Cost of dialysis therapies in rural and remote Australia - a micro-costing analysis.

BACKGROUND: Maintenance dialysis is a costly and resource intense activity. In Australia, inadequate health infrastructure and poor access to technically skilled staff can limit service provision in remote areas where many Aboriginal dialysis patients live. With most studies based on urban service provision, there is little evidence to guide service development. However permanent relocation to an urban area for treatment can have significant social and financial impacts that are poorly quantified. This study is part of a broader project to quantify the costs and benefits of dialysis service models in urban and remote locations in Australia's Northern Territory (NT). METHODS: We undertook a micro-costing analysis of dialysis service delivery costs in urban, rural and remote areas in the NT from the payer perspective. Recurrent maintenance costs (salaries, consumables, facility management and transportation) as well as capital costs were included. Missing and centralised costs were standardised; results were inflated to 2017 values and reported in Australian dollars. RESULTS: There was little difference between the average annual cost for urban and rural services with respective median costs of $85,919 versus $84,629. However remote service costs were higher ($120,172 - $124,492), driven by higher staff costs. The inclusion of capital costs did not add substantially to annual costs. Annual home haemodialysis costs ($42,927) were similar to other jurisdictions despite the significant differences in program delivery and payment of expenses not traditionally borne by governments. Annual peritoneal dialysis costs ($58,489) were both higher than home and in-centre haemodialysis by recent national dialysis cost studies. CONCLUSION: The cost drivers for staffed services were staffing models and patient attendance rates. Staff salaries and transport costs were significantly higher in remote models of care. Opportunities to reduce expenditure exist by encouraging community supported services and employing local staff. Despite the delivery challenges of home haemodialysis including high patient attrition, the program still provides a cost benefit compared to urban staffed services. The next component of this study will examine patient health service utilisation and costs by model of care to provide a more comprehensive analysis of the overall cost of providing services in each location.

Reduced retinal transduction and enhanced transgene-directed immunogenicity with intravitreal delivery of rAAV following posterior vitrectomy in dogs.

Adeno-associated virus (AAV) vector-based gene therapy is a promising treatment strategy for delivery of neurotrophic transgenes to retinal ganglion cells (RGCs) in glaucoma patients. Retinal distribution of transgene expression following intravitreal injection (IVT) of AAV is variable in animal models and the vitreous humor may represent a barrier to initial vector penetration. The primary goal of our study was to investigate the effect of prior core vitrectomy with posterior hyaloid membrane peeling on pattern and efficiency of transduction of a capsid amino acid substituted AAV2 vector, carrying the green fluorescent protein (GFP) reporter transgene following IVT in dogs. When progressive intraocular inflammation developed starting 4 weeks post IVT, the study plan was modified to allow detailed characterization of the etiology as a secondary goal. Unexpectedly, surgical vitrectomy was found to significantly limit transduction, whereas in non-vitrectomized eyes transduction efficiency reached upwards to 37.3% of RGC layer cells. The developing retinitis was characterized by mononuclear cell infiltrates resulting from a delayed-type hypersensitivity reaction, which we suspect was directed at the GFP transgene. Our results, in a canine large animal model, support caution when considering surgical vitrectomy before IVT for retinal gene therapy in patients, as prior vitrectomy appears to significantly reduce transduction efficiency and may predispose the patient to development of vector-induced immune reactions.

Stem-cell therapy for dilated cardiomyopathy: a pilot study evaluating retrograde coronary venous delivery.

OBJECTIVE: To evaluate retrograde coronary venous stem-cell delivery for Dobermanns with dilated cardiomyopathy. METHODS: Retrograde coronary venous delivery of adipose-derived mesenchymal stem cells transduced with tyrosine mutant adeno-associated virus 2 to express stromal-derived factor-1 was performed in Dobermanns with dilated cardiomyopathy. Cases were followed for 2 years and electrocardiograms (ECG), echocardiograms and Holter monitoring were performed. RESULTS: Delivery of cells was feasible in 15 of 15 dogs. One dog died following the development of ventricular fibrillation 24 hours after cell delivery. The remaining 14 dogs were discharged the following day without complications. Echocardiographic measurements of left ventricular size and function showed continued progression of disease. On the basis of Kaplan-Meier product limit estimates, median survival for dogs following stem-cell delivery was 620 days (range of 1-799 days). When including only the occult-dilated cardiomyopathy population and excluding those dogs already in congestive heart failure, median survival was 652 days (range of 46-799 days). CLINICAL SIGNIFICANCE: Retrograde venous delivery of tyrosine mutant adeno-associated virus 2-stromal-derived factor-1 adipose-derived mesenchymal stem cells appears safe. Stem-cell therapy in dogs with occult-dilated cardiomyopathy does not appear to offer advantage compared to recently published survival data in similarly affected Dobermanns.

