Prospective evaluation of a D-optimal designed population pharmacokinetic study

Recently, methods for computing D-optimal designs for population pharmacokinetic studies have become available. However there are few publications that have prospectively evaluated the benefits of D-optimality in population or single-subject settings. This study compared a population optimal design with an empirical design for estimating the base pharmacokinetic model for enoxaparin in a stratified randomized setting. The population pharmacokinetic D-optimal design for enoxaparin was estimated using the PFIM function (MATLAB version 6.0.0.88). The optimal design was based on a one-compartment model with lognormal between subject variability and proportional residual variability and consisted of a single design with three sampling windows (0-30 min, 1.5-5 hr and 11 - 12 hr post-dose) for all patients. The empirical design consisted of three sample time windows per patient from a total of nine windows that collectively represented the entire dose interval. Each patient was assigned to have one blood sample taken from three different windows. Windows for blood sampling times were also provided for the optimal design. Ninety six patients were recruited into the study who were currently receiving enoxaparin therapy. Patients were randomly assigned to either the optimal or empirical sampling design, stratified for body mass index. The exact times of blood samples and doses were recorded. Analysis was undertaken using NONMEM (version 5). The empirical design supported a one compartment linear model with additive residual error, while the optimal design supported a two compartment linear model with additive residual error as did the model derived from the full data set. A posterior predictive check was performed where the models arising from the empirical and optimal designs were used to predict into the full data set. This revealed the optimal'' design derived model was superior to the empirical design model in terms of precision and was similar to the model developed from the full dataset. This study suggests optimal design techniques may be useful, even when the optimized design was based on a model that was misspecified in terms of the structural and statistical models and when the implementation of the optimal designed study deviated from the nominal design.

Teamwork in Health and Rehabilitation Sciences: Evaluation of a multiprofessional workshop

This paper outlines a multiprofessional education workshop piloted and subsequently conducted with a cohort of 81 graduate entry students of occupational therapy, physiotherapy, speech pathology and audiology. The rationale for, and format of, the workshop is outlined, followed by comparisons between students' knowledge about teamwork prior to and after the four-hour workshop. The workshop was based on a real case scenario of a child with Developmental Coordination Disorder (DCD). Students completed pre- and post-workshop questionnaires about their knowledge of DCD, teamwork and the roles of various professionals and parents; and a post-workshop questionnaire about their views regarding the utility of the workshop, its strengths, and learning outcomes. The evaluation indicated that the workshop was overwhelmingly successful from the students' perspective in: (1) enhancing their understanding about DCD and its multifaceted impact on school age children; (2) developing a deeper appreciation of the importance of teamwork itself; (3) refining their understanding of their own profession's role and (4) developing an appreciation of the role of other professions and parents in working with children with complex needs, and their families. Limitations of this study and directions for future research are discussed.

An evaluation of continuous positive airway pressure (CPAP) therapy in the treatment of hypernasality following traumatic brain injury - A report of 3 cases

Objective: To evaluate the effectiveness of continuous positive airway pressure (CPAP) therapy in the treatment of hypernasality following traumatic brain injury (17111). Design: An A-B-A experimental research design. Assessments were conducted prior to commencement of the program, midway, immediately posttreatment, and 1 month after completion of the CPAP therapy program. Participants: Three adults with dysarthria and moderate to severe hypernasality subsequent to TBI. Outcome Measures: Perceptual evaluation using the Frenchay Dysarthria Assessment, the Assessment of Intelligibility of Dysarthric Speech, and a speech sample analysis, and instrumental evaluation using the Nasometer. Results: Between assessment periods, varying degrees of improvement in hypernasality and sentence intelligibility were noted. At the 1-month post-CPAP assessment, all 3 participants demonstrated reduced nasalance values, and 2 exhibited increased sentence intelligibility. Conclusions: CPAP may be a valuable treatment of impaired velopharyngeal function in the TBI population.

