The Construction of a Predictive Composite Index for Decision-Making of CSF Diversion Surgery in Pediatric Patients following Prenatal Myelomeningocele Repair.

BACKGROUND AND PURPOSE: There is a wide range of clinical and radiographic factors affecting individual surgeons' ultimate decision for CSF diversion for pediatric patients following prenatal myelomeningocele repair. Our aim was to construct a composite index (CSF diversion surgery index) that integrates conventional clinical measures and neuroimaging biomarkers to predict CSF diversion surgery in these pediatric patients. MATERIALS AND METHODS: This was a secondary retrospective analysis of data from 33 patients with prenatal myelomeningocele repair (including 14 who ultimately required CSF diversion surgery). Potential independent variables, including the Management of Myelomeningocele Study Index (a dichotomized variable based on the shunt-placement criteria from the Management of Myelomeningocele Study), postnatal DTI measures (fractional anisotropy and mean diffusivity in the genu of the corpus callosum and the posterior limb of internal capsule), fronto-occipital horn ratio at the time of DTI, gestational ages, and sex, were evaluated using stepwise logistic regression analysis to identify the most important predictors. RESULTS: The CSF diversion surgery index model showed that the Management of Myelomeningocele Study Index and fractional anisotropy in the genu of the corpus callosum were significant predictors (P < .05) of CSF diversion surgery. The predictive value of the CSF diversion surgery index was also affected by fractional anisotropy in the posterior limb of the internal capsule and sex with marginal effect (.05

.10). The overall CSF diversion surgery index model fit the data well with statistical significance (eg, likelihood ratio: P < .001), with the performance (sensitivity = 78.6%; specificity = 86.5%, overall accuracy = 84.8%) superior to all individual indices in sensitivity and overall accuracy, and most of the individual indices in specificity. CONCLUSIONS: The CSF diversion surgery index model outperformed all single predictor models and, with additional validation, may potentially be developed and incorporated into a sensitive and robust clinical tool to assist clinicians in hydrocephalus management.

Meniscal allograft transplantation in the paediatric population: early referral is justified.

PURPOSE: The need for meniscal allograft transplantation (MAT) in children is rare, and as a result, there is a paucity of evidence detailing survivorship and clinical outcome. MAT has been shown to significantly reduce pain and improve function in the adult population. The aim of this study was to document the outcomes of a single surgeon case series of MAT in the paediatric population. METHODS: Analysis of a prospective meniscal allograft transplantation (MAT) group database of 280 patients was performed. Twenty-three patients met the inclusion criteria-undergoing MAT aged 18 years or younger. RESULTS: Fourteen were female and nine were male with median age of 17 (range 8-18). Thirteen (57%) were right knee and nineteen (83%) were lateral. Additional procedures included high tibial osteotomy, anterior cruciate ligament reconstruction, and microfracture procedures. The median follow-up was 3.8 years (range of 0.2 to 7.8 years). There have been no cases of graft failure. All patients demonstrated improvement in all the modalities of the KOOS outcome scores. At 5 years, the Lysholm score had improved from 57.9 to 87.6 (SD 12.1), Tegner activity score had improved from 2 to 5 (range 4-7) and IKDC score had improved from 40.6 to 78.6 (SD 15.8). Four patients required secondary surgical intervention. No patients developed a superficial or deep infection. CONCLUSION: Meniscal allograft transplantation in children is founded on the successful results of MAT in the adult population. We have demonstrated in this series that MAT can improve function and reduce pain in the paediatric population, and is, therefore, a viable treatment option for the management of the symptomatic paediatric meniscal-deficient knee. Early referral should be considered in the patients with post-meniscectomy syndrome, pain on weight bearing with a history of previous menisectomy. LEVEL OF EVIDENCE: IV.

Spinal Imaging Findings of Open Spinal Dysraphisms on Fetal and Postnatal MRI.

