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Objective The role of anticoagulation (AC) in the management of otogenic cerebral venous sinus thrombosis (OCVST) remains controversial. Our study aims to better define when AC is used in OCVST. Methods MEDLINE, EMBASE, and The Cochrane Library were searched from inception to February 14, 2019 for English and English-translated articles. References cited in publications meeting search criteria were searched. Titles and abstracts were screened and identified in the literature search, assessing baseline risk of bias on extracted data with the methodological index for nonrandomized studies (MINORS) scale. Random effects meta-regression followed by random forest machine learning analysis across 16 moderator variables between AC and nonanticoagulated (NAC) cohorts was conducted. Results A total of 92% of treated patients were free of neurologic symptoms at the last follow-up (mean 29.64 months). Four percent of AC and 14% of NAC patients remained symptomatic (mean 18.72 and 47.10 months). 3.5% of AC patients experienced postoperative wound hematomas. AC and NAC recanalization rates were 81% (34/42) and 63% (five-eights), respectively. OCVST was correlated with cholesteatoma and intracranial abscess. Among the analyzed covariates, intracranial abscess was most predictive of AC and cholesteatoma was most predictive of NAC. Comorbid intracranial abscess and cholesteatoma were predictive of AC. Conclusion The present study is the first to utilize machine learning algorithms in approaching OCVST. Our findings support the therapeutic use of AC in the management of OCVST when complicated by thrombophilia, intracranial abscess, and cholesteatoma. Patients with intracranial abscess and cholesteatoma may benefit from AC and surgery. Patients with cholesteatoma can be managed with NAC and surgery.

Abnormal protein aggregation has been linked to many neurodegenerative diseases, including Parkinson’s disease (PD). The main pathological hallmark of PD is the formation of Lewy bodies (LBs) and Lewy neurites, both of which contain the presynaptic protein alpha-synuclein (α-syn). Under normal conditions, native α-syn exists in a soluble unfolded state but undergoes misfolding and aggregation into toxic aggregates under pathological conditions. Toxic α-syn species, especially oligomers, can cause oxidative stress, membrane penetration, synaptic and mitochondrial dysfunction, as well as other damage, leading to neuronal death and eventually neurodegeneration. Early diagnosis and treatments targeting PD pathogenesis are urgently needed. Given its critical role in PD, α-syn is an attractive target for the development of both diagnostic tools and effective therapeutics. This review summarizes the progress toward discovering imaging probes and aggregation inhibitors for α-syn. Relevant strategies and techniques in the discovery of α-syn-targeted drugs are also discussed.

The present status of antibiotic resistant requires an urgent invention of novel agents that act on clinically unexplored antibacterial targets. The enzyme MraY (phospho-MurNAc-pentapeptide translocase), essential for bacterial cell wall synthesis, fulfils this criterion as it has not been explored as a target in a clinical context. Specifically, the enzyme is involved in the lipid-linked cycle of peptidoglycan biosynthesis and is reportedly targeted by naturally-occurring nucleoside antibiotics. The antimicrobial 'caprazamycin' class of nucleoside antibiotics targets Mycobacterium tuberculosis and clinically relevant Gram-negative bacteria such as Pseudomonas aeruginosa besides various drug resistant strains and is therefore an eligible starting point for the development of novel agents. In this review, we aim to summarise the structure-activity relationships of the natural, semi-synthetic as well as synthetic analogues of nucleoside antibiotic caprazamycins. This review highlights caprazamycins as promising lead structures for development of potent and selective antimicrobial agents that target MraY, the bacterial enzyme involved in the first membrane-dependent step in bacterial peptidoglycan assembly.

Background There is currently insufficient evidence to support the use of lipid-lowering drug treatment (LLT) for primary prevention of cardiovascular disease (CVD) in the elderly. Objectives We examined the relationship of early initiation of LLT with short- and long-term all-cause and CVD mortality in persons older than 65 years in this post hoc study from the Second Australian National Blood Pressure study (ANBP2). Methods This was an in- and post-trial observational study. About 4257 hypertensive participants aged 65 to 84 years within Australian family practices were randomized to an angiotensin-converting enzyme inhibitor or a diuretic treatment group. After excluding participants with a prior history of CVD, the cohort was stratified into "LLT" and "no LLT" subgroups based on LLT status at randomization. Results At randomization, the participants had a mean age of 72 years, average blood pressure of 168/91 mm Hg and estimated 5-year CVD risk of 18.7 ± 8.3%. In the overall study population, the association of LLT with long-term (11-years) all-cause and non-CVD mortality was significant (hazard ratio [HR] 0.78 [95% confidence interval {CI} 0.66–0.92, P = .003] and HR 0.70 [95% CI 0.54–0.90, P = .006], respectively). Magnitudes of the association of LLT with long-term mortality and the association with short-term mortality were similar; however, no statistically significant association with short-term mortality was observed. In the subgroup analysis by baseline 5-year CVD risk, LLT participants in the highest risk tertile had a substantially lower relative risk for short-term all-cause mortality (HR 0.31, 95% CI 0.13–0.71, P for interaction .02) compared to those with lower estimated CVD risk. All analyses were adjusted for baseline and in-trial characteristics. Conclusion Our study showed a strong association between LLT and reduced long-term all-cause mortality. Thus, our findings support recommendations of the use of LLT in patients over 65 years, particularly those with high CVD risk who were more likely to obtain additional benefits in the short term. The findings also suggested that mortality benefits of LLT for the elderly may take longer to become evident.

Located in the midline lamina terminalis of the anterior wall of the third ventricle, the median preoptic nucleus is a thin elongated nucleus stretching around the rostral border of the anterior commissure. Its neuronal elements, composed of various types of excitatory glutamatergic and inhibitory GABAergic neurons, receive afferent neural signals from (1) neighboring subfornical organ and organum vasculosum of the lamina terminalis related to plasma osmolality and hormone concentrations, e.g., angiotensin II; (2) from peripheral sensors such as arterial baroreceptors and cutaneous thermosensors. Different sets of these MnPO glutamatergic and GABAergic neurons relay output signals to hypothalamic, midbrain, and medullary regions that drive homeostatic effector responses. Included in the effector responses are (1) thirst, antidiuretic hormone secretion and renal sodium excretion that subserve osmoregulation and body fluid homeostasis; (2) vasoconstriction or dilatation of skin blood vessels, and shivering and brown adipose tissue thermogenesis for core temperature homeostasis; (3) inhibition of hypothalamic and midbrain nuclei that stimulate wakefulness and arousal, thereby promoting both REM and non-REM sleep; and (4) activation of sympathetic pathways that drive vasoconstriction and heart rate to maintain arterial pressure and the perfusion of vital organs. The small size of MnPO belies its massive homeostatic significance.

