Correlation of frailty assessment metrics in one-year follow-up of aged care residents: a sub-study of a randomised controlled trial.

INTRODUCTION: Frailty is increasingly recognised as a dynamic syndrome, with multiple causes, dimensions and consequences. There is little understanding of how those frailty assessment metrics interact over time. The aim of this study was to describe the longitudinal correlation between five frailty metrics, namely multimorbidity, muscular strength, mood alterations, cognitive capacity, and functional capacity in a cohort study of aged care (nursing home) residents. METHODS: 248 aged care residents with Frailty Index at baseline of < 0.4 and no dementia were followed for 12 months. A multimorbidity score and an activity of daily living limitation score were created using individual items of the Frailty Index. Muscular strength was measured by grip strength. Cognitive capacity was measured using the Montreal Cognitive Assessment (MoCA) test. Mood alterations were measured using the anxiety/depression screening question from EQ-5D. We analysed the inter-individual correlation at baseline, association between baseline and future change, and within-individual correlation at baseline, 6 and 12 months. RESULTS: Population analysis shows that metrics were not associated at baseline. All of the studied metrics at baseline were associated with change in 12 months, with the exception of anxiety/depression scores. Pairwise within-individual correlation was strong between MoCA and grip strength (0.13, p = 0.02) and activity of daily living (- 0.48, p < 0.001), and between activities of daily living and multimorbidity index (0.28, p < 0.001). No within-individual correlation was found between anxiety depression score and other metrics. CONCLUSION: The results suggest an interdependence between comorbidities, physical capacity, cognition and activities of daily living in aged care residents. Comprehensive measurement of frailty-related metrics may provide improved understanding of frailty progression at later life stages.

Prevalence and changes in analgesic medication utilisation 1 year prior to total joint replacement in an older cohort of patients.

OBJECTIVES: To evaluate the prevalence and change in analgesic medications use prior to joint replacement in older patients between 2001 and 2012. METHODS: A population based epidemiological study was conducted. Opioids, non-steroidal anti-inflammatories (NSAIDs), paracetamol, corticosteroid injections, medications for neuropathic pain, hypnotics, and muscle relaxants supplied 1 year prior to total knee replacement (TKR, n = 15,517) and hip replacement (THR, n = 10,018) were assessed. Patient characteristics and surgical indication adjusted prevalence ratios (PRs) and 95% confidence intervals (CI) are provided. RESULTS: From 2001 to 2012, in the TKR cohort (median age 78.9) the prevalence of opioid use prior to surgery increased from 37% to 49% (PR = 1.01, 95% CI 1.00-1.01, P = 0.01), while in the THR cohort (median age 81.1) it increased from 44% to 54% (PR = 1.01, 95% CI 1.01-1.02, P < 0.001). Paracetamol use increased from 52% to 61% (PR = 1.0, 95% CI 1.0-1.0, P = 0.913) in the TKR cohort and from 55% to 67% (PR = 1.01, 95% CI 1.00-1.01, P = 0.005) in the THR cohort. Neuropathic pain medication use increased from 5% to 11% in the TKR cohort (PR = 1.04, 95% CI 1.02-1.06, P < 0.0001) and from 6% to 12% in the THR cohort (PR = 1.06, 95% CI 1.04-1.09, P < 0.0001). NSAID use decreased from 76% to 50% in the TKR cohort (PR = 0.96, 95% CI 0.95-0.96, P < 0.0001), and from 81% to 47% in THR cohort (PR = 0.95, 95% CI 0.94-0.95, P < 0.0001). Corticosteroid injections prevalence also decreased (TKR: 21-18%, PR = 0.97, 95% CI 0.96-0.97, P < 0.001, THR: 18-17%, PR = 0.97, 95% CI 0.96-0.98, P < 0.001). CONCLUSION: Pain medication utilization prior to joint replacement surgery changed significantly in this national older cohort of patients during the 2000s.

