Development of a variable-energy, high-intensity, pulsed-mode ion source for low-energy nuclear astrophysics studies.

The primary challenge in directly measuring nuclear reaction rates near stellar energies is their small cross sections. The signal-to-background ratio in these complex experiments can be significantly improved by employing high-current (mA-range) beams and novel detection techniques. Therefore, the electron cyclotron resonance ion source at the Laboratory for Experimental Nuclear Astrophysics underwent a complete upgrade of its acceleration column and microwave system to obtain high-intensity, pulsed proton beams. The new column uses a compression design with O-ring seals for vacuum integrity. Its voltage gradient between electrode sections is produced by the parallel resistance of channels of chilled, deionized water. It also incorporates alternating, transverse magnetic fields for electron suppression and an axially adjustable beam extraction system. Following this upgrade, the operational bremsstrahlung radiation levels and high-voltage stability of the source were vastly improved, over 3.5 mA of target beam current was achieved, and an order-of-magnitude increase in normalized brightness was measured. Beam optics calculations, structural design, and further performance results for this source are presented.

Characterisation of the interactive properties of microcrystalline cellulose-carboxymethyl cellulose hydrogels.

Combinations of microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (Na-CMC) are commonly used as stabilising agents and suspending agents in pharmaceutical formulations. This paper is based on a study of the interactions that take place during the process of hydrogel formation, break down, and recovery. Also considered is the binding that occurs between the MCC and the Na-CMC. Avicel RC 591, a processed mixture of MCC and Na-CMC, is one of the more commonly used commercial suspending agents for aqueous compositions. Avicel RC 591 is used as an effective, blended stabilising agent. In this study, the contributions made by each of the components of Avicel RC 591 have been rationalised by monitoring the behaviour of the individual components in Avicel RC 591 suspensions or solutions. The hydrogels that are formed by Avicel RC 591 and by their laboratory formulated equivalent, which is spray dried (MCC+Na-CMC), have been characterised by confocal microscopy scanning electron microscopy and by dynamic light scattering. A 3D network structure that is formed by the MCC, in Avicel RC 591 is visualised. This network is supported by hydrogen bonding and by ionic interactions among and between the MCC, the Na-CMC and water. The strength of the network determines the physical properties of the hydrogel system, as seen in the rheological behaviour.

Bayesian hierarchical modeling for a non-randomized, longitudinal fall prevention trial with spatially correlated observations.

Because randomization of participants is often not feasible in community-based health interventions, non-randomized designs are commonly employed. Non-randomized designs may have experimental units that are spatial in nature, such as zip codes that are characterized by aggregate statistics from sources like the U.S. census and the Centers for Medicare and Medicaid Services. A perennial concern with non-randomized designs is that even after careful balancing of influential covariates, bias may arise from unmeasured factors. In addition to facilitating the analysis of interventional designs based on spatial units, Bayesian hierarchical modeling can quantify unmeasured variability with spatially correlated residual terms. Graphical analysis of these spatial residuals demonstrates whether variability from unmeasured covariates is likely to bias the estimates of interventional effect. The Connecticut Collaboration for Fall Prevention is the first large-scale longitudinal trial of a community-wide healthcare intervention designed to prevent injurious falls in older adults. Over a two-year evaluation phase, this trial demonstrated a rate of fall-related utilization at hospitals and emergency departments by persons 70 years and older in the intervention area that was 11 per cent less than that of the usual care area, and a 9 per cent lower rate of utilization from serious injuries. We describe the Bayesian hierarchical analysis of this non-randomized intervention with emphasis on its spatial and longitudinal characteristics. We also compare several models, using posterior predictive simulations and maps of spatial residuals.

Prediction of drug release from ethylcellulose coated pellets.

The aim of this study was to elucidate the underlying drug release mechanisms in pellets coated with aqueous ethylcellulose dispersion, providing long term stable drug release profiles and containing different types of starter cores. The systems were thoroughly characterized using mechanical analysis; the sensitivity of drug release to the osmolality of the release medium was measured; scanning electron microscopy and optical macroscopy were used to monitor the pellets' morphology and dimensions upon exposure to different media, and drug release was measured from single and ensembles of pellets as well as from thin, free films. All experimental results indicate that diltiazem HCl release from pellets coated with ethylcellulose containing small amounts of poly(vinyl alcohol)-poly(ethylene glycol) graft copolymer is primarily controlled by drug diffusion through the intact polymeric membranes, irrespective of the type of starter core (consisting of microcrystalline cellulose or sugar, optionally coated with ethylcellulose). Importantly, the apparent diffusion coefficient of the drug in the macromolecular networks could easily be determined with thin free films and successfully be used to quantitatively predict the release rate from coated pellets. Thus, based on this knowledge and using the presented mathematical theories the development of new/ optimization of existing controlled drug delivery systems of this type can be significantly facilitated.