In response to dehydration, humans experience thirst. This subjective state is fundamental to survival as it motivates drinking, which subsequently corrects the fluid deficit. To elicit thirst, previous studies have manipulated blood chemistry to produce a physiological thirst stimulus. In the present study, we investigated whether a physiological stimulus is indeed required for thirst to be experienced. Functional MRI (fMRI) was used to scan fully hydrated participants while they imagined a state of intense thirst and while they imagined drinking to satiate thirst. Subjective ratings of thirst were significantly higher for imagining thirst compared with imagining drinking or baseline, revealing a successful dissociation of thirst from underlying physiology. The imagine thirst condition activated brain regions similar to those reported in previous studies of physiologically evoked thirst, including the anterior midcingulate cortex (aMCC), anterior insula, precentral gyrus, inferior frontal gyrus, middle frontal gyrus, and operculum, indicating a similar neural network underlies both imagined thirst and physiologically evoked thirst. Analogous brain regions were also activated during imagined drinking, suggesting the neural representation of thirst contains a drinking-related component. Finally, the aMCC showed an increase in functional connectivity with the insula during imagined thirst relative to imagined drinking, implying functional connectivity between these two regions is needed before thirst can be experienced. As a result of these findings, this study provides important insight into how the neural representation of subjective thirst is generated and how it subsequently motivates drinking behavior.

Brain regions that regulate fluid satiation are not well characterized, yet are essential for understanding fluid homeostasis. We found that oxytocin-receptor-expressing neurons in the parabrachial nucleus of mice (OxtrPBN neurons) are key regulators of fluid satiation. Chemogenetic activation of OxtrPBN neurons robustly suppressed noncaloric fluid intake, but did not decrease food intake after fasting or salt intake following salt depletion; inactivation increased saline intake after dehydration and hypertonic saline injection. Under physiological conditions, OxtrPBN neurons were activated by fluid satiation and hypertonic saline injection. OxtrPBN neurons were directly innervated by oxytocin neurons in the paraventricular hypothalamus (OxtPVH neurons), which mildly attenuated fluid intake. Activation of neurons in the nucleus of the solitary tract substantially suppressed fluid intake and activated OxtrPBN neurons. Our results suggest that OxtrPBN neurons act as a key node in the fluid satiation neurocircuitry, which acts to decrease water and/or saline intake to prevent or attenuate hypervolemia and hypernatremia., The authors show that oxytocin-receptor-expressing neurons in the parabrachial nucleus are key regulators of fluid homeostasis that suppress fluid intake when activated, but do not decrease food intake after fasting or salt intake after salt depletion.

Background/aims: After completion of a randomised controlled trial, an extended follow-up period may be initiated to learn about longer term impacts of the intervention. Since extended follow-up studies often involve additional eligibility restrictions and consent processes for participation, and a longer duration of follow-up entails a greater risk of participant attrition, missing data can be a considerable threat in this setting. As a potential source of bias, it is critical that missing data are appropriately handled in the statistical analysis, yet little is known about the treatment of missing data in extended follow-up studies. The aims of this review were to summarise the extent of missing data in extended follow-up studies and the use of statistical approaches to address this potentially serious problem. Methods: We performed a systematic literature search in PubMed to identify extended follow-up studies published from January to June 2015. Studies were eligible for inclusion if the original randomised controlled trial results were also published and if the main objective of extended follow-up was to compare the original randomised groups. We recorded information on the extent of missing data and the approach used to treat missing data in the statistical analysis of the primary outcome of the extended follow-up study. Results: Of the 81 studies included in the review, 36 (44%) reported additional eligibility restrictions and 24 (30%) consent processes for entry into extended follow-up. Data were collected at a median of 7 years after randomisation. Excluding 28 studies with a time to event primary outcome, 51/53 studies (96%) reported missing data on the primary outcome. The median percentage of randomised participants with complete data on the primary outcome was just 66% in these studies. The most common statistical approach to address missing data was complete case analysis (51% of studies), while likelihood-based analyses were also well represented (25%). Sensitivity analyses around the missing data mechanism were rarely performed (25% of studies), and when they were, they often involved unrealistic assumptions about the mechanism. Conclusion: Despite missing data being a serious problem in extended follow-up studies, statistical approaches to addressing missing data were often inadequate. We recommend researchers clearly specify all sources of missing data in follow-up studies and use statistical methods that are valid under a plausible assumption about the missing data mechanism. Sensitivity analyses should also be undertaken to assess the robustness of findings to assumptions about the missing data mechanism.

The use of multiple imputation has increased markedly in recent years, and journal reviewers may expect to see multiple imputation used to handle missing data. However in randomized trials, where treatment group is always observed and independent of baseline covariates, other approaches may be preferable. Using data simulation we evaluated multiple imputation, performed both overall and separately by randomized group, across a range of commonly encountered scenarios. We considered both missing outcome and missing baseline data, with missing outcome data induced under missing at random mechanisms. Provided the analysis model was correctly specified, multiple imputation produced unbiased treatment effect estimates, but alternative unbiased approaches were often more efficient. When the analysis model overlooked an interaction effect involving randomized group, multiple imputation produced biased estimates of the average treatment effect when applied to missing outcome data, unless imputation was performed separately by randomized group. Based on these results, we conclude that multiple imputation should not be seen as the only acceptable way to handle missing data in randomized trials. In settings where multiple imputation is adopted, we recommend that imputation is carried out separately by randomized group.

Background Information is scarce regarding effects of antihypertensive medication on blood pressure variability ( BPV ) and associated clinical outcomes. We examined whether antihypertensive treatment changes BPV over time and whether such change (decline or increase) has any association with long‐term mortality in an elderly hypertensive population. Methods and Results We used data from a subset of participants in the Second Australian National Blood Pressure study (n=496) aged ≥65 years who had 24‐hour ambulatory blood pressure recordings at study entry (baseline) and then after a median of 2 years while on treatment (follow‐up). Weighted day‐night systolic BPV was calculated for both baseline and follow‐up as a weighted mean of daytime and nighttime blood pressure standard deviations. The annual rate of change in BPV over time was calculated from these BPV estimates. Furthermore, we classified both BPV estimates as high and low based on the baseline median BPV value and then classified BPV changes into stable: low BPV , stable: high BPV , decline: high to low , and increase: low to high . We observed an annual decline (mean± SD : −0.37±1.95; 95% CI, −0.54 to −0.19; P BPV between baseline and follow‐up. Having constant stable: high BPV was associated with an increase in all‐cause mortality (hazard ratio: 3.03; 95% CI, 1.67–5.52) and cardiovascular mortality (hazard ratio: 3.70; 95% CI, 1.62–8.47) in relation to the stable: low BPV group over a median 8.6 years after the follow‐up ambulatory blood pressure monitoring. Similarly, higher risk was observed in the decline: high to low group. Conclusions Our results demonstrate that in elderly hypertensive patients, average BPV declined over 2 years of follow‐up after initiation of antihypertensive therapy, and having higher BPV (regardless of any change) was associated with increased long‐term mortality.