Evaluation of three co-morbidity measures to predict mortality in patients undergoing total joint arthroplasty.

OBJECTIVE: To evaluate the 90 days and 1 year mortality predictive ability of the RxRisk-V, Charlson, and Elixhauser co-morbidity measures in total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients. METHOD: A retrospective study of 11,848 THAs and 18,972 TKAs (2001-2002) was conducted. Death within 90 days and 1 year of the surgery were the main endpoints. Co-morbidity measures were calculated using either medication or hospitalisation history. Logistic regression models were employed and discrimination and calibration were assessed. Specifically, models with unweighted and weighted measure scores, models with the specific conditions, and a model combining conditions identified by all measures were assessed. RESULTS: In THAs, the best performing prediction models included co-morbidities from all three measures (90 days: c = 0.84, P = 0.284, 1 year: c = 0.79, P = 0.158). Individually, the model with Charlson conditions performed best at 90 days mortality (c = 0.80, P = 0.777) and the Charlson and Elixhauser performed similarly at 1 year (both c = 0.77, P > 0.05). In TKAs, the best performing prediction model included co-morbidities from all measures (90 days: c = 0.82, P = 0.349, 1 year: c = 0.78, P = 0.873). Individually, the model with Elixhauser conditions performed best with 90 days mortality (c = 0.79, P = 0.435) and all performed similarly at 1 year (c = 0.74-0.75, all P > 0.05). CONCLUSIONS: A combined model with co-morbidities identified by the Elixhauser, Charlson, and RxRisk-V was the best mortality prediction model. The RxRisk-V did not perform as well as the others. Because of the Elixhauser and Charlson's similar performance we suggest basing the choice of measurement use on factors such as the need of specific conditions and modelling limitations.

Increased risk of hospital admission for dehydration or heat-related illness after initiation of medicines: a sequence symmetry analysis.

WHAT IS KNOWN AND OBJECTIVE: Although several studies have identified factors which increase the risk of heat-related illness, few have assessed the contribution of medicines. To address this knowledge gap, our study aimed to assess the risk of hospital admission for dehydration or other heat-related illness following initiation of medicines. METHODS: We conducted a retrospective analysis using prescription event symmetry analysis (PESA) of 6700 veterans with incident hospital admission for dehydration or heat-related illness (ICD-10-AM codes E86, X30, T67), between 1 January 2001 and 30 June 2013. The main outcome measure was first ever hospital admission for dehydration or heat-related illness following initiation of commonly used medicines. RESULTS AND DISCUSSION: A significantly higher risk of incident hospital admission for dehydration or heat-related illness was observed following initiation of anticoagulants, cardiovascular medicines, NSAIDs, antipsychotics, antidepressants and anticholinergic agents. The risk of hospital admission for dehydration or heat-related illness ranged from 1·17 (SSRIs) to 2·79 (ACEI plus diuretic combination product). No significant association was observed between initiation of anticonvulsants, anti-Parkinson's agents, hypnotics, anxiolytics or antihistamines and hospital admission for dehydration or heat-related illness. WHAT IS NEW AND CONCLUSION: Many commonly used medicines were found to be associated with increased risk of hospitalization for dehydration or heat-related illness. Initiation of ACE inhibitors in combination with diuretics had the highest risk. Prescribers and patients should be aware of the potential for medicines to be associated with increased risk of dehydration and heat-related illness.

Hospitalization for drug-induced hepatotoxicity: linking Y-codes with pharmaceutical claims data to identify implicated medicines.