BACKGROUND AND PURPOSE: Fetal MRI has become a valuable tool in the evaluation of open spinal dysraphisms making studies comparing prenatal and postnatal MRI findings increasingly important. Our aim was to determine the accuracy of predicting the level of the spinal dysraphic defect of open spinal dysraphisms on fetal MR imaging and to report additional findings observed when comparing fetal and postnatal MR imaging of the spine in this population. MATERIALS AND METHODS: A single-center retrospective analysis was performed of fetal MRIs with open spinal dysraphisms from 2004 through 2016 with available diagnostic postnatal spine MR imaging. Images were reviewed by 2 board-certified fellowship-trained pediatric neuroradiologists. Corresponding clinical/operative reports were reviewed. RESULTS: One hundred nineteen fetal MRIs of open spinal dysraphisms were included. The level of the osseous defect between fetal and postnatal MR imaging was concordant in 42.9% (51/119) of cases and was 1 level different in 39% (47/119) of cases. On postnatal MR imaging, type II split cord malformation was seen in 8.4% (10/119) of cases, with only 50% (5/10) of these cases identified prospectively on fetal MR imaging. Syrinx was noted in 3% (4/119) of prenatal studies, all cervical, all confirmed on postnatal MR imaging. CONCLUSIONS: Fetal MR imaging is accurate in detecting the level of the spinal dysraphic defect, which has an impact on prenatal counseling, neurologic outcomes, and eligibility for fetal surgery. In addition, fetal MR imaging is limited in its ability to detect split cord malformations in patients with open spinal dysraphisms. Although rare, fetal MR imaging has a high specificity for detection of cervical spinal cord syrinx.

Does intentional weight loss improve daytime sleepiness? A systematic review and meta-analysis.

Obesity is associated with excessive daytime sleepiness, but its causality remains unclear. We aimed to assess the extent to which intentional weight loss affects daytime sleepiness. Electronic databases were searched through 24 October 2016. Studies involving overweight or obese adults, a weight loss intervention and repeated valid measures of daytime sleepiness were included in the review. Two independent reviewers extracted data on study characteristics, main outcome (change in daytime sleepiness score standardized by standard deviation of baseline sleepiness scores), potential mediators (e.g. amount of weight loss and change in apnoea-hypopnoea index) and other co-factors (e.g. baseline demographics). Forty-two studies were included in the review. Fifteen before-and-after studies on surgical weight loss interventions showed large improvements in daytime sleepiness, with a standardized effect size of -0.97 (95% confidence interval [CI] -1.21 to -0.72). Twenty-seven studies on non-surgical weight loss interventions showed small-to-moderate improvement in daytime sleepiness, with a standardized effect size of -0.40 (95%CI -0.52 to -0.27), with no difference between controlled and before-and-after studies. We found a nonlinear association between amount of weight loss and change in daytime sleepiness. This review suggests that weight loss interventions improve daytime sleepiness, with a clear dose-response relationship. This supports the previously hypothesized causal effect of obesity on daytime sleepiness. It is important to assess and manage daytime sleepiness in obese patients.

Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection.

BACKGROUND: Rhinovirus (RV) infection in asthma induces varying degrees of airway inflammation (e.g. neutrophils), but the underlying mechanisms remain unclear. OBJECTIVE: The major goal was to determine the role of genetic variation [e.g. single nucleotide polymorphisms (SNPs)] of Toll-interacting protein (Tollip) in airway epithelial responses to RV in a type 2 cytokine milieu. METHODS: DNA from blood of asthmatic and normal subjects was genotyped for Tollip SNP rs5743899 AA, AG and GG genotypes. Human tracheobronchial epithelial (HTBE) cells from donors without lung disease were cultured to determine pro-inflammatory and antiviral responses to IL-13 and RV16. Tollip knockout and wild-type mice were challenged with house dust mite (HDM) and infected with RV1B to determine lung inflammation and antiviral response. RESULTS: Asthmatic subjects carrying the AG or GG genotype (AG/GG) compared with the AA genotype demonstrated greater airflow limitation. HTBE cells with AG/GG expressed less Tollip. Upon IL-13 and RV16 treatment, cells with AG/GG (vs. AA) produced more IL-8 and expressed less antiviral genes, which was coupled with increased NF-κB activity and decreased expression of LC3, a hallmark of the autophagic pathway. Tollip co-localized and interacted with LC3. Inhibition of autophagy decreased antiviral genes in IL-13- and RV16-treated cells. Upon HDM and RV1B, Tollip knockout (vs. wild-type) mice demonstrated higher levels of lung neutrophilic inflammation and viral load, but lower levels of antiviral gene expression. CONCLUSIONS AND CLINICAL RELEVANCE: Our data suggest that Tollip SNP rs5743899 may predict varying airway response to RV infection in asthma.