Pathological hyperphosphorylation of tau and subsequent aggregation to form neurofibrillary tangles (NFTs) is closely related to progression of neurodegenerative diseases such as Alzheimer's disease (AD) and progressive supranuclear palsy. A recent study showed that MK-8719 (6) is a selective and potent small molecule inhibitor of human O-GlcNAcase (hOGA). The pharmacological inhibition of OGA, the sole enzyme involved in removal of a sugar moiety (O-GlcNAc residue) from tau, increases global O-GlcNAc levels within the brain and reduces tau phosphorylation. The OGA inhibitor slows neurodegeneration and improves cognitive function in AD and related tauopathies. Here, we discuss the findings of that study and the development of OGA inhibitors as novel therapeutic strategy for treatment of age-related memory impairment in neurodegenerative diseases.

Numerous post-translational modifications (PTMs) of the Parkinson's disease (PD) associated α-synuclein (α-syn) protein have been recognised to play critical roles in disease aetiology. Indeed, dysregulated phosphorylation and proteolysis are thought to modulate α-syn aggregation and disease progression. Among the PTMs, enzymatic glycosylation with N-acetylglucosamine (GlcNAc) onto the protein's hydroxylated amino acid residues is reported to deliver protective effects against its pathogenic processing. This modification has been reported to alter its pathogenic self-assembly. As such, manipulation of the protein's O-GlcNAcylation status has been proposed to offer a PD therapeutic route. However, targeting upstream cellular processes can lead to mechanism-based toxicity as the enzymes governing O-GlcNAc cycling modify thousands of acceptor substrates. Small glycopeptides that couple the protective effects of O-GlcNAc with the selectivity of recognition sequences may prove useful tools to modulate protein aggregation. Here we discuss efforts to probe the effects of various O-GlcNAc modified peptides on wild-type α-synuclein aggregation.

To review the demographics, treatment modalities, and survival of children with vestibular schwannomas.Analysis using the Surveillance, Epidemiology, and End Results (SEER) database.Pediatric patients from birth to 18 years in the SEER database were included from 2004 to 2014 based on a diagnosis of vestibular schwannoma using the primary site International Classification of Diseases (ICD) O-3 code of C72.4: acoustic nerve and the ICD O-3 histology codes of 9540/1: neurofibromatosis, Not Otherwise Specified (NOS); 9560/0: neurilemoma, NOS; or 9570/0: neuroma, NOS.One hundred forty-eight pediatric vestibular schwannomas (VSs) cases were identified. The mean age at diagnosis was 13.9 years (range, 4.0-18.0). Eighty-five (57.4%) patients were women. Seventy-seven (52.0%) patients had isolated unilateral VSs while 71 (48.0%) patients had either bilateral VSs or unilateral VSs with other brain, spinal cord, or cranial nerve tumors. Eighty two (55.4%) patients received surgical resection only, 45 (30.4%) received no treatment, 6 (4.1%) received radiation only, and 12 (8.1%) received surgery and radiation. The median tumor size for patients who received no treatment was 9.5 mm (interquartile range [IQR]: 8.0) compared with 33.5 mm (IQR: 23.0) for patients who received surgical care and 41.0 mm (IQR: 1.5) for patients who received both surgery and radiation (p 0.001). The 5-year overall survival rate was 97%.Pediatric VSs tend to be diagnosed in adolescence. No men or women predominance was appreciated. Treatment varied according to tumor size. Survival rates for children with vestibular schwannomas are excellent. These data may assist healthcare providers when counseling children with vestibular schwannomas and their families.

Many mammals develop an urge to ingest salt (NaCl), that is, salt appetite, in response to sodium depletion. As well, physical or psychological stresses have been shown to cause an increased intake of NaCl in rabbits, mice, and rats. Hormonal signals may mediate stress-induced salt appetite because animals treated with the stress hormone adrenocorticotropic hormone (ACTH) also increase NaCl intake. Adrenal steroids mediate ACTH-induced salt appetite because it is prevented by bilateral adrenalectomy and is reproduced by treatment with a combination of corticosterone, deoxycorticosterone, and aldosterone. Salt appetite in humans is less well-defined compared with many other animal species and is usually manifested as an increased liking of, or preference for, salted food or beverages. To date, laboratory studies have failed to demonstrate an influence of stress on salt intake or salt preference in humans; however, these investigations were limited in their scope, and more investigation of this topic is needed.

e21634 Background: Hyperprogressive disease(HPD) is a recently recognized type of accelerated tumor progression with immune checkpoint inhibitor(ICI) therapy. A recent meta-analysis identified serum lactate dehydrogenase(LDH) above upper limit of normal(ULN), liver metastases and > 2 metastatic sites to be associated with increased likelihood of HPD. Methods: We performed a single-center retrospective analysis of NSCLC patients treated with ICI from 2/2017-1/2020. We defined HPD using combined criteria of failure to complete > 4 cycles of ICI and radiological progression with development of new lesions or marked clinical progression where restaging was not achievable because of rapid decline in performance status. Treatment discontinuation/interruption because of toxicity alone, was not designated as HPD. Results: HPD was seen in 9/41(22%) patients treated with at least 1 cycle of ICI. In 6/9 there was marked radiological progression (new lesions/significant progression of existing lesions); in the remaining 3 restaging was not possible because of rapid decline which mandated treatment cessation. Patients with HPD were more likely to have a raised LDH, liver metastases or > 2 metastatic sites but these differences were not statistically significant. 9/9 versus 5/32 patients in the HPD/non-HPD cohorts respectively progressed within 10 weeks of treatment (p < 0.001) and 7/9 versus 12/32 respectively did not survive beyond 6months (p = 0.057). Conclusions: This small study has shown a non-statistically significant trend for association between HPD, raised LDH, liver metastases and presence of > 2 metastatic sites. A better understanding of risk/predictive factors for HPD is essential for improved patient selection for treatment with ICI. [Table: see text]

A reversible post-translational protein modification which involves addition of N-acetylglucosamine (GlcNAc) onto hydroxyl groups of serine and/or threonine residues which is known as O-GlcNAcylation, has emerged as a potent competitor of phosphorylation. This glycosyltransfer reaction is catalyzed by the enzyme O-linked β-N-acetylglucosamine transferase (OGT). This enzyme uses uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the end product of hexosamine biosynthetic pathway, to modify numerous nuclear and cytosolic proteins. O-GlcNAcylation influences cancer cell metabolism in such a way that hyper-O-GlcNAcylation is considered as a prominent trait of many cancers, and is proposed as a major factor enabling cancer cell proliferation and progression. Growing evidence supports a connection between O-GlcNAcylation and major oncogenic factors, including for example, c-MYC, HIF-1α, and NF-κB. A comprehensive study of the roles of O-GlcNAc modification of oncogenic factors is warranted as a thorough understanding may help drive advances in cancer diagnosis and therapy. The focus of this article is to highlight the interplay between oncogenic factors and O-GlcNAcylation along with OGT in cancer cell proliferation and survival. The prospects for OGT inhibitors will also be discussed.

