious, early identification of which infants currently undergo transfusion may identify those who will receive the greatest benefit from recombinant human erythropoietin therapy. The SNAP distinguished those infants who were given transfusions from those who did not receive transfusions, even after adjusting for phlebotomy blood loss.

Iron utilization after iron dextran administration for iron deficiency in patients with dialysis-associated anemia: a prospective analysis and comparison of two agents.

We sought to determine the rate and extent of iron utilization after administration of intravenous iron dextran and to compare the efficacy of iron dextran preparations of differing molecular weight. We randomized patients to receive either a 500-mg dose of iron dextran molecular weight (MW) 267,000 (group A) or iron dextran MW 96,000 (group B) administered in five sequential 100-mg doses, and examined indices of iron status before and at weekly intervals up to 4 weeks later. Although mean iron utilization was greater in the nine group A patients (46.7% +/- 21.3%) than in the 11 group B patients (31.7% +/- 26.6%), the difference was not statistically significant (P = 0.19). Iron utilization in both groups was substantially incomplete. Changes in serum ferritin and hemoglobin did not differ between the treatments (P = 0.49 and P = 0.34, respectively). We conclude that iron utilization after iron dextran administration is substantial within the first week after completing a course of therapy, associated with stable iron indices after the first 2 weeks, and incomplete for at least the first 4 weeks. Degree of iron utilization appears independent of molecular weight within the range we examined.