Encouraging practitioners to use resources: evaluation of the national implementation of a resource to improve the clinical management of alcohol-related problems in Indigenous primary care settings

This paper reports on the evaluation of the implementation of the National Recommendations for the Clinical Management of Alcohol-Related Problems in Indigenous Primary Care Settings undertaken in 2001 through 74 standardized workshops, which sought to determine: ( 1) whether this approach to implementation influenced the likelihood that the National Recommendations would be used; ( 2) whether it influenced participants' willingness to engage with Indigenous patients regarding alcohol-related issues; and ( 3) whether the implementation as a whole influenced both practice and clinicians' willingness to engage. Evaluation included pre-/post-workshop and follow-up questionnaires and a focus group. The findings presented indicate that distribution of clinical resources alone is not sufficient to ensure use and that, particularly for medical practitioners, appropriate introduction not only increases use but also positively influences willingness to engage with alcohol-related problems as part of primary clinical care. Further, the enthusiasm for guideline production should be tempered by the need to develop effective implementation strategies.

The use of cusum analysis in the early detection and management of hospital bed occupancy crises

Objective: To assess the value of cusum analysis in hospital bed management. Design: Comparative analysis of medical patient flows, bed occupancy, and emergency department admission rates and access block over 2 years. Setting: Internal Medicine Services and Emergency Department in a teaching hospital. Interventions: Improvements in bed use and changes in the level of available beds. Main outcome measures: Average length of stay; percentage occupancy of available beds; number of patients waiting more than 8 hours for admission (access block); number of medical patients occupying beds in non-medical wards; and number of elective surgical admissions. Results: Cusum analysis provided a simple means of revealing important trends in patient flows that were not obvious in conventional time-series data. This prompted improvements in bed use that resulted in a decrease of 9500 occupied bed-days over a year. Unfortunately and unexpectedly, after some initial improvement, the levels of access block, medical ward congestion and elective surgical admissions all then deteriorated significantly. This was probably caused by excessive bed closures in response to the initial improvement in bed use. Conclusion: Cusum analysis is a useful technique for the early detection of significant changes in patient flows and bed use, and in determining the appropriate number of beds required for a given rate of patient flow.

Evaluation of the Western Australian Department of Health telehealth project

In 1999, the Department of Health in Western Australia began a telehealth project, which finished in 2004. The 75 videoconferencing sites funded by the project were part of a total state-wide videoconference network of 104 sites. During the period from January 2002 to December 2003, a total of 3266 consultations, case reviews and patient education sessions took place. Clinical use grew to 30% of all telehealth activity. Educational use was approximately 40% (1416 sessions) and management use was about 30% (1031 sessions). The average overhead cost per telehealth session across all regions and usage types was $A192. Meaningful comparisons of the results of the present study with other public health providers were difficult, because many of the available Websites on telehealth were out of date. Despite the successful use of telehealth to deliver clinical services in Western Australia, sustaining the effort in the post-project phase will present significant challenges.

Analysis of O-glycosylation site occupancy in bovine kappa-casein glycoforms separated by two-dimensional gel electrophoresis

The ability of two-dimensional gel electrophoresis (2-DE) to separate glycoproteins was exploited to separate distinct glycoforms of kappa-casein that differed only in the number of O-glycans that were attached. To determine where the glycans were attached, the individual glycoforms were digested in-gel with pepsin and the released glycopeptides were identified from characteristic sugar ions in the tandem mass spectrometry (MS) spectra. The O-glycosylation sites were identified by tandem MS after replacement of the glycans with ammonia/aminoethanethiol. The results showed that glycans were not randomly distributed among the five potential glycosylation sites in kappa-casein. Rather, glycosylation of the monoglycoform could only be detected at a single site, T-152. Similarly the diglycoform appeared to be modified exclusively at T-152 and T-163, while the triglycoform was modified at T-152, T-163 and T-154. While low levels of glycosylation at other sites cannot be excluded the hierarchy of site occupation between glycoforms was clearly evident and argues for an ordered addition of glycans to the protein. Since all five potential O-glycosylation sites can be glycosylated in vivo, it would appear that certain sites remain latent until other sites are occupied. The determination of glycosylation site occupancy in individual glycoforms separated by 2-DE revealed a distinct pattern of in vivo glycosylation that has not been recognized previously.