Fluid satiation, or quenching of thirst, is a critical homeostatic signal to stop drinking; however, its underlying neurocircuitry is not well characterized. Cutting‐edge genetically encoded tools and techniques are now enabling researchers to pinpoint discrete neuronal populations that control fluid satiation, revealing that hindbrain regions, such as the nucleus of the solitary tract, area postrema, and parabrachial nucleus, primarily inhibit fluid intake. By contrast, forebrain regions such as the lamina terminalis, primarily stimulate thirst and fluid intake. One intriguing aspect of fluid satiation is that thirst is quenched tens of minutes before water reaches the circulation, and the amount of water ingested is accurately calibrated to match physiological needs. This suggests that ‘preabsorptive’ inputs from the oropharyngeal regions, esophagus or upper gastrointestinal tract anticipate the amount of fluid required to restore fluid homeostasis, and provide rapid signals to terminate drinking once this amount has been consumed. It is likely that preabsorptive signals are carried via the vagal nerve to the hindbrain. In this review, we explore our current understanding of the fluid satiation neurocircuitry, its inputs and outputs, and its interconnections within the brain, with a focus on recent studies of the hindbrain, particularly the parabrachial nucleus.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for 60-80% of dementia cases. For many years, AD causality was attributed to amyloid-β (Aβ) aggregated species. Recently, multiple therapies that target Aβ aggregation have failed in clinical trials, since Aβ aggregation is found in AD and healthy patients. Attention has therefore shifted toward the aggregation of the tau protein as a major driver of AD. Numerous inhibitors of tau-based pathology have recently been developed. Diagnosis of AD has shifted from measuring late stage senile plaques to early stage biomarkers, amyloid-β and tau monomers and oligomeric assemblies. Synthetic peptides and some derivative structures are being explored for use as theranostic tools as they possess the capacity both to bind the biomarkers and to inhibit their pathological self-assembly. Several studies have demonstrated that O-linked glycoside addition can significantly alter amyloid aggregation kinetics. Furthermore, natural O-glycosylation of amyloid-forming proteins, including amyloid precursor protein (APP), tau, and α-synuclein, promotes alternative nonamyloidogenic processing pathways. As such, glycopeptides and related peptidomimetics are being investigated within the AD field. Here we review advancements made in the last 5 years, as well as the arrival of sugar-based derivatives.

There are limited and inconsistent data suggesting that mild iodine deficiency in pregnancy might be associated with poorer developmental outcomes in children. Between 2011 and 2015, we conducted a prospective cohort study in Australia examining the relationship between maternal iodine intake in pregnancy and childhood neurodevelopment, assessed using Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), in 699 children at 18 months. Maternal iodine intake and urinary iodine concentration (UIC) were assessed at study entry (

Objectives We used elective total joint replacement (TJR) as a case study to demonstrate selection bias toward offering this procedure to younger and healthier patients. Study Design and Setting Longitudinal data from 2,202 men were integrated with hospital data and mortality records. Study participants were followed from recruitment (1996–1999) until TJR, death, or 2007 (end of follow-up). A propensity score (PS) was constructed to quantify each subject's likelihood of undergoing TJR. TJR recipients were later matched to their non-TJR counterparts by PS and year of hospitalization. Ten-year mortality from index admission was compared between cases and controls. Results Overall, 819 (37.2%) had TJR. Those were younger, healthier, and belonged to higher socioeconomic classes compared with those who were not proposed for surgery. Of the TJR recipients, 718 were matched to 1,109 controls. Cases and controls had similar characteristics and similar years of follow-up from recruitment till index admission. Nonetheless, controls were more likely to die (39.5%) compared with 14.5% in TJR cases (P Conclusion Selection for elective procedures may introduce bias in prognostic features not accounted for by PS matching. Caution must be exercised when long-term outcomes are compared between surgical and nonsurgical groups in a population at risk for that surgical procedure.

Background: Several studies have shown that the Australian Medicare-funded chronic disease management programme can lead to improvements in care processes. No study has examined the impact on long-term health outcomes. Aims: This retrospective cohort study assessed the association between provision of a general practitioner management plan and time to next potentially preventable hospitalisation for older patients with heart failure. Methods: We used the Australian Government Department of Veterans' Affairs (DVA) claims database and compared patients exposed to a general practitioner management plan with those who did not receive the service. Kaplan–Meier analysis and Cox proportional hazards models were used to compare time until next potentially preventable hospitalisation for heart failure between the exposed and unexposed groups. Results: There were 1993 patients exposed to a general practitioner management plan and 3986 unexposed patients. Adjusted results showed a 23% reduction in the rate of potentially preventable hospitalisation for heart failure at any time (adjusted hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.92; P = 0.0051) among those with a general practitioner management plan compared with the unexposed patients. Within one year, 8.6% of the exposed group compared with 10.7% of the unexposed group had a potentially preventable hospitalisation for heart failure. Conclusions: A general practitioner management plan is associated with delayed time to next potentially preventable hospitalisation for heart failure.

Background: Chronic alcohol intake produces multiple neuroadaptive changes, including up- and downregulation of neuropeptides and receptors. There are widespread projections of relaxin-3 containing neurons to, and abundant relaxin family peptide 3 receptor (RXFP3) expression within, brain regions involved in modulating alcohol intake. Recently we demonstrated the involvement of relaxin-3/RXFP3 signalling in alcohol-seeking in rats; therefore in this study we examined whether relaxin-3 and/or RXFP3 expression were altered by chronic alcohol intake in alcohol-preferring iP rats. Methods: Expression of relaxin-3 mRNA in the hindbrain nucleus incertus and RXFP3 radioligand binding levels in discrete forebrain regions were investigated following voluntary intake of alcohol or sucrose for 12 weeks, with a 2 day washout, using quantitative in situ hybridisation histochemistry and in vitro receptor autoradiography, respectively, in cohorts of adult, male iP rats. Results: Levels of relaxin-3 mRNA in the hindbrain nucleus incertus were positively correlated with the level of intake of both alcohol (r(12) = 0.59, p = 0.03) and sucrose (r(7) = 0.70, p = 0.04) in iP rats. Dense binding of the RXFP3-selective radioligand, [ 125 ]-R3/I5, was detected in hypothalamic and extrahypothalamic sites, but no significant changes in the density of RXFP3 were observed in the brain regions quantified following chronic sucrose or ethanol intake. Conclusions: Our findings suggest high endogenous relaxin-3 expression may be associated with higher intake of rewarding substances, rather than its expression being regulated in response to their intake, consistent with an active role for the relaxin-3/RXFP3 system in modulating ingestive and alcohol-related behaviours.