Traumatic central cord syndrome: neurological and functional outcome at 3 years.

STUDY DESIGN: Retrospective cohort analysis with prospective follow-up. OBJECTIVES: To evaluate neurological and functional recovery following central cord syndrome. SETTING: Northern Ireland, population 1.8 million. METHODS: Twenty-seven cords were identified in 1 year. Five managed conservatively and 22 with surgery. American Spinal Injury Association (ASIA) motor scores (AMS) were calculated to assess neurological recovery. Rotterdam scores assessed functional independence at 3 years. RESULTS: Average age was 62 years. Mechanism of injury was a fall with neck hyperextension in 81% patients. Average AMS in surgical patients improved from injury, preoperatively, postoperatively, 6 months and 3 years from 51, 81, 83, 90 to 96, respectively. Conservative patients improved from time of injury to day 10 from 57 to 86 and then fell to 84 at 6 months. By 3 years, this had recovered to 91. There was no statistical significant difference in AMS (P=0.15)/change in AMS (ΔAMS) (P=0.92) or percentage of motor deficit resolution (P=0.23) between groups at 3 years. Two patients underwent surgery within 48 h and achieved full motor recovery by 3 years, but this was not significant (P=0.2). ASIA score improvement had a positive correlation with age at injury. Patients treated with surgery had better Rotterdam scores at 3 years than those managed conservatively (P=0.05). CONCLUSIONS: This study confirms the natural history of central cord syndrome. Although it demonstrates equivocal neurological recovery for both groups, patients treated with surgery regained a greater degree of functional independence.

Structural basis of pathogen recognition by an integrated HMA domain in a plant NLR immune receptor.

Plants have evolved intracellular immune receptors to detect pathogen proteins known as effectors. How these immune receptors detect effectors remains poorly understood. Here we describe the structural basis for direct recognition of AVR-Pik, an effector from the rice blast pathogen, by the rice intracellular NLR immune receptor Pik. AVR-PikD binds a dimer of the Pikp-1 HMA integrated domain with nanomolar affinity. The crystal structure of the Pikp-HMA/AVR-PikD complex enabled design of mutations to alter protein interaction in yeast and in vitro, and perturb effector-mediated response both in a rice cultivar containing Pikp and upon expression of AVR-PikD and Pikp in the model plant Nicotiana benthamiana. These data reveal the molecular details of a recognition event, mediated by a novel integrated domain in an NLR, which initiates a plant immune response and resistance to rice blast disease. Such studies underpin novel opportunities for engineering disease resistance to plant pathogens in staple food crops.

Trends in body mass index according to educational attainment for urban Australian adults between 1980 and 2007.

BACKGROUND: We have previously demonstrated that between the years 1980 and 2000, the mean body mass index (BMI) of the urban Australian population increased, with greater increases observed with increasing BMI. The current study aimed to quantify trends over time in BMI according to level of education between 1980 and 2007. METHODS: We compared data from the 1980, 1983 and 1989 National Heart Foundation Risk Factor Prevalence Studies, 1995 National Nutrition Survey, 2000 Australian Diabetes, Obesity and Lifestyle Study and the 2007 National Health Survey. For survey comparability, analyses were restricted to urban Australian residents aged 25-64 years. BMI was calculated from measured height and weight. The education variable was dichotomised at completion of secondary school. Four age-standardised BMI indicators were compared over time by sex and education: mean BMI, mean BMI of the top 5% of the BMI distribution, prevalence of obesity (BMI⩾30 kg m(-)(2)), prevalence of class II(+) obesity (BMI⩾35 kg m(-)(2)). RESULTS: Between 1980 and 2007, the mean BMI among men increased by 2.5 and 1.7 kg m(-)(2) for those with low and high education levels, respectively, corresponding to increases in obesity prevalence of 20 (from 12-32%) and 11 (10-21%) %-points. Among women, mean BMI increased by 2.9 and 2.4 kg m(-)(2) for those with low and high education levels, respectively, corresponding to increases in obesity prevalence of 16 (12-28%) and 12 (7-19%) %-points. The prevalence of class II(+) obesity among men increased by 9 (1-10%) and 4 (1-5%) %-points for those with low and high education levels, and among women increased by 8 (4-12%) and 4 (2-6%) %-points. Absolute and relative differences between education groups generally increased over time. CONCLUSIONS: Educational differences in BMI have persisted among urban Australian adults since 1980 without improvement. Obesity prevention policies will need to be effective in those with greatest socio-economic disadvantage if we are to equitably and effectively address the population burden of obesity and its corollaries.