WHAT IS KNOWN AND OBJECTIVE: Hospital admissions associated with an adverse drug reaction are often coded to the International Classification of Diseases external cause Y-codes, denoting the medicine class deemed to cause the adverse drug reaction. Matching hospital data with outpatient dispensing data has the potential to identify the specific causative medicines but the ability to identify the causative medicines in this way has not been previously assessed. This study aimed to determine the proportion of Y-coded hospitalizations for drug-induced hepatotoxicity that could be matched with a potential causative medicine from outpatient dispensing data. METHODS: A retrospective cohort study was undertaken from 1 Jan 2005 to 30 June 2012 using data from the Australian Government Department of Veterans' Affairs of all admissions coded to drug-induced hepatotoxicity. Medicine use in the 6 months prior to hospitalization was examined to identify the probable causative medicines. RESULTS AND DISCUSSION: Thirty five admissions were identified for 31 patients. All admissions were preceded by use of medicines known to cause hepatotoxicity. Twenty four admissions had a Y-code recorded, of which 19 admissions had at least one Y-code specifying the causative medicine class (22 Y-codes). Of the 22 Y-codes, 95% could be successfully matched with a medicine from the same class that had been dispensed in the 6 months prior to admission. Further, 92% were preceded by use of multiple hepatotoxic medicines. WHAT IS NEW AND CONCLUSION: Results of our study demonstrate that hospital administrative data can be linked to prescription dispensing data to identify specific medicines suspected of causing the adverse drug reaction.

Chromosome 9p deletion in clear cell renal cell carcinoma predicts recurrence and survival following surgery.

BACKGROUND: Wider clinical applications of 9p status in clear cell renal cell carcinoma (ccRCC) are limited owing to the lack of validation and consensus for interphase fluorescent in situ hybridisation (I-FISH) scoring technique. The aim of this study was to analytically validate the applicability of I-FISH in assessing 9p deletion in ccRCC and to clinically assess its long-term prognostic impact following surgical excision of ccRCC. METHODS: Tissue microarrays were constructed from 108 renal cell carcinoma (RCC) tumour paraffin blocks. Interphase fluorescent in situ hybridisation analysis was undertaken based on preset criteria by two independent observers to assess interobserver variability. 9p status in ccRCC tumours was determined and correlated to clinicopathological variables, recurrence-free survival and disease-specific survival. RESULTS: There were 80 ccRCCs with valid 9p scoring and a median follow-up of 95 months. Kappa statistic for interobserver variability was 0.71 (good agreement). 9p deletion was detected in 44% of ccRCCs. 9p loss was associated with higher stage, larger tumours, necrosis, microvascular and renal vein invasion, and higher SSIGN (stage, size, grade and necrosis) score. Patients with 9p-deleted ccRCC were at a higher risk of recurrence (P=0.008) and RCC-specific mortality (P=0.001). On multivariate analysis, 9p deletion was an independent predictor of recurrence (hazard ratio 4.323; P=0.021) and RCC-specific mortality (hazard ratio 4.603; P=0.007). The predictive accuracy of SSIGN score improved from 87.7% to 93.1% by integrating 9p status to the model (P=0.001). CONCLUSIONS: Loss of 9p is associated with aggressive ccRCC and worse prognosis in patients following surgery. Our findings independently confirm the findings of previous reports relying on I-FISH to detect 9p (CDKN2A) deletion.

Multiparameter DNA content analysis identifies distinct groups in primary breast cancer.