Summary Objectives Though the effect of age has been studied in some cancer types, its prognostic significance in oropharyngeal squamous cell carcinoma (OPSCC) remains controversial. Our purpose is to determine the impact of age at diagnosis on overall survival ( OS ) and disease-specific survival ( DSS ) in patients with OPSCC. If the effect is significant, we aim to clarify the age at which prognosis worsens. Materials and methods 15,978 Patients with OPSCC were identified from the Surveillance, Epidemiology, and End Results (SEER) database and separated into 10 year age groups. We obtained data on age at diagnosis, primary location, race, stage, sex, radiological treatment status, and surgical treatment status. Kaplan–Meier methods were used to calculate the OS and DSS for each age group. DSS analysis was supported by a Simple Multivariable Cox Proportional Hazard Regression of all significant variables studied. Results Significant disadvantage in OS and DSS was found with increasing age. A three-group stratification was depicted with the best survival in patients aged 1–44, mildly inferior survival in patients aged 45–64, and increasingly worse survival in patients 65 and older. Multivariable analysis demonstrated statistically significant increases in hazard ratio (HR) after age 65 when compared to ages 1-64. Conclusion Increasing age after 65 is associated with worsening OS and DSS in OPSCC. Poorer prognosis is due to multiple factors, possibly including the effects of aging, which make elderly patients more susceptible to the pathogenesis of OPSCC.

SummaryObjective: Using three risk-adjustment methods we evaluated whether co-morbidity derived from electronic hospital patient data provided significant improvement on age adjustment when predicting major outcomes following an elective total joint replacement (TJR) due to osteoarthritis.Methods: Longitudinal data from 819 elderly men who had had a TJR were integrated with hospital morbidity data (HMD) and mortality records. For each participant, any mor bidity or health-related outcome was retrieved from the linked data in the period 1970 through to 2007 and this enabled us to better account for patient co-morbidities. Co-mor bidities recorded in the HMD in all admissions preceding the index TJR admission were used to construct three risk-adjustment methods, namely Charlson co-morbidity index (CCI), Elixhauser’s adjustment method, and number of co-morbidities. Postoperative outcomes evaluated included length of hospital stay, 90-day readmission, and 1-year and 2-year mortality. These were modelled using Cox proportional hazards regression as a function of age for the baseline models, and as a function of age and each of the risk-adjustment methods. The difference in the statistical performance between the models that included age alone and those that also included the co-morbidity adjustment method was as sessed by measuring the difference in the Harrell’s C estimates between pairs of mod els applied to the same patient data using Bootstrap analysis with 1000 replications.Results: Number of co-morbidities did not provide any significant improvement in model discrimination when added to baseline models observed in all outcomes. CCI significantly improved model discrimination when predicting post-operative mortality but not when length of stay or readmission was modelled. For every one point increase in CCI, postoperative 1- and 2-year mortality increased by 37% and 30%, respectively. Elixhauser’s method outperformed the other two providing significant improvement on age adjustment in all outcomes.Conclusion: The predictive performance of co-morbidity derived from electronic hospital data is outcome and risk-adjustment method specific.

Mandatory iodine fortification of bread was introduced in 2009 in Australia in response to the reemergence of iodine deficiency. The aim of this study was to assess iodine intake, urinary iodine concentration (UIC) and their correlation in pregnant women (n = 783) recruited from South Australia 2 years following mandatory iodine fortification. Total iodine intake (food and supplements) and UIC were assessed at study entry (150 μg/L.

Much progress has been made during the past 30 years with respect to elucidating the neural and endocrine pathways by which bodily needs for water and energy are brought to conscious awareness through the generation of thirst and hunger. One way that circulating hormones influence thirst and hunger is by acting on neurones within sensory circumventricular organs (CVOs). This is possible because the subfornical organ and organum vasculosum of the lamina terminalis (OVLT), the sensory CVOs in the forebrain, and the area postrema in the hindbrain lack a normal blood-brain barrier such that neurones within them are exposed to blood-borne agents. The neural signals generated by hormonal action in these sensory CVOs are relayed to several sites in the cerebral cortex to stimulate or inhibit thirst or hunger. The subfornical organ and OVLT respond to circulating angiotensin II, relaxin and hypertonicity to drive thirst-related neural pathways, whereas circulating amylin, leptin and possibly glucagon-like peptide-1 act at the area postrema to influence neural pathways inhibiting food intake. As a result of investigations using functional brain imaging techniques, the insula and anterior cingulate cortex, as well as several other cortical sites, have been implicated in the conscious perception of thirst and hunger in humans. Viral tracing techniques show that the anterior cingulate cortex and insula receive neural inputs from thirst-related neurones in the subfornical organ and OVLT, with hunger-related neurones in the area postrema having polysynaptic efferent connections to these cortical regions. For thirst, initially, the median preoptic nucleus and, subsequently, the thalamic paraventricular nucleus and lateral hypothalamus have been identified as likely sites of synaptic links in pathways from the subfornical organ and OVLT to the cortex. The challenge remains to identify the links in the neural pathways that relay signals originating in sensory CVOs to cortical sites subserving either thirst or hunger.

James Baillie and Mark Meckler’s (B&M) “Truth and Objectivity Regained” misconstrues the author’s previous argument. More surprisingly, they also fail to distinguish their own earlier arguments from their current views. This Reply seeks to clear up the confusion. It challenges B&M’s claims concerning the “function” of beliefs and statements, and defends the view that objectivity is a matter of degree, depending upon the reasonableness of a statement’s background conditions.

Background and purpose Joint Replacement Registries play a significant role in monitoring arthroplasty outcomes by publishing data on survivorship of individual prostheses or combinations of prostheses. The difference in outcomes can be device- or non-device-related, and these factors can be analyzed separately. Although registry data indicate that most prostheses have similar outcomes, some have a higher than anticipated rate of revision when compared to all other prostheses in their class. This report outlines how the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) has developed a method to report prostheses with a higher than expected rate of revision. These are referred to as “outlier” prostheses. Material and methods Since 2004, the AOANJRR has developed a standardized process for identifying outliers. This is based on a 3-stage process consisting of an automated algorithm, an extensive analysis of individual prostheses or combinations by registry staff, and finally a meeting involving a panel from the Australian Orthopaedic Association Arthroplasty Society. Outlier prostheses are listed in the Annual Report as (1) identified but no longer used in Australia, (2) those that have been re-identified and that are still used, and (3) those that are being identified for the first time. Results 78 prostheses or prosthesis combinations have been identified as being outliers using this approach (AOANJRR 2011 Annual Report). In addition, 5 conventional hip prostheses were initially identified, but after further analysis no longer met the defined criteria. 1 resurfacing hip prosthesis was initially identified, subsequently removed from the list, and then re-identified the following year when further data were available. All unicompartmental and primary total knee prostheses identified as having a higher than expected rate of revision have continued to be re-identified. Interpretation It is important that registries use a transparent and accountable process to identify an outlier prosthesis. This paper describes the development, implementation, assessment, and impact of the approach used by the Australian Registry.