Improved long term stability of aqueous ethylcellulose film coatings: importance of the type of drug and starter core.

Instability during long term storage due to further gradual coalescence of the film remains one of the major challenges when using aqueous polymer dispersions for controlled release coatings. It has recently been shown that the addition of small amounts of poly(vinyl acetate)-poly(ethylene glycol)-graft-copolymer (PVA-PEG-graft-copolymer) to aqueous ethylcellulose dispersion provides long term stable drug release patterns even upon open storage under stress conditions in the case of theophylline matrix cores. However, the transferability of this approach to other types of drugs and starter cores exhibiting different osmotic activity is yet unknown. The aim of this study was to evaluate whether this novel approach is also applicable to freely water-soluble drugs and osmotically active sugar starter cores. Importantly, long term stable drug release profiles from coated diltiazem HCl-layered sugar cores could be achieved even upon open storage for 1 year under stress conditions (40 degrees C and 75% relative humidity). However, to provide desired drug release profiles the amount of added PVA-PEG-graft-copolymer must be adjusted. A minimal critical content of 10% (w/w) of this hydrophilic additive was identified, under which further polymer particle coalescence upon long term storage under stress conditions cannot be excluded. Potentially too rapid drug release can effectively be slowed down by increasing the coating level. Thus, adapting the polymer blend ratio and coating thickness desired and long term stable drug release profiles (even under stress conditions and open storage) can be provided for very different types of drugs and starter cores by the addition of small amounts of PVA-PEG-graft-copolymer to aqueous ethylcellulose dispersion.

How to improve the storage stability of aqueous polymeric film coatings.

The major aim of this study was to identify an easy tool to improve the long term stability of polymeric film coatings applied from aqueous dispersions. Drug release profiles from ethylcellulose-coated theophylline pellets were monitored during 6 months open storage under ambient and stress conditions ["room temperature/ambient relative humidity (RH)" and "40 degrees C/75%RH"]. The pellets were cured for 1 or 2 d at 60 degrees C or for 1 or 2 d at 60 degrees C/75%RH (followed by 1 d at 60 degrees C for drying). Drug release was measured in 0.1 M HCl and in phosphate buffer pH 7.4. Interestingly, the addition of only small amounts of poly(vinyl alcohol)-poly(ethylene glycol) graft copolymer provided stable drug release profiles under all the investigated conditions, irrespective of the type of release medium, coating level, polymer blend ratio and curing conditions. The addition of small amounts of propylene glycol alginate resulted in unaltered drug release kinetics during open storage under ambient conditions, but decreasing theophylline release rates during open storage under stress conditions, due to further gradual polymer particle coalescence. When adding small amounts of carrageenan to the ethylcellulose coatings, essentially stable theophylline release patterns (with slight variations) were obtained. As coating conditions were not optimized for each system, further work is necessary to distinguish polymer from process effects. The observed stabilizing effects of the investigated added polymers might be attributable to their hydrophilic nature, trapping water within the coatings during film formation and, thus, facilitating polymer particle coalescence. This new concept can be used to overcome one of the major practical obstacles associated with aqueous polymeric film coatings today: storage instability.

pH-sensitive film coatings: towards a better understanding and facilitated optimization.