BACKGROUND: Multiparameter flow cytometry is a robust and reliable method for determining tumour DNA content applicable to formalin-fixed paraffin-embedded (FFPE) tissue. This study examined the clinical and pathological associations of DNA content in primary breast cancer using an improved multiparametric technique. METHODS: The FFPE tissue from 201 primary breast cancers was examined and the cancers categorised according to their DNA content using multiparametric flow cytometry incorporating differential labelling of stromal and tumour cell populations. Mathematical modelling software (ModFit 3.2.1) was used to calculate the DNA index (DI) and percentage S-phase fraction (SPF%) for each tumour. Independent associations with clinical and pathological parameters were sought using backward stepwise Binary Logistic Regression (BLR) and Cox's Regression (CR) analysis. RESULTS: Tumours were grouped into four categories based on the DI of the tumour cell population. Low DI tumours (DI=0.76-1.14) associated with progesterone receptor-positive status (P=0.012, BLR), intermediate DI (DI=1.18-1.79) associated with p53 mutant tumours (P=0.001, BLR), high DI (DI1.80) tumours with human epidermal growth factor receptor 2 (HER2)-positive status (P=0.004, BLR) and 'multiploid tumours' (two or more tumour DNA peaks) did not show any significant associations. Tumours with high SPF% (10%) independently associated with poor overall survival (P=0.027, CR). CONCLUSION: Multiparametric flow analysis of FFPE tissue can accurately assess tumour DNA content. Tumour sub-populations associated with biomarkers of prognosis or likely response to therapy. The alterations in DNA content present the potential for greater understanding of the mechanisms underlying clinically significant biomarker changes in primary breast cancer.

Utilisation of disease modifying treatment and diversity of treatment pathways in relapsing remitting multiple sclerosis.

BACKGROUND: There is minimal information on the utilisation of Disease Modifying Treatment (DMTs) for multiple sclerosis. The appropriate and safe use of medicines is informed by utilisation studies. Outcomes can inform health interventions to improve appropriate use of medicines and post marketing surveillance activities to improve safety. OBJECTIVE: To evaluate utilisation and treatment patterns of disease modifying treatments (DMTs) for relapsing remitting multiple sclerosis (RRMS). METHODS: A representative sample of the Australian pharmaceutical benefits scheme data were analysed (2006-2016). Demographics of incident users and trends in incident and prevalent users were determined. Individual patient treatment pathways were determined by sequential initiation of medicines in two different periods (2006-2013 and 2014-2019). RESULTS: There were 20,660 patients with at least one dispensing of a DMT for RRMS during the study period (median age 41 years, 75% female). Incident and prevalent use increased by 20% and 88%, respectively. The market was responsive to 13 new listings of DMTs over the study period. Sequential treatment was found for 66% of initiators in 2006-2013 and 28.5% of initiators in 2014-2019. Diverse treatment pathways were found, with 278 and 93 unique sequences in 2006-2013 and 2014-2019, respectively. CONCLUSION: The availability of new DMTs has influenced both initial treatment choice and prevalence of users. Individualised treatment patterns and exposure to multiple medicines over time will challenge traditional pharmacovigilance systems.

Variation in health service use by veterans with an accepted disability of post-traumatic stress disorder who had a service record post 1975: a cluster analysis.

BACKGROUND: The use of health services is likely to vary among veterans with an accepted disability of post-traumatic stress disorder (PTSD), however, the extent of variation is not known. We aimed to determine the extent and type of health services used by veterans with an accepted disability of PTSD. METHODS: The cohort included veterans who served post 1975, were eligible for all Australian Government Department of Veterans' Affairs funded health services, had PTSD as an accepted disability prior to July 2015 and were alive at the 30 June 2016. Veterans were assigned to groups based on their use of health services using K-means cluster analysis. RESULTS: The cohort comprised five clusters involving 2286 veterans. The largest cluster (43%) were a younger, general practitioner (GP) managed cluster who saw their GP quarterly and the psychiatrist twice a year. The second GP cluster (30%) had higher levels of physical comorbidity. The psychiatrist managed cluster (14%) had a mean of 12 psychiatrist visits and one PTSD hospitalisation in the year. The remaining two clusters involved GP and allied healthcare, but no psychologist care. High levels of antidepressant use occurred in all clusters, ranging from 44% up to 69%. The psychiatrist managed cluster had 47% on antipsychotics and 58% on anxiolytics. CONCLUSION: Our study highlights the heterogeneity in health service use. These results identify the significant health utilisation required for up to one-sixth of veterans with PTSD and the significant role of primary care physicians in supporting veterans with PTSD.

Collaborative home medicines review delays time to next hospitalization for warfarin associated bleeding in Australian war veterans.