Objective: The incidence of joint replacements is considered an indicator of symptomatic end-stage osteoarthritis (OA). We analysed data from two national joint replacement registries in order to investigate whether evidence of a pattern of progression of end-stage hip and knee OA could be found in data from large unselected populations. Design: We obtained data on 78,634 hip and 122,096 knee arthroplasties from the Australian Orthopaedic Association National Joint Replacement Registry and 19,786 hip and 12,082 knee arthroplasties from the Norwegian Arthroplasty Register. A multi-state model was developed where individuals were followed from their first recorded hip or knee arthroplasty for OA to receiving subsequent hip and/or knee arthroplasties. We used this model to estimate relative hazard rates and probabilities for each registry separately. Results: The hazard rates of receiving subsequent arthroplasties in non-cognate joints were higher on the contralateral side than on the ipsilateral side to the index arthroplasty, especially if the index was a hip arthroplasty. After 5 years, the estimated probabilities of having received a knee contralateral to the index hip were more than 1.7 times the probabilities of having received a knee ipsilateral to the index hip. Conclusion: The results indicate that there is an association between the side of the first hip arthroplasty and side of subsequent knee arthroplasties. Further studies are needed to investigate whether increased risk of receiving an arthroplasty in the contralateral knee is related to having a hip arthroplasty and/or preoperative factors such as pain and altered gait associated with hip OA Refereed/Peer-reviewed

Purpose: This study aimed to examine the effect of antidepressant use on persistence with newly initiated oral antidiabetic medicines in older people. Methods: A retrospective study of administrative claims data from the Australian Government Department of Veterans' Affairs, from 1 July 2000 to 30 June 2008 of new users of oral antidiabetic medicines (metformin or sulfonylurea). Antidepressant medicine use was determined in the 6 months preceding the index date of the first dispensing of an oral antidiabetic medicine. The outcome was time to discontinuation of diabetes therapy in those with antidepressant use compared with those without. Competing risks regression analyses were conducted with adjustment for covariates. Results: A total of 29,710 new users of metformin or sulfonylurea were identified, with 7171 (24.2%) dispensed an antidepressant. Median duration of oral antidiabetic medicines was 1.81 years (95% CI 1.72–1.94) for those who received an antidepressant at the time of diabetes medicine initiation, by comparison to 3.23 years (95% CI 3.10–3.40) for those who did not receive an antidepressant. Competing risk analyses showed a 42% increased likelihood of discontinuation of diabetes medications in persons who received an antidepressant (subdistribution hazard ratio 1.42, 95% CI 1.37–1.47, p

Aim To determine the effect of neonatal docosahexaenoic acid (DHA) supplementation in preterm infants on later respiratory-related hospitalisations. Methods We enrolled 657 infants in a multicentre, randomised, controlled trial designed to study the long-term efficacy of higher dose dietary DHA in infants born

Background: Little is known about the impact of a general practitioner management plan (GPMP) on health outcomes of patients with diabetes. Aim: To examine the impact of a GPMP on the risk of hospitalisation for diabetes. Methods: A retrospective study using administrative data from the Australian Government Department of Veterans’ Affairs was conducted (1 July 2006 to 30 June 2014) of diabetes patients either exposed or unexposed to a GPMP. The primary end-point was the risk of first hospitalisation for a diabetes-related complication and was assessed using Cox proportional hazard regression models with death as a competing risk. Secondary end-points included rates of receiving guideline care for diabetes, with differences assessed using Poisson regression analyses. Results: A total of 16 214 patients with diabetes were included; 8091 had a GPMP, and 8123 did not. After 1 year, 545 (6.7%) patients with a GPMP and 634 (7.8%) of patients without a GPMP were hospitalised for a diabetes complication. There was a 22% reduction in the risk of being hospitalised for a diabetes complication (adjusted hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.69–0.87, P < 0.0001) for those who received a GPMP by comparison to those who did not. Increased rates of diabetes guideline care, HbA1c claims (adjusted HR 1.29, 95% CI 1.25–1.33) and microalbuminura claims (adjusted HR 1.65, 95% CI 1.58–1.72) were observed after a GPMP. Conclusion: Provision of a GPMP in older patients with diabetes resulted in improved health outcomes, delaying the risk of hospitalisation at 12 months for diabetes complications. GPMP should be included as part of routine primary care for older patients with diabetes. Refereed/Peer-reviewed

This Chapter concerns public perceptions about who should have access to scarce antiviral drugs and vaccines in a flu pandemic. Two methods of public engagement are compared and evaluated; namely a survey, and a deliberative forum. In undertaking public engagement, researchers and policy makers may be motivated by the desire to build policy which is acceptable and workable in the community, that is instrumental goals are foremost. With instrumental goals in mind, there are a number of ways to collect community views but they may provide quite different answers as shown in the two examples described here. In the chapter we explore, the relationship between choice of method of engagement and (i) the findings of the engagement exercise, and (ii) the acceptability and applicability of these findings in a policy context.

Background We assessed risks of incident in-hospital complications and 1-year and 5-year mortality following elective primary total joint replacement (TJR), focusing on obesity. Methods Longitudinal data from a population-based cohort of 819 men who had had TJR were integrated with validated hospital morbidity data and mortality records. Complications recorded in the index admission were classified as major or minor by 13 independent orthopaedic surgeons. Results Of 819 men (mean age 76.3 (SD 4.5) years), 331 patients (40.4%) had an in-hospital complication from whom 155 (18.9%) had at least one major complication that was classified as potentially life threatening. Obesity and age were independently associated with increased risk of major complications. Compared with patients without complications, those with major complications experienced significantly greater mortality in 1 year (5.8% versus 1.2%, P = 0.001) and 5 years (16.8% versus 8.0%, P = 0.002) following TJR. In Cox regressions, age, Charlson Co-morbidity index and major complications were independently associated with 1-year mortality. Age and Charlson Co-morbidity index were also associated with 5-year mortality. Similarly, risk of dying within 5 years of TJR was higher among patients with class II obesity compared with patients with normal weight. The most frequently reported complications were those in the cardio-respiratory and general systems. Complications in the cardio-respiratory system significantly increased hazard of 1- and 5-year mortality. Conclusion The elderly and the obese are more likely to develop adverse outcomes following a primary TJR. Our findings may assist clinicians in better selecting elderly patients for surgery, and informing them about their individual level of risk.

Background. Since the mapping of the human genome in 2003, the development of biomarker targeted therapy and clinical adoption of “personalized medicine” has accelerated. Models for insurance subsidy of biomarker/test/drug packages (“codependent technologies” or technologies that work better together) are not well developed. Our aim was to create a framework to assess the safety, effectiveness, and cost-effectiveness of these technologies for a national coverage or reimbursement decision. Methods. We extracted information from assessments of recent Australian reimbursement applications that concerned genetic tests and treatments to identify items and evidence gaps considered important to the decision-making process. Relevant international regulatory and reimbursement guidance documents were also reviewed. Items addressing causality theory were included to help explain the relationship between biomarker and treatment. The framework was reviewed by policy makers and technical experts, prior to a public consultation process. Results. The framework consists of 5 components—context, clinical benefit, evidence translation, cost-effectiveness, and financial impact—and a checklist of 79 items. To determine whether the biomarker test, the drug, both, or neither should be subsidized, we considered it crucial to identify whether the biomarker is a treatment effect modifier or a prognostic factor. To aid in this determination, the framework explicitly allows the linkage of different types of evidence to examine whether targeting the biomarker varies the likely clinical benefit of the drug, and if so, to what extent. Conclusions. The first national framework to assess personalized medicine for coverage or reimbursement decisions has been developed and introduced and may be a suitable model for other health systems.