The major aims of this study were: (i) to prepare and characterize polymeric film coatings with pH-dependent properties for oral administration; and (ii) to better understand the underlying mass transport mechanisms upon exposure to simulated gastric and intestinal fluids. Propylene glycol alginate (containing free carboxylic groups) was chosen as a pH-sensitive film former, which was blended with different amounts of ethylcellulose (being water-insoluble throughout the gastro-intestinal tract). The water uptake kinetics of thin free films in 0.1M HCl and phosphate buffer pH 7.4 were monitored gravimetrically and quantitatively described using an appropriate analytical solution of Fick's law of diffusion. Interestingly, the addition of only a low percentage (2.5-10%) of propylene glycol alginate to ethylcellulose significantly increased both, the rate and extent of the films' water uptake, irrespective of the pH of the release medium. Importantly, diffusion was found to be the pre-dominant mass transport mechanism for all system compositions and types of release media. The apparent water diffusivity in the polymeric films could quantitatively be determined as a function of the polymer blend ratio. It significantly increased with increasing pH of the release medium, due to the presence of the free carboxylic groups in propylene glycol alginate. Also the dry mass loss of the polymer networks was much more pronounced at high compared to low pH. The differences in both water uptake as well as dry mass loss resulted in a clear pH-dependence of the drug release kinetics from coated pellets. Importantly, desired pH-sensitive release rates can easily be adjusted by varying the propylene glycol alginate content.

How to adjust desired drug release patterns from ethylcellulose-coated dosage forms.

The aim of this study was to provide an easy and efficient tool to adjust desired drug release kinetics from (aqueous) ethylcellulose-coated solid dosage forms and to better understand the underlying mass transport mechanisms. Pure ethylcellulose films are poorly permeable for many substances and can result in very low release rates for certain drugs from coated dosage forms, if the film coatings are completely formed and remain intact upon exposure to the release media. To increase the permeability of the polymeric membranes, different amounts of a water-soluble poly(vinyl alcohol)-poly(ethylene glycol) graft copolymer (PVA-PEG graft copolymer) were added to an aqueous ethylcellulose dispersion (Aquacoat ECD). Importantly, the presence of only a low percentage of this hydrophilic copolymer significantly increased the resulting water uptake rate and extent, dry weight loss and drug permeability of the films. In contrast to hydroxypropyl methylcellulose (HPMC), the PVA-PEG graft copolymer does not cause flocculation of the colloidal coating dispersion (leading to potentially variable release rates). Interestingly, the transport of water as well as of the model drug theophylline through the polymeric networks was primarily controlled by pure diffusion. The penetration kinetics could be quantitatively described by Fick's law of diffusion, irrespective of the type of release medium and PVA-PEG graft copolymer content. Most important from a practical point of view, a broad spectrum of pH-independent drug release rates can easily be obtained from drug-loaded pellets by simply varying the PVA-PEG graft copolymer content. An appropriate curing step after coating is required, but interestingly the investigated curing conditions (differing in time and relative humidity) resulted in very similar drug release patterns, indicating that stable film structures are likely to be achieved.

Urinary retention after tension-free vaginal tape procedure: incidence and treatment.

OBJECTIVES: To review our experience with persistent urinary retention after the tension-free vaginal tape (TVT) procedure and report our treatment results. Ulmsten recently introduced the TVT procedure for female stress urinary incontinence. Although the morbidity is minimal, no surgical procedure is without risks, and experience will better define the morbidity of the TVT procedure. METHODS: Since November 1998, we have collectively performed 600 TVT procedures. Of these, 17 patients (2.8%) developed urinary retention or symptoms consistent with obstruction (including hesitancy, straining to void, or feeling of incomplete emptying) lasting more than 1 week from the date of the procedure. We reviewed the operative record, noting the operative time, estimated blood loss, presence of bladder penetration, and any reported complications. All 17 patients subsequently underwent transvaginal release on an outpatient basis. RESULTS: Seventeen patients (mean age 56 years, range 38 to 81) underwent sling release a mean of 64 days (range 6 to 228) after the TVT procedure. All patients voided to completion within 24 hours of release and reported no further subjective complaints of outlet obstruction. None of the subjects reported de novo urge incontinence or urgency. In each patient, the estimated blood loss was minimal; the operative time averaged 15 minutes. One urethral injury occurred and was managed intraoperatively without sequelae. Sixteen patients who underwent sling release have remained dry; the remaining patient, in whom a urethral injury was repaired, redeveloped stress incontinence and underwent an uncomplicated successful transvaginal sling procedure. CONCLUSIONS: Outlet obstruction is a risk of the TVT procedure and occurred with an incidence of 2.8% in our experience. The TVT mesh can be released by a simple vaginal incision under local anesthesia with rapid return to normal voiding. Although the number of patients studied was small, stress incontinence did not recur after uncomplicated release in our series.