New developments in service delivery. Are GP led sexual health clinics acceptable and satisfactory for patients attending?

Worldwide, sexually transmitted infections (STls) are among the most common causes of disease. The aim of this study was to evaluate why people attend a community based sexual health clinic and the benefits and satisfaction levels of providing this service to them. Phase I of the study was a cross sectional survey. Phase II was a retrospective review. Phase 1: N ='80 (41 F, 39 M - mean age 24.8 (SD 6.49)), 45 (56.3%) requested a general sexual health screen. Phase 2: N = 273, (139 F, 134 M - mean age 23.7 (SD 5.87)) 47 (15.5%/) reported use of condoms, 126(41.6%) do not use condoms ever, while 73 (24.1%) reported using condoms sometimes. 47 individuals (17%) tested positive for chlamydia. Attendees to the clinic expressed a high level of satisfaction overall with the services provided. The low use of condoms amongst a subgroup of patients with several sexual partners and the high level of chlamydia are causes for concern.

Seizure characterisation using frequency-dependent multivariate dynamics.

The characterisation of epileptic seizures assists in the design of targeted pharmaceutical seizure prevention techniques and pre-surgical evaluations. In this paper, we expand on the recent use of multivariate techniques to study the cross-correlation dynamics between electroencephalographic (EEG) channels. The maximum overlap discrete wavelet transform (MODWT) is applied in order to separate the EEG channels into their underlying frequencies. The dynamics of the cross-correlation matrix between channels, at each frequency, are then analysed in terms of the eigenspectrum. By examination of the eigenspectrum, we show that it is possible to identify frequency-dependent changes in the correlation structure between channels which may be indicative of seizure activity. The technique is applied to EEG epileptiform data and the results indicate that the correlation dynamics vary over time and frequency, with larger correlations between channels at high frequencies. Additionally, a redistribution of wavelet energy is found, with increased fractional energy demonstrating the relative importance of high frequencies during seizures. Dynamical changes also occur in both correlation and energy at lower frequencies during seizures, suggesting that monitoring frequency-dependent correlation structure can characterise changes in EEG signals during these. Future work will involve the study of other large eigenvalues and inter-frequency correlations to determine additional seizure characteristics.

Targeting recombinant adeno-associated virus vectors to enhance gene transfer to pancreatic islets and liver.

Human pancreatic islet cells and hepatocytes represent the two most likely target cells for genetic therapy of type I diabetes. However, limits to the efficiency of rAAV serotype 2 (rAAV2)-mediated gene transfer have been reported for both of these cell targets. Here we report that nonserotype 2 AAV capsids can mediate more efficient transduction of islet cells, with AAV1 being the most efficient serotype in murine islets, suggesting that receptor abundance could be limiting. In order to test this, we generated rAAV particles that display a ligand (ApoE) that targets the low-density lipoprotein receptor, which is present on both of these cell types. The rAAV/ApoE viruses greatly enhanced the efficiency of transduction of both islet cells ex vivo and murine hepatocytes in vivo when compared to native rAAV2 serotype (220- and four-fold, respectively). The use of receptor-targeted rAAV particles may circumvent the lower abundance of receptors on certain nonpermissive cell types.

Mutational analysis of the adeno-associated virus type 2 (AAV2) capsid gene and construction of AAV2 vectors with altered tropism.