WHAT IS KNOWN AND BACKGROUND: Unintended bleeds are a common complication of warfarin therapy. We aimed to determine the impact of general practitioner-pharmacist collaborative medication reviews in the practice setting on hospitalization-associated bleeds in patients on warfarin. METHOD: We undertook a retrospective cohort study using administrative claims data for the ambulatory veteran and war widow population, Australia. Participants were veterans, war widows and their dependents aged 65 years and over dispensed warfarin. The exposed groups were those exposed to a general practitioner (GP)-pharmacist collaborative home medication review. The service includes GP referral, a home visit by an accredited pharmacist to identify medication-related problems, a pharmacist report with follow-up undertaken by the GP. The outcome measure was time to next hospitalization for bleeding. RESULTS: There were 816 veterans exposed to a home medicines review and 16,320 unexposed patients, with an average age of 81.5 years, and six to seven co-morbidities. Adjusted results showed a 79% reduction in likelihood of hospitalization for bleeding between 2 and 6 months (HR, 0.21 95% CI, 0.05-0.87) amongst those who had received a home medicines reviewed compared to the unexposed patients. No effect was seen in the time period from review to 2 months, nor in the time period 6 to 12 months post a review. WHAT IS NEW AND CONCLUSION: Medicines review in the practice setting delays time to next hospitalization for bleeding in those treated with warfarin in the period 2 to 6 months after the review, but is not sustained over time. Six monthly medication reviews may be required for patients on warfarin who are considered at high risk of bleeding.

Prevalence of multiple risk factors for poor outcomes associated with COVID-19 among an elderly Australian population.

BACKGROUND AND OBJECTIVES: Increasing age, male sex and various chronic conditions have been identified as important risk factors for poor outcomes from COVID-19. The aim of this study was to examine the prevalence of risk factors for poor outcomes due to COVID-19 infection in an older population. METHOD: The proportion of the population with one or more risk factors and the prevalence of individual risk factors and multiple risk factors were calculated among Department of Veterans' Affairs (DVA) clients aged ≥70 years. RESULTS: There were 103,422 DVA clients included. Of these, 79% in the community and 82% in residential aged care had at least one risk factor for poor outcomes from COVID-19. Hypertension was most prevalent, followed by chronic heart and airways disease. Over half had ≥2 risk factors, and one in five had ≥3 risk factors across multiple body systems. DISCUSSION: A substantial proportion of older Australians are at risk of poor outcomes from COVID-19 because of their multimorbid risk profile. These patients should be prioritised for proactive monitoring to avoid unintentional harm due to potential omission of care during the pandemic.

Use of medicines associated with dry mouth and dental visits in an Australian cohort.

BACKGROUND: Poor recognition of medicine-induced dry mouth can have a number of adverse effects, including difficulties with speech, chewing and swallowing dry foods, gum disease, dental caries and oral candidosis. This study examined the prevalence of use of medicines that cause dry mouth and claims for dental services funded by the Department of Veterans' Affairs (DVA) in an Australian cohort. METHODS: We used the DVA administrative health claims data to identify persons using medicines that can cause dry mouth at 1st of September 2016 and determine their DVA dental claims in the subsequent year. Results were stratified by gender, residence in community or residential aged cared facility and number of medicines. RESULTS: We identified 50 679 persons using medicines known to cause dry mouth. Of these, 72.6% were taking only one medicine that may cause dry mouth, and 21.6% were taking two. Less than half (46.2%) of all people taking at least one of these medicines had a dental claim in the following year. A smaller proportion of women (35.9%) made claims than men (56.9%), χ2  = 2248.77, P < 0.0001. CONCLUSIONS: Targeted interventions raising awareness of the relationship between some medicines and dry mouth, and the importance of dental visits are warranted.

Safety of meningococcal B vaccine (4CMenB) in adolescents in Australia.