On the change of support problem for spatio-temporal data.

In practice, spatial data are sometimes collected at points (i.e. point-referenced data) and at other times are associated with areal units (i.e. block data). The change of support problem is concerned with inference about the values of a variable at points or blocks different from those at which it has been observed. In the context of block data which can be sensibly viewed as averaging over point data, we propose a unifying approach for prediction from points to points, points to blocks, blocks to points, and blocks to blocks. The approach includes fully Bayesian kriging. We also extend our approach to the the case of spatio-temporal data, wherein a judicious specification of spatio-temporal association enables manageable computation. Exemplification of the static spatial case is provided using a dataset of point-level ozone measurements in the Atlanta, Georgia metropolitan area. The dynamic spatial case is illustrated using a temporally extended version of this dataset, enabling comparison at the common time point.*To whom correspondence should be addressed.

United States experience with tension-free vaginal tape procedure for urinary stress incontinence: assessment of safety and tolerability.

PURPOSE: The tension-free vaginal tape (TVT) procedure is an operation for treatment of stress urinary incontinence. A polypropylene mesh tape is placed to support the midurethra through a small vaginal incision. In this study, we present our preliminary results evaluating the safety, tolerability, and perioperative morbidity of this procedure. MATERIALS AND METHODS: One hundred patients with stress urinary incontinence underwent the TVT procedure as part of an observational study. Patients were evaluated prospectively with history and pelvic examination, urodynamic studies, perioperative protocol, outcome and satisfaction questionnaire, and postoperative visits at 3 weeks and 2 months. RESULTS: The procedure was performed with the patient under local anesthesia, using intravenous sedation in 97 patients and regional anesthesia in 3. Mean surgical time was 35.5 minutes. Bladder penetration occurred in 24 patients. Forty-two required overnight urethral catheterization. Mean hospital stay was 0.18 days. By 24 hours after the procedure, 95% were able to void. At 3-week follow-up, 88% of patients were completely continent and 9% significantly improved. CONCLUSIONS: The TVT procedure for stress urinary incontinence is a safe, minimally invasive operation with minimal perioperative morbidity. Considering these preliminary findings and long-term European data of 1 to 3 years' experience with continence rate averaging 85%, the TVT procedure may prove to be the operation of choice to treat stress urinary incontinence for many women.

The tension-free vaginal tape procedure for the treatment of stress incontinence in the female patient.

The newest development in the treatment of female stress incontinence is the tension-free vaginal tape (TVT) procedure. This procedure was first described by Ulmsten et al. in 1996 and involves recreating suburethral support with a polypropylene mesh, without repositioning the bladder or urethra. In their initial study, Ulmsten et al. reported an 84% cure rate at 2-year follow-up. The purpose of this report is to discuss the evolution and technical aspects of the TVT procedure and to outline the pre- and postoperative care recommended. A brief summary of our initial experience in our first 100 patients is included.

Comparing hierarchical models for spatio-temporally misaligned data using the deviance information criterion.

Bayes and empirical Bayes methods have proven effective in smoothing crude maps of disease risk, eliminating the instability of estimates in low-population areas while maintaining overall geographic trends and patterns. Recent work extends these methods to the analysis of areal data which are spatially misaligned, that is, involving variables (typically counts or rates) which are aggregated over differing sets of regional boundaries. The addition of a temporal aspect complicates matters further, since now the misalignment can arise either within a given time point, or across time points (as when the regional boundaries themselves evolve over time). Hierarchical Bayesian methods (implemented via modern Markov chain Monte Carlo computing methods) enable the fitting of such models, but a formal comparison of their fit is hampered by their large size and often improper prior specifications. In this paper, we accomplish this comparison using the deviance information criterion (DIC), a recently proposed generalization of the Akaike information criterion (AIC) designed for complex hierarchical model settings like ours. We investigate the use of the delta method for obtaining an approximate variance estimate for DIC, in order to attach significance to apparent differences between models. We illustrate our approach using a spatially misaligned data set relating a measure of traffic density to paediatric asthma hospitalizations in San Diego County, California.

Identifiability and convergence issues for Markov chain Monte Carlo fitting of spatial models.