Adeno-associated virus type 2 (AAV2) has proven to be a valuable vector for gene therapy. Characterization of the functional domains of the AAV capsid proteins can facilitate our understanding of viral tissue tropism, immunoreactivity, viral entry, and DNA packaging, all of which are important issues for generating improved vectors. To obtain a comprehensive genetic map of the AAV capsid gene, we have constructed 93 mutants at 59 different positions in the AAV capsid gene by site-directed mutagenesis. Several types of mutants were studied, including epitope tag or ligand insertion mutants, alanine scanning mutants, and epitope substitution mutants. Analysis of these mutants revealed eight separate phenotypes. Infectious titers of the mutants revealed four classes. Class 1 mutants were viable, class 2 mutants were partially defective, class 3 mutants were temperature sensitive, and class 4 mutants were noninfectious. Further analysis revealed some of the defects in the class 2, 3, and 4 mutants. Among the class 4 mutants, a subset completely abolished capsid formation. These mutants were located predominantly, but not exclusively, in what are likely to be beta-barrel structures in the capsid protein VP3. Two of these mutants were insertions at the N and C termini of VP3, suggesting that both ends of VP3 play a role that is important for capsid assembly or stability. Several class 2 and 3 mutants produced capsids that were unstable during purification of viral particles. One mutant, R432A, made only empty capsids, presumably due to a defect in packaging viral DNA. Additionally, five mutants were defective in heparan binding, a step that is believed to be essential for viral entry. These were distributed into two amino acid clusters in what is likely to be a cell surface loop in the capsid protein VP3. The first cluster spanned amino acids 509 to 522; the second was between amino acids 561 and 591. In addition to the heparan binding clusters, hemagglutinin epitope tag insertions identified several other regions that were on the surface of the capsid. These included insertions at amino acids 1, 34, 138, 266, 447, 591, and 664. Positions 1 and 138 were the N termini of VP1 and VP2, respectively; position 34 was exclusively in VP1; the remaining surface positions were located in putative loop regions of VP3. The remaining mutants, most of them partially defective, were presumably defective in steps of viral entry that were not tested in the preliminary screening, including intracellular trafficking, viral uncoating, or coreceptor binding. Finally, in vitro experiments showed that insertion of the serpin receptor ligand in the N-terminal regions of VP1 or VP2 can change the tropism of AAV. Our results provide information on AAV capsid functional domains and are useful for future design of AAV vectors for targeting of specific tissues.

Mother-to-child transmission of human immunodeficiency virus (HIV) in Ireland: a prospective study.

Symptomatic HIV infection was first diagnosed in an Irish child in 1985. A prospective study was initiated to determine the vertical transmission rate (VTR) of HIV and the average age of infant seroreversion and to monitor clinical, immunologic and virologic evidence for HIV infection in seroreverters. Ninety three HIV positive infants have been prospectively identified since 1985. The predominant underlying maternal risk factor for HIV infection is intravenous drug use (IVDU) (96 per cent). Of 93 infants, median gestational age was 40 weeks and median birth weight 3125 grams. Ninety-four per cent of infants were bottle fed. Currently 72 (77 per cent) infants are uninfected, 12 (13 per cent) are infected, 4 (4.5 per cent) are indeterminate and 5 (5.5 per cent) have been lost to follow up. The intermediate estimate of vertical transmission rate (VTR) is 14.3 per cent. The median age at documented seroreversion was 12 months. There are no significant differences between infected and non-infected children in male/female ratio, gestational age, mode of delivery or birth weight. Strategies to reduce the transmission of HIV among drug users in combination with routine antenatal screening and antiretroviral prophylaxis of vertical transmission are all measures which can reduce HIV infection in our children.

Use of composite scores (megascores) to measure deficit in amyotrophic lateral sclerosis.

The Tufts Quantitative Neuromuscular Exam (TQNE) consists of 28 items that were designed to measure voluntary motor deficit in amyotrophic lateral sclerosis (ALS) and related diseases. Individual raw data were converted to Z scores for standardization and then grouped into five megascores with statistical and clinical relevance. The derived megascores were Mega 1, pulmonary function; Mega 2, bulbar function; Mega 3, timed hand activities; Mega 4, isometric arm strength; and Mega 5, isometric leg strength. Megascores should enhance the usefulness of testing in therapeutic trials and in analyzing the natural history of ALS and related diseases.