Predictors of outcome in palliative colonic stent placement for malignant obstruction.

BACKGROUND: Emergency surgery for large bowel obstruction carries significant morbidity and mortality. After initially promising results, concerns have been raised over complication rates for self-expandable metal stents (SEMS) in both the palliative and bridge-to-surgery settings. This article documents the technique used at the authors' institution, and reports on success and complication rates, as well as identifying predictors of endoscopic reintervention or surgical treatment. METHODS: Data were collected for a prospective cohort of consecutive patients undergoing attempted colonoscopic SEMS insertion at a single institution between 1998 and 2013. Multivariable logistic models were fitted to assess possible predictors of endoscopic reintervention and surgical treatment. RESULTS: Palliative SEMS insertion was attempted in 146 patients. Primary colorectal cancer was the most common cause of obstruction (95.2 per cent). The majority of patients (77.4 per cent) were treated in an acute setting, with a high technical success rate of 97.3 per cent. The perforation rate was 4.8 per cent and the 30-day procedural mortality rate 2.7 per cent. No predictors of early complications were identified, although patients with metastases and those who received chemotherapy were more likely to have late complications. Some 30.8 per cent of patients required at least one further intervention, with 11.0 per cent of the cohort requiring a stoma. Endoscopic reintervention was largely successful. CONCLUSION: SEMS offer a valid alternative to operative intervention in the palliative management of malignant large bowel obstruction. Patients receiving chemotherapy are more likely to receive endoscopic reintervention, which is largely successful.

The relationship between body mass index prior to old age and disability in old age.

OBJECTIVES: To analyse the relationship between body mass index (BMI) in middle-age and disability status in old-age using data from the Melbourne Collaborative Cohort Study (MCCS). METHODS: A total of 41 514 participants enroled in the MCCS between 1990-1994. Height and weight were measured at baseline and disability, defined as limitations to self-care activities of daily living (ADLs) and self-care plus mobility activities, was identified at follow-up (2003-2007). In all, 6300 participants were <65 years at baseline, 70 years at follow-up and not missing BMI at baseline or ADLs at follow-up. The association between BMI in six categories (BMI 18.5-22.5; 22.5-25; 25-27.5; 27.5-30; 30-35; 35+) and disability status was analysed using logistic regression. Models were stratified by sex, and sequentially adjusted for age, education, country of birth, then smoking, alcohol, fruit and vegetable intake, and physical activity. RESULTS: Adjusted odds ratios for composite self-care ADL and mobility limitations compared with BMI 18.5-22.5 kg m(-2) were 1.73 (95%CI 1.14-2.64) for BMI 30-35 kg m(-2) and 3.46 (1.78-6.73) for BMI 35+ kg m(-2) in males. In females, adjusted odds ratios were 1.29 (1.00-1.68) for BMI 22.5-25 kg m(-2), 1.74 (1.35-2.24) for BMI 25-27.5 kg m(-2), 2.58 (1.98-3.36) for BMI 27.5-30 kg m(-2), 2.74 (2.10-3.58) for BMI 30-35 kg m(-2) and 4.21 (3.12-5.88) for BMI 35+ kg m(-2). CONCLUSION: A graded relationship was observed between BMI and disability in males and females, across the continuum of BMI. These results highlight the importance of a healthy body weight at middle age in order to reduce the risk of disability in old age.

Economic implications of obesity among people with atherothrombotic disease.