Pharmacological evaluation of an [I-123] labelled imidazopyridine-3-acetamide for the study of benzodiazepine receptors

In vitro binding of the iodinated imidazopyri dine, N',N'-dimethyl-6-methyl-(4'-[I-123]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide [I-123]IZOL to benzodiazepine binding sites on brain cortex, adrenal and kidney membranes is reported. Saturation experiments showed that [I-123]IZOL, bound to a single class of binding site (n(H)=0.99) on adrenal and kidney mitochondrial membranes with a moderate affinity (K-d=30 nM). The density of binding sites was 22 +/- 6 and 1.2 +/- 0.4 pmol/mg protein on adrenal and kidney membranes, respectively. No specific binding was observed in mitochondrial-synaptosomal membranes of brain cortex. In biodistribution studies in rats, the highest uptake of [I-123]IZOL was found 30 min post injection in adrenals (7.5% ID/g), followed by heart, kidney, lung (1% ID/g) and brain (0.12% ID/g), consistent with the distribution of peripheral benzodiazepine binding sites. Pre-administration of unlabelled IZOL and the specific PBBS drugs, PK 11195 and Ro 5-4864 significantly reduced the uptake of [I-123]IZOL by 30% (p < 0.05) in olfactory bulbs and by 51-86% (p < 0.01) in kidney, lungs, heart and adrenals, while it increased by 30% to 50% (p < 0.01) in the rest of the brain and the blood. Diazepam, a mixed CBR-PBBS drug, inhibited the uptake in kidney, lungs, heart, adrenals and olfactory bulbs by 32% to 44% (p < 0.01) but with no effect on brain uptake and in blood concentration. Flumazenil, a central benzodiazepine drug and haloperidol (dopamine antagonist/sigma receptor drug) displayed no effect in [I-123]IZOL in peripheral organs and in the brain. [I-123]IZOL may deserve further development for imaging selectively peripheral benzodiazepine binding sites. (c) 2006 Elsevier Inc. All rights reserved.

A cost-effectiveness analysis of heroin detoxification methods in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD)

This economic evaluation was part of the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD) project. Data from four trials of heroin detoxification methods, involving 365 participants, were pooled to enable a comprehensive comparison of the cost-effectiveness of five inpatient and outpatient detoxification methods. This study took the perspective of the treatment provider in assessing resource use and costs. Two short-term outcome measures were used-achievement of an initial 7-day period of abstinence, and entry into ongoing post-detoxification treatment. The mean costs of the various detoxification methods ranged widely, from AUD $491 (buprenorphine-based outpatient); to AUD $605 for conventional outpatient; AUD $1404 for conventional inpatient; AUD $1990 for rapid detoxification under sedation; and to AUD $2689 for anaesthesia per episode. An incremental cost-effectiveness analysis was carried out using conventional outpatient detoxification as the base comparator. The buprenorphine-based outpatient detoxification method was found to be the most cost-effective method overall, and rapid opioid detoxification under sedation was the most costeffective inpatient method.

Evaluation of immune effects of fowlpox vaccine strains and field isolates

The immune effects of fowlpox virus (FPV) field isolates and vaccine strains were evaluated in chickens infected at the age of 1 day and 6 weeks. The field isolates and the obsolete vaccine strain (FPV S) contained integrated reticuloendotheliosis virus (REV) provirus, while the current vaccine strain (FPVST) carries only REV LTR sequences. An indirect antibody ELISA was used to measure the FPV-specific antibody response. The non-specific humoral response was evaluated by injection of two T-cell-dependent antigens, sheep red blood cells (SRBC) and bovine serum albumin (BSA). There was no significant difference in the antibody response to FPV between chickens infected with FPV various isolates and strains at either age. In contrast, antibody responses to both SRBC and BSA were significantly lower in 1-day-old chickens inoculated with field isolates and FPV S at 2-3 weeks post-inoculation. Furthermore, cell-mediated immune (CMI) responses measured by in vitro lymphocyte proliferation assay and in vivo using a PHA-P skin test were significantly depressed in chickens inoculated with field isolates and FPV S at the same periods. In addition, thymus and bursal weights were lower in infected chickens. These immunosuppressive effects were not observed in chickens inoculated with the current vaccine strain, FPVST, at any time. The results of this study suggest that virulent field isolates and FPV S have immunosuppressive effects when inoculated into young chickens, which appeared in the first 3 weeks post infection. REV integrated in the FPV field isolates and FPV S may have played a central role in the development of immunosuppression. (c) 2006 Elsevier B.V. All rights reserved.