The natural history of motoneuron loss in amyotrophic lateral sclerosis.

Using a quantitative, reliable, sensitive and valid measurement technique, we analyzed the rate and pattern of motor deterioration in 50 strictly defined ALS patients for up to 67 months. We observed that the rate of motoneuron loss was linear and symmetric. Bulbar function deteriorated more slowly than respiratory, arm, and leg function. The loss of leg strength was slower than in the arm. No correlation was observed between age at onset and rate of deterioration, or with different regions of onset. Arm strength changed more slowly in women, but other functions showed no male-female differences. These data should prove useful in the design of clinical trials and in generating testable hypotheses of the etiology of this disease.

Hemodynamic correlates of left ventricular versus right ventricular radionuclide volumetric responses to vasodilator therapy in congestive heart failure secondary to ischemic or dilated cardiomyopathy.

Previous studies have failed to demonstrate the clinical relevance of radionuclide functional measurements during treatment of congestive heart failure (CHF). In the present study, data derived before and during nitroprusside infusion were analyzed in 16 patients with CHF to compare correlations of changes in left (LV) and right ventricular (RV) radionuclide measurements with simultaneous changes in 8 hemodynamic variables. Nitroprusside infusion decreased systemic artery pressure, pulmonary arterial wedge pressure, pulmonary artery pressure, right atrial pressure, and pulmonary and systemic vascular resistance, and increased cardiac output. Nitroprusside decreased LV and RV end-diastolic and end-systolic volumes and increased LV and RV ejection fraction and stroke volume. Changes in RV volumes exceeded changes in LV volumes. LV radionuclide measurements did not correlate significantly with any hemodynamic measurement except for a weak correlation between changes in LV end-systolic volume and right atrial pressure (r = 0.51). In contrast, the combination of changes in RV end-systolic volume and stroke volume predicted changes in pulmonary artery peak systolic (r = 0.90) and mean (r = 0.89) pressures. Changes in pulmonary arterial wedge pressure correlated with changes in RV end-diastolic (r = 0.78) and end-systolic (r = 0.71) volumes. In conclusion, LV radionuclide measurements are of limited value in predicting hemodynamic responses to vasodilator therapy in CHF, whereas RV volumes are strongly influenced by load changes. Their responses to nitroprusside correlate well with changes in pulmonary artery and pulmonary arterial wedge pressures.

The relationship between estrogen levels and diets of Caucasian American and Oriental immigrant women.

The relationship between diet and estrogens was studied in two groups of women with different dietary habits and breast cancer risks. Plasma estrogens and androgens and 24-h urinary and fecal excretion of estrogens were measured in premenopausal and postmenopausal Caucasians and recent Oriental immigrants from Southeast Asia to Hawaii. Premenopausal Caucasians had 30-75% higher plasma estrone and estradiol levels than their age-matched cohorts in Hawaii, and the postmenopausal Caucasians had 3-fold higher plasma levels of estradiol. The Oriental women excreted more than twice the amount of estrogen in their feces but they excreted significantly less in their urine. Thus, the ratio of urinary-to-fecal excretion was approximately 3-5 times higher in young Caucasian women. Analysis of dietary components and plasma estrogens in premenopausal women showed a positive correlation between daily intake of total fat and saturated fat and plasma estrone and estradiol concentrations.

Quantitative motor assessment in amyotrophic lateral sclerosis.

Reliable measurements are needed to document the natural history of ALS and to determine therapeutic efficacy. We have devised a standardized protocol that generates interval data sensitive to change-the Tufts Quantitative Neuromuscular Exam (TQNE). The TQNE consists of the following four major categories: pulmonary function, oropharyngeal function, timed functional activities, and isometric strength using an electronic strain gauge. The 29-item exam takes about 1 hour to administer and has excellent test-retest reliability.

The costs of surgery for limb-threatening ischemia.