OBJECTIVE: The purpose of this study was to ascertain the impact of obesity on the cost of disease management in people with or at high risk of atherothrombotic disease from a governmental perspective using a bottom-up approach to cost estimation. In addition, the aim was also to explore the causes of any differences found. METHOD: The health-care costs of obesity were estimated from 2819 participants recruited into the nationwide Australian REACH Registry with established atherothrombotic disease or at least three risk factors for atherothrombosis. Enrollment was in 2004, through primary care general practices. Information was collected on the use of cardiovascular drugs, hospitalizations and ambulatory care services. 'Bottom-up' costing was undertaken by assigning unit costs to each health-care item, based on Australian Government-reimbursed figures 2006-2007. Linear-mixed models were used to estimate associations between direct medical costs and body mass index (BMI) categories. RESULTS: Annual pharmaceutical costs per person increased with increasing BMI category, even after adjusting for gender, age, living place, formal education, smoking status, hypertension and diabetes. Adjusted annual pharmaceutical costs of overweight and obese participants were higher ($7 (P=0.004) and $144 (<0.001), respectively) than those of the normal weight participants. This was due to participants in higher BMI categories receiving more pharmaceuticals than normal weight participants. There was no significant change across the BMI categories in annual ambulatory care costs and annual hospital costs. CONCLUSION: In these participants with or at high risk of atherothrombotic disease, annual pharmaceutical costs were greater in participants of higher BMI category, but there was not such a gradient in the annual hospital or ambulatory care costs. The greater cardiovascular pharmaceutical costs for participants of higher BMI categories remained even after adjusting for a range of demographic factors and comorbidities. Our results suggest that these costs are explained by the higher number of drugs used among people with atherothrombotic disease. Further investigation is needed to understand the reasons for this level of drug use.

Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice.

BACKGROUND AND PURPOSE: Galegine and guanidine, originally isolated from Galega officinalis, led to the development of the biguanides. The weight-reducing effects of galegine have not previously been studied and the present investigation was undertaken to determine its mechanism(s) of action. EXPERIMENTAL APPROACH: Body weight and food intake were examined in mice. Glucose uptake and acetyl-CoA carboxylase activity were studied in 3T3-L1 adipocytes and L6 myotubes and AMP activated protein kinase (AMPK) activity was examined in cell lines. The gene expression of some enzymes involved in fat metabolism was examined in 3T3-L1 adipocytes. KEY RESULTS: Galegine administered in the diet reduced body weight in mice. Pair-feeding indicated that at least part of this effect was independent of reduced food intake. In 3T3-L1 adipocytes and L6 myotubes, galegine (50 microM-3 mM) stimulated glucose uptake. Galegine (1-300 microM) also reduced isoprenaline-mediated lipolysis in 3T3-L1 adipocytes and inhibited acetyl-CoA carboxylase activity in 3T3-L1 adipocytes and L6 myotubes. Galegine (500 microM) down-regulated genes concerned with fatty acid synthesis, including fatty acid synthase and its upstream regulator SREBP. Galegine (10 microM and above) produced a concentration-dependent activation of AMP activated protein kinase (AMPK) in H4IIE rat hepatoma, HEK293 human kidney cells, 3T3-L1 adipocytes and L6 myotubes. CONCLUSIONS AND IMPLICATIONS: Activation of AMPK can explain many of the effects of galegine, including enhanced glucose uptake and inhibition of acetyl-CoA carboxylase. Inhibition of acetyl-CoA carboxylase both inhibits fatty acid synthesis and stimulates fatty acid oxidation, and this may to contribute to the in vivo effect of galegine on body weight.

Oral versus non-oral hormone replacement therapy: how important is the route of administration?