The marked increase in popularity of Bayesian methods in statistical practice over the last decade owes much to the simultaneous development of Markov chain Monte Carlo (MCMC) methods for the evaluation of requisite posterior distributions. However, along with this increase in computing power has come the temptation to fit models larger than the data can readily support, meaning that often the propriety of the posterior distributions for certain parameters depends on the propriety of the associated prior distributions. An important example arises in spatial modelling, wherein separate random effects for capturing unstructured heterogeneity and spatial clustering are of substantive interest, even though only their sum is well identified by the data. Increasing the informative content of the associated prior distributions offers an obvious remedy, but one that hampers parameter interpretability and may also significantly slow the convergence of the MCMC algorithm. In this paper we investigate the relationship among identifiability, Bayesian learning and MCMC convergence rates for a common class of spatial models, in order to provide guidance for prior selection and algorithm tuning. We are able to elucidate the key issues with relatively simple examples, and also illustrate the varying impacts of covariates, outliers and algorithm starting values on the resulting algorithms and posterior distributions.

Air quality and pediatric emergency room visits for asthma in Atlanta, Georgia, USA.

Pediatric emergency room visits for asthma were studied in relation to air quality indices in a spatio-temporal investigation of approximately 130,000 visits (approximately 6,000 for asthma) to the major emergency care centers in Atlanta, Georgia, during the summers of 1993-1995. Generalized estimating equations, logistic regression, and Bayesian models were fitted to the data. In logistic regression models comparing estimated exposures of asthma cases with those of the nonasthma patients, controlling for temporal and demographic covariates and using residential zip code to link patients to spatially resolved ozone levels, the estimated relative risk per 20 parts per billion (ppb) increase in the maximum 8-hour ozone level was 1.04 (p < 0.05). The estimated relative risk for particulate matter less than or equal to 10 microm in aerodynamic diameter (PM10) was 1.04 per 15 microg/m3 (p < 0.05). Exposure-response trends (p < 0.01) were observed for ozone (>100 ppb vs. <50 ppb: odds ratio = 1.23, p = 0.003) and PM10 (>60 microg/m3 vs. <20 microg/m3: odds ratio = 1.26, p = 0.004). In models with ozone and PM10, both terms became nonsignificant because of collinearity of the variables (r= 0.75). The other analytical approaches yielded consistent findings. This study supports accumulating evidence regarding the relation of air pollution to childhood asthma exacerbation.

The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma.

BACKGROUND: Prostate carcinoma poses a significant public health problem. Although a minority of men with newly diagnosed prostate carcinoma manifest bone metastases or skeletal abnormalities, a significant proportion of men will develop these complications over the course of their lives. Patients at highest risk for bone metastases include those with high grade, high stage neoplasms, those who fail primary curative therapies such as radical prostatectomy or radiation therapy, and those who develop biochemical recurrence after hormonal therapy. METHODS: The relative risks and prognostic factors for bone metastases in each of these settings will be reviewed. RESULTS: In comparison with men without prostate carcinoma, benign skeletal complications (osteopenia and fractures) occur at significantly increased rates among men with untreated prostate carcinoma. Moreover, the incidence rate of these conditions increases dramatically among those men who are receiving endocrine therapy. The duration and intensity of the endocrine therapy may be associated with the incidence rate and severity of skeletal complications. CONCLUSIONS: Given the significant incidence rate and quality of life implications of skeletal complications and bone metastases, there is an urgent need to identify effective preventive therapies and treatments. Bisphosphonates may have a role in preventing osteopenia and, potentially, bone metastases among men with prostate carcinoma.

Creating local bibliographic databases: new tools for evidence-based health care.

The Internet has created new opportunities for librarians to present literature search results to clinicians. In order to take full advantage of these opportunities, libraries need to create locally maintained bibliographic databases. A simple method of creating a local bibliographic database and publishing it on the Web is described. The method uses off-the-shelf software and requires minimal programming. A hedge search strategy for outcome studies of clinical process interventions is created, and Ovid is used to search MEDLINE. The search results are saved and imported into EndNote libraries. The citations are modified, exported to a Microsoft Access database, and published on the Web. Clinicians can use a Web browser to search the database. The bibliographic database contains 13,803 MEDLINE citations of outcome studies. Most searches take between four and ten seconds and retrieve between ten and 100 citations. The entire cost of the software is under $900. Locally maintained bibliographic databases can be created easily and inexpensively. They significantly extend the evidence-based health care services that libraries can offer to clinicians.