The clinical courses of 106 patients with limb-threatening ischemia were traced for as long as 5 years to determine the cost of their care. Seventy-eight patients initially treated with vascular reconstruction accrued an average of $40,769 +/- $3726 in costs over a mean follow-up period of 805 +/- 57 days, during which they had an average of 2.4 +/- 0.2 hospitalizations or 67 +/- 6 inpatient days. Twenty-eight high-risk patients treated with primary amputation accrued $40,563 +/- $4729 in costs over a mean follow-up period of 663 +/- 97 days, during which they had an average of 2.2 +/- 0.3 hospitalizations or 85 +/- 10 inpatient days. Successful revascularization resulted in lower costs ($28,374) than did primary amputation ($40,563) or failed reconstruction ($56,809). Patients with ischemic tissue loss accrued costs more rapidly than did patients with rest pain only. The high cost of providing care for these patients and the advent of diagnosis related group reimbursement mandate that proposed treatment protocols be evaluated not only for their effectiveness but also for their cost-effectiveness.

Comparison of left and right ventricular end-systolic pressure-volume relations in congestive heart failure.

A hemodynamic-radionuclide study was performed to compare the relations between end-systolic pressure and volume in the left and right ventricles in 10 patients with biventricular failure, and to correlate the end-systolic pressure-volume slope with baseline variables of systolic function. During nitroprusside or nitroglycerin infusion, or a combination of both, linear relations were found between end-systolic pressure and volume for both ventricles. In 9 of 10 patients, the end-systolic pressure-volume slope was greater for the left ventricle (mean +/- SD 1.12 +/- 0.36 mm Hg X m2/ml) than for the right ventricle (0.46 +/- 0.27 mm Hg X m2/ml) (p less than 0.001). In all 10 patients, the volume-axis intercept of the pressure-volume relation was greater for the left ventricle (82 +/- 66 ml/m2) than for the right ventricle (2 +/- 30 ml/m2) (p less than 0.005). Right ventricular pressure-volume slope correlated weakly with baseline right ventricular ejection fraction (r = 0.69, p less than 0.05), strongly with the baseline right ventricular end-systolic pressure-volume ratio (r = 0.89) and inversely with baseline right ventricular end-systolic volume (r = -0.86). In conclusion, 1) in patients with severe biventricular failure, changes in systolic pressure influence end-systolic volume more strongly in the right than in the left ventricle. 2) For the right ventricle, the slope of the end-systolic pressure-volume relation is directly related to rest indexes of systolic function. 3) The greater the end-systolic volume at rest, the greater the predicted improvement in right ventricular emptying for any vasodilator-induced reduction in pulmonary artery end-systolic pressure.

Effects of gastric inhibitory polypeptide on dispersed pancreatic acinar cells from the guinea pig.

Purified natural porcine gastric inhibitory polypeptide (GIP), in high concentrations, was found to stimulate outflow of 45Ca, increase cellular accumulation of cyclic GMP and cyclic AMP and cause release of amylase from dispersed pancreatic acinar cells. Synthetic GIP increased cellular cyclic AMP levels, but did not affect outflux of calcium, cellular levels of cyclic GMP or release of amylase. The discrepancy between results with natural and synthetic preparations of porcine GIP may be explained by a possible contamination of natural GIP with cholecystokinin. Other examined pancreatic secretory stimulating peptides which induce cyclic AMP accumulation in acinar cells, also increase release of amylase. Synthetic GIP increased levels of cyclic AMP without affecting amylase release. This suggests that the correlation between amylase release and total cellular accumulation of cyclic AMP in response to GIP is not close.

Deformability and cell membrane properties of erythrocytes in Duchenne muscular dystrophy.

In many investigations of the hypothesis of a membrane defect in Duchenne muscular dystrophy, the erythrocyte has been the cell of choice, but reported abnormalities in the Duchenne erythrocyte are disputed. Techniques of microsieving, cell surface staining and measurement of cell water diffusion turnover rate have been used in this investigation to examine erythrocyte properties. Measurements of pressure drop-velocity relations were carried out in a capillary pore rheometer using pure erythrocyte suspensions. The study showed that Duchenne erythrocytes do not behave differently from normal, results which are in substantial agreement with similar microsieving studies. A nuclear magnetic resonance method was used to measure cell water diffusion efflux which, using our cell surface data, could be related to cell membrane permeability. Under normal conditions and conditions of chemical interference with the membrane protein, the results revealed that the membrane pathways involved in water diffusion in Duchenne erythrocytes are unaltered.