Although there are differences in the pharmacokinetic profiles of oral and non-oral routes of administration the clinical relevance of these differences remains to be determined. Likewise, there are differences in the metabolic and haemostatic effects of different routes of administration of oestrogen but these may have clinical relevance. For some parameters, such as lipids and lipoproteins, glucose and insulin metabolism, there are greater benefits from oral administration; for others, particularly haemostatic changes and effects on CRP, there are advantages from transdermal administration. For the potential benefits of HRT on CHD, these differences probably have less impact than the effect of the dose of hormones used and the lowest effective should be prescribed. Irrespective of dose, certain small sub-groups of patients should be specifically treated with an oral regimen eg those with lipid and lipoprotein abnormalities and impaired glucose tolerance whereas others should be treated with a transdermal regimen eg those with a personal or relevant family history of venous thrombosis. However, the vast majority of patients possess none of these risk factors and for them it will come down to personal preference. The availability of different combinations and doses of hormones, as well as different routes of administration, allows HRT to be tailored to the individual and there are few women for whom a suitable form of HRT cannot be found. Although data are lacking we believe it unwise to believe that fully transdermal combination therapy will not impact on risk of incident breast cancer. Based on current evidence transdermal HRT may also cause more irregular and breakthrough bleeding with sequential and continuous therapies than oral counterparts.

Drugs for preventing postoperative nausea and vomiting.

BACKGROUND: Drugs can prevent postoperative nausea and vomiting, but their relative efficacies and side effects have not been compared within one systematic review. OBJECTIVES: The objective of this review was to assess the prevention of postoperative nausea and vomiting by drugs and the development of any side effects. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to May 2004), EMBASE (January 1985 to May 2004), CINAHL (1982 to May 2004), AMED (1985 to May 2004), SIGLE (to May 2004), ISI WOS (to May 2004), LILAC (to May 2004) and INGENTA bibliographies. SELECTION CRITERIA: We included randomized controlled trials that compared a drug with placebo or another drug, or compared doses or timing of administration, that reported postoperative nausea or vomiting as an outcome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted outcome data. MAIN RESULTS: We included 737 studies involving 103,237 people. Compared to placebo, eight drugs prevented postoperative nausea and vomiting: droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine and granisetron. Publication bias makes evidence for differences among these drugs unreliable. The relative risks (RR) versus placebo varied between 0.60 and 0.80, depending upon the drug and outcome. Evidence for side effects was sparse: droperidol was sedative (RR 1.32) and headache was more common after ondansetron (RR 1.16). AUTHORS' CONCLUSIONS: Either nausea or vomiting is reported to affect, at most, 80 out of 100 people after surgery. If all 100 of these people are given one of the listed drugs, about 28 would benefit and 72 would not. Nausea and vomiting are usually less common and, therefore, drugs are less useful. For 100 people, of whom 30 would vomit or feel sick after surgery if given placebo, 10 people would benefit from a drug and 90 would not. Between one to five patients out of every 100 people may experience a mild side effect, such as sedation or headache, when given an antiemetic drug. Collaborative research should focus on determining whether antiemetic drugs cause more severe, probably rare, side effects. Further comparison of the antiemetic effect of one drug versus another is not a research priority.

Lung function and respiratory health in adolescents of very low birth weight.

AIMS: To determine if very low birth weight (VLBW; birth weight <1500 g) is associated with reduced lung function and respiratory health in adolescence and, if it is, whether this impairment is associated with prematurity or intrauterine growth restriction. METHODS: A geographically defined cohort of 128 VLBW infants and an age, sex, and school matched comparison group born in 1980/81 were studied. The cohort and comparison group were assessed at 15 years of age. The birth weight ratio of the index cases (observed birth weight/expected birth weight for the gestation) was determined to assess the degree of growth restriction. Respiratory support received during the neonatal period was obtained from hospital records. Smoking habits and respiratory morbidity were obtained through questionnaires. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and forced expiratory flow when 25-75% of FVC is expired (FEF(25-75%)) were measured using a portable spirometer. The values are expressed as percentage predicted for height, age, and gender using standard reference values. Adjustments were made for smoking habits of mother and children. RESULTS: The differences in means between index and comparison groups for FEF(25-75%) (-12.42%; p < 0.001) and FEV1/FVC (-3.53%; p < 0.001) ratio were statistically significant. The differences in FVC and FEV1 were not significant. No correlation was found between the birth weight ratio and lung function among the index cohort. Chronic cough, wheezing, and asthma were more common among the index cohort than in the comparison group. Within the index group, there was no difference in lung function between those who received and those who did not receive respiratory support. CONCLUSION: Adolescents who were VLBW compared with matched controls showed medium and small airways obstruction. This was associated with prematurity rather than intrauterine growth restriction or having received respiratory support during the neonatal period. The index VLBW cohort compared with their controls were also more prone to chronic cough, wheezing, and asthma.