Introduction: We sought community opinion on consent alternatives when linking childhood immunisation and hospital attendance records for the purpose of vaccine safety surveillance. Methods: We conducted computer-assisted telephone interviewing (CATI) of a sample of rural and metropolitan residents of South Australia in 2011. Results: Of 2002 households interviewed (response rate 55.6%), 96.4% supported data linkage for postmarketing surveillance of vaccines; very few were completely opposed (1.5%) or undecided (2.2%). The majority (75.3%) trusted the privacy protections used in data linkage and most wished to have minimal or no direct involvement, preferring either opt-out consent (40.4%) or no consent (30.6%). A quarter of respondents (24.6%) favoured opt-in consent, but their preferences were divergent; half requested consent be sought prior to every use (11.4%) while the remainder preferred to give broad consent just once (3.4%) or renewed at periodic intervals (9.8%). Over half of the respondents gave higher priority to rapid vaccine safety surveillance (56.5%) rather than first seeking parental consent (26.6%) and one in seven was undecided (14.5%). Although 91.6% of respondents believed childhood vaccines are safe, over half (53.1%) were very or somewhat concerned that a vaccine could cause a serious reaction. Nevertheless, 92.4% of the parents in the sample (556/601) reported every child in their care as being fully immunised according to the National Immunisation Program schedule. Only 3.7% of parents (22/601) reported one or more children as under immunised, and 3.9% (23/601) reported that none of their children were immunised. Conclusions: This survey demonstrates that data linkage for vaccine safety surveillance has substantial community support and that a system utilising opt-out consent or no consent was preferred to one using opt-in consent. These findings should inform public health policy and practice; data linkage should be established where feasible to address limitations in passive surveillance systems Refereed/Peer-reviewed

Background and purpose: An increasing number of patients have several joint replacement procedures during their lifetime. We investigated the use and suitability of multi-state model techniques in providing a more comprehensive analysis and description of complex arthroplasty histories held in arthroplasty registries than are allowed for with traditional survival methods. Patients and methods: We obtained data from the Australian Orthopaedic Association National Joint Replacement Registry on patients (n = 84,759) who had undergone a total hip arthroplasty for osteoarthritis in the period 2002–2008. We set up a multi-state model where patients were followed from their first recorded arthroplasty to several possible states: revision of first arthroplasty, either a hip or knee as second arthroplasty, revision of the second arthroplasty, and death. The Summary Notation for Arthroplasty Histories (SNAH) was developed in order to help to manage and analyze this type of data. Results: At the end of the study period, 12% of the 84,759 patients had received a second hip, 3 times as many as had received a knee. The estimated probabilities of having received a second arthroplasty decreased with age. Males had a lower transition rate for receiving a second arthroplasty, but a higher mortality rate. Interpretation: Multi-state models in combination with SNAH codes are well suited to the management and analysis of arthroplasty registry data on patients who experience multiple joint procedures over time. We found differences in the progression of joint replacement procedures after the initial total hip arthroplasty regarding type of joint, age, and sex. Refereed/Peer-reviewed

Relaxin-3 is a neuropeptide that is implicated in the regulation of stress responses and memory. The elucidation of its precise physiological role(s) has, however, been hampered by cross-activation of the relaxin-2 receptor, RXFP1, in the brain. The current study undertook to develop analogues of human relaxin-3 (H3 relaxin) that can selectively bind and activate its receptor, RXFP3. We developed a high-affinity selective agonist (analogue 2) by removal of the intra-A chain disulfide bond and deletion of 10 residues from the N terminus of the A chain. Further truncation of this analogue from the C terminus of the B chain to Cys(B22) and addition of an Arg(B23) led to a high-affinity, RXFP3-selective, competitive antagonist (analogue 3). Central administration of analogue 2 in rats increased food intake, which was blocked by prior coadministration of analogue 3. These novel RXFP3-selective peptides represent valuable pharmacological tools to study the physiological roles of H3 relaxin/RXFP3 systems in the brain and important leads for the development of novel compounds for the treatment of affective and cognitive disorders.

Background Although ambient air pollution exposure has been linked with poor health in many parts of the world, no previous study has investigated the effect on morbidity in the city of Adelaide, South Australia. Objective To explore the association between particulate matter (PM) and hospitalisations, including respiratory and cardiovascular admissions in Adelaide, South Australia. Methods For the study period September 2001 to October 2007, daily counts of all-cause, cardiovascular and respiratory hospital admissions were collected, as well as daily air quality data including concentrations of particulates, ozone and nitrogen dioxide. Visibility codes for present weather conditions identified days when airborne dust or smoke was observed. The associations between PM and hospitalisations were estimated using time-stratified case-crossover analyses controlling for covariates including temperature, relative humidity, other pollutants, day of the week and public holidays. Results Mean PM10 concentrations were higher in the warm season, whereas PM2.5 concentrations were higher in the cool season. Hospital admissions were associated with PM10 in the cool season and with PM2.5 in both seasons. No significant effect of PM on all-age respiratory admissions was detected, however cardiovascular admissions were associated with both PM2.5 and PM10 in the cool season with the highest effects for PM2.5 (4.48%, 95% CI: 0.74%, 8.36% increase per 10 μg/m3 increase in PM2.5). Conclusion These findings suggest that despite the city's relatively low levels of air pollution, PM concentrations are associated with increases in morbidity in Adelaide. Further studies are needed to investigate the sources of PM which may be contributing to the higher cool season effects.

Concern that mild iodine deficiency in pregnancy may adversely affect neurodevelopment of offspring has led to recommendations for iodine supplementation in the absence of evidence from randomised controlled trials. The primary objective of the study was to investigate the effect of iodine supplementation during pregnancy on childhood neurodevelopment. Secondary outcomes included pregnancy outcomes, maternal thyroid function and general health. Women with a singleton pregnancy of fewer than 20 weeks were randomly assigned to iodine (150 μg/d) or placebo from trial entry to birth. Childhood neurodevelopment was assessed at 18 months by using Bayley Scales of Infant and Toddler Development (Bayley-III). Iodine status and thyroid function were assessed at baseline and at 36 weeks’ gestation. Pregnancy outcomes were collected from medical records. The trial was stopped after 59 women were randomly assigned following withdrawal of support by the funding body. There were no differences in childhood neurodevelopmental scores between the iodine treated and placebo groups. The mean cognitive, language and motor scores on the Bayley-III (iodine versus placebo, respectively) were 99.4 ± 12.2 versus 101.7 ± 8.2 (mean difference (MD) −2.3, 95 % confidence interval (CI) −7.8, 3.2; P = 0.42), 97.2 ± 12.2 versus 97.9 ± 11.5 (MD −0.7, 95 % CI −7.0, 5.6; P = 0.83) and 93.9 ± 10.8 versus 92.4 ± 9.7 (MD 1.4, 95 % CI −4.0, 6.9; P = 0.61), respectively. No differences were identified between groups in any secondary outcomes. Iodine supplementation in pregnancy did not result in better childhood neurodevelopment in this small trial. Adequately powered randomised controlled trials are needed to provide conclusive evidence regarding the effect of iodine supplementation in pregnancy. The trial was registered with the Australian New Zealand Clinical Trials Registry at http://www.anzctr.org.au . The registration number of this trial is ACTRN12610000411044 . The trial was registered on 21 May 2010.