The burden of disease and injury in Australia.

An overview of the results of the Australian Burden of Disease (ABD) study is presented. The ABD study was the first to use methodology developed for the Global Burden of Disease study to measure the burden of disease and injury in a developed country. In 1996, mental disorders were the main causes of disability burden, responsible for nearly 30% of total years of life lost to disability (YLD), with depression accounting for 8% of the total YLD. Ischaemic heart disease and stroke were the main contributors to the disease burden disability-adjusted life years (DALYs), together causing nearly 18% of the total disease burden. Risk factors such as smoking, alcohol consumption, physical inactivity, hypertension, high blood cholesterol, obesity and inadequate fruit and vegetable consumption were responsible for much of the overall disease burden in Australia. The lessons learnt from the ABD study are discussed, together with methodological issues that require further attention.

An in vivo/in vitro comparison with a leuprolide osmotic implant for the treatment of prostate cancer.

An osmotically driven implantable system was designed and characterized for the delivery of leuprolide over a year-long duration. Leuprolide has been used in the treatment of prostate cancer since the 1980s. The DUROS implant consists of a titanium alloy cylinder, measures 4 mm in diameter by 45 mm in length and holds approximately 150 microl of formulation. Stability studies indicated that leuprolide was stable, as a solution formulation in DMSO, for several years at 37 degrees C. In vitro release rate testing, at weekly intervals, showed zero-order delivery for 1 year. DUROS implants demonstrated release rates that were reproducible and similar to one another after storage at 25 degrees C for 18 months prior to testing. In vivo studies, with implants placed subcutaneously, revealed delivery rates comparable to those observed under in vitro conditions. Leuprolide stability was also comparable between in vivo and in vitro conditions. Steady leuprolide serum levels produced by the implant resulted in the desired pharmacodynamic efficacy endpoint of testosterone suppression, both in canines and in humans. The good agreement between in vivo/in vitro delivery rates was as expected for a delivery system based on the principles of osmosis.

Chiral recognition between a substituted cyclooctatetraene dianion and a half crown ether substituted with ibuprofen.

(S)-Verbenol was substituted onto cyclooctatetraene (COT) via an ether linkage. In tetrahydrofuran (THF), Cs(+) or Na(+) counterions are tightly ion associated with the verbenoxy-COT dianion. A cosolvent, consisting of an ibuprofen unit connected to a half crown ether, was added to the verbenoxy-COT(2)(-),M(+)(2) solutions. The intimate interaction between the chiral cosolvent (ibuprofoxymethoxyethoxyethane) and the ion-associated counterion (either Na(+) or Cs(+)) forces a chiral recognition between the verbenoxy moiety and the ibuprofoxy moiety. When a molar excess of the cosolvent is present in the dianion THF solution, separation of the cosolvent associated with the verbenoxy-COT(2)(-),M(+)(2) complex from the uncomplexed cosolvent allows partial resolution of the enantiomers of ibuprofoxymethoxyethoxyethane.

The Australian Burden of Disease Study: measuring the loss of health from diseases, injuries and risk factors.

This is an overview of the first burden of disease and injury studies carried out in Australia. Methods developed for the World Bank and World Health Organization Global Burden of Disease Study were adapted and applied to Australian population health data. Depression was found to be the top-ranking cause of non-fatal disease burden in Australia, causing 8% of the total years lost due to disability in 1996. Mental disorders overall were responsible for nearly 30% of the non-fatal disease burden. The leading causes of total disease burden (disability-adjusted life years [DALYs]) were ischaemic heart disease and stroke, together causing nearly 18% of the total disease burden. Depression was the fourth leading cause of disease burden, accounting for 3.7% of the total burden. Of the 10 major risk factors to which the disease burden can be attributed, tobacco smoking causes an estimated 10% of the total disease burden in Australia, followed by physical inactivity (7%).