Purpose: Here we describe some available statistical models and illustrate their use for analysis of arthroplasty registry data in the presence of the competing risk of death, when the influence of covariates on the revision rate may be different to the influence on the probability (that is, risk) of the occurrence of revision. Patients and methods: Records of 12,525 patients aged 75–84 years who had received hemiarthroplasty for fractured neck of femur were obtained from the Australian Orthopaedic Association National Joint Replacement Registry. The covariates whose effects we investigated were: age, sex, type of prosthesis, and type of fixation (cementless or cemented). Extensions of competing risk regression models were implemented, allowing the effects of some covariates to vary with time. Results The revision rate was significantly higher for patients with unipolar than bipolar prostheses (HR = 1.38, 95% CI: 1.01– 1.89) or with monoblock than bipolar prostheses (HR = 1.45, 95% CI: 1.08–1.94). It was significantly higher for the younger age group (75–79 years) than for the older one (80–84 years) (HR = 1.28, 95% CI: 1.05–1.56) and higher for males than for females (HR = 1.37, 95% CI: 1.09–1.71). The probability of revision, after correction for the competing risk of death, was only significantly higher for unipolar prostheses than for bipolar prostheses, and higher for the younger age group. The effect of fixation type varied with time; initially, there was a higher probability of revision for cementless prostheses than for cemented prostheses, which disappeared after approximately 1.5 years. Interpretation: When accounting for the competing risk of death, the covariates type of prosthesis and sex influenced the rate of revision differently to the probability of revision. We advocate the use of appropriate analysis tools in the presence of competing risks and when covariates have time-dependent effects. Refereed/Peer-reviewed

Aim: To identify and evaluate the management and care of older people with multiple chronic health problems (MCHP). Methods: Administrative health data from the Department of Veterans' Affairs and bio-social data from the Australian Longitudinal Study of Ageing are used to determine prevalence of MCHP, treatment patterns and patient outcomes. Focus groups and semistructured interviews are used to gain patient and health practitioner perspectives. Results: The prevalence of MCHP in older people is high (65%) and is associated with increased use of health services, mortality and poorer self-rated health. Australian disease-specific guidelines fail to address MCHP, and treatment conflicts with the potential to cause harm, were common. Conclusion: Improvements in the care and management of older people with MCHP requires: a multifaceted approach, across the health-care system; better coordination of holistic, patient-centred multidisciplinary care; and effective communication and education of all stakeholders. The Health reform agenda in Australia provides an opportunity for change.

Purpose: Warfarin management in the elderly population is complex as medicines prescribed for concomitant diseases may further increase the risk of major bleeding associated with warfarin use. We aimed to quantify the excess risk of bleeding-related hospitalisation when warfarin was co-dispensed with potentially interacting medicines. Methods: A retrospective cohort study was undertaken over a 4-year period from July 2002 to June 2006 to examine bleeding risk associated with medications co-administered in patients taking warfarin using an administrative claims database from the Australian Department of Veterans' Affairs. All veterans aged 65 years and over who were new users of warfarin were followed until death or study end. Risk of bleeding was assessed using a Poisson GEE model adjusting for age, gender, socioeconomic status, co-morbidity index, previous bleeding related hospitalisations and indicators of health service use. Results: Overall, 17661 veterans who used warfarin at any time during the study period were included. The overall incidence rate of bleeding-related hospitalisations was 4.1 (95% CI 3.7-4.6) per 100 person-years in veterans who were not receiving potentially interacting medicines. Bleeding-related hospitalisation rates were significantly increased when warfarin was co-prescribed with low-dose aspirin (Adjusted rate ratio (AdjRR) 1.44, 95% CI 1.00-2.07), clopidogrel (AdjRR 2.23, 95% CI 1.48-3.36), clopidogrel with aspirin (AdjRR 3.44, 95% CI 1.28-9.23), amiodarone (AdjRR 3.33, 95% CI 1.38-8.00) and antibiotics (AdjRR 2.34, 95% CI 1.55-3.54). Conclusions: Models assessing bleeding risk with warfarin should take account of the range of potentially harmful medicine combinations used in elderly people with comorbid conditions.

Objective To assess the associations of smoking, body weight, and physical activity with risk of undergoing total joint replacement (TJR) in a population-based cohort of men. Methods A cohort study of 11,388 men that integrated clinical data with hospital morbidity data and mortality records was undertaken. The risk of undergoing TJR was modeled on baseline weight, height, comorbidity, socioeconomic status, years of smoking, and exercise in 3 separate age groups, using Cox proportional hazards regressions and competing risk regressions (CRRs). Results Dose-response relationships between weight and risk of TJR and between smoking and risk of TJR were observed. Being overweight independently increased the risk of TJR, while smoking lowered the risk. The decreased risk among smokers was demonstrated in both Cox and CRR models and became apparent after 23 years of exposure. Men who were in the highest quartile (≥48 years of smoking) were 42–51% less likely to undergo TJR than men who had never smoked. Tests for trend in the log hazard ratios (HRs) across both smoking and weight quantiles yielded significant P values. Vigorous exercise increased the hazard of TJR; however, the association reached statistical significance only in the 70–74-year-old age group (adjusted HR 1.64 [95% confidence interval 1.19–2.24]). Adjusting for Deyo-Charlson Index or Elixhauser's comorbidity measures did not eliminate these associations. Conclusion Our findings indicate that being overweight and reporting vigorous physical activity increase the risk of TJR. This study is the first to demonstrate a strong inverse dose-response relationship between duration of smoking and risk of TJR. More research is needed to better understand the role of smoking in the pathogenesis of osteoarthritis.

BACKGROUND: Docosahexaenoic acid (DHA) has been associated with downregulation of inflammatory responses. OBJECTIVE: To report the effect of DHA supplementation on long-term atopic and respiratory outcomes in preterm infants. METHODS: This study is a multicenter, randomized controlled trial comparing the outcomes for preterm infants RESULTS: Six hundred fifty-seven infants were enrolled (322 to high-DHA diet, 335 to standard), and 93.5% completed the 18-month follow-up. There was a reduction in BPD in boys (relative risk [RR]: 0.67 [95% confidence interval (CI): 0.47–0.96]; P = .03) and in all infants with a birth weight of CONCLUSIONS: DHA supplementation for infants of