BACKGROUND: Four-component meningococcal B (4CMenB) vaccine is licensed in many countries but has had limited use in adolescents despite this age group being at increased risk of meningococcal disease. OBJECTIVES: To assess the safety profile of two doses of 4CMenB in adolescents. METHODS: Cluster randomised controlled trial of senior school students in South Australia (SA) with participating schools randomised to intervention (4CMenB) or control. Vaccine safety was monitored using the South Australian Vaccine Safety Surveillance System (SAVSS), a spontaneous reporting system for adverse events following immunisation (AEFI) with enhanced follow-up of AEFI. RESULTS: 58,637 doses of 4CMenB vaccine were administered to 30,522 students (median age 16 years) during 2017-2018. Of 18,348 and 12,174 students vaccinated in 2017 and 2018, 97.3% and 84.3%, respectively, received both scheduled doses (N = 28,115). 193 AEFI in 187 students were reported with a reporting rate of 0.32% (95%CI: 0.28-0.39%). Seventy individuals sought medical review, including nine serious adverse events. 98% (166/169) of those who were contactable for AEFI follow-up (87.6% 169/193) reported resolution of the event. Most common AEFI were injection site reaction (126/193), headache (99/193) and nausea (61/193). AEFI were more frequently reported in females (aOR = 1.409 (95%CI: 1.002, 1.980)), schools with high level of educational advantage (adjusted Odds Ratio (aOR) = 1.515 (95%CI: 1.005, 2.284)), following first dose (aOR = 1.619 (95%CI: 1.168, 2.244)), and in 2017 (aOR = 1.437 (95%CI: 1.001, 2.064)). Reported AEFI declined with increasing age (aOR = 0.771 (95%CI: 0.673, 0.883)). CONCLUSION: In this largest post-licensure use of 4CMenB in adolescents, the low AEFI reporting rate provides real-world evidence of 4CMenB safety in this age group. (ClinicalTrials.gov number: NCT03089086).

Focal cerebral oxygenation and neurological outcome with or without brain tissue oxygen-guided therapy in patients with traumatic brain injury.

BACKGROUND: In patients with severe traumatic brain injury (TBI), the depth and duration of cerebral hypoxia are independent predictors of outcome. This study aimed to evaluate the efficacy of brain oxygen-guided therapy in improving cerebral oxygenation and neurological outcome in severe TBI patients. METHODS: Thirty TBI patients had brain oxygen monitors placed contralateral to the side of mass lesions, or to the non-dominant side if injury was diffuse. The first 10 patients (Group 1, observational) had brain tissue oxygen (PbrO2) monitored, but not treated. The next 20 patients (Group 2, interventional) were treated according to brain tissue oxygen-guided algorithms aiming to improve cerebral oxygen availability. The 6-month neurological outcome of Group 2 patients was compared with that of Group 1 patients and with contemporary control patients (Group 3) treated without the use of brain oxygen monitoring. FINDINGS: The mean duration of brain hypoxic episodes (PbrO2 <15 mmHg) was 106 minutes in Group 1, and 34 minutes in Group 2 (p=0.01). Brain tissue oxygen was <15 mmHg for 10% of monitoring time in Group 1 and 2.8% in Group 2 (p=0.12). The peak incidence of cerebral hypoxic events in both groups occurred during post-injury day 5. The mean Injury Severity Score (ISS) of patients experiencing cerebral hypoxia was higher than that of patients without cerebral hypoxic episodes (33.7 vs 24.2, p=0.04). There was no statistically significant difference in neurological outcome between those patients treated with and those without brain oxygen-guided therapy. CONCLUSIONS: In TBI patients, brain tissue oxygen-guided therapy is associated with decreased duration of episodes of cerebral hypoxia. Larger studies are indicated to determine the effects of this therapy on neurological outcome.

Patient-specific prescriber feedback can increase the rate of osteoporosis screening and treatment: results from two national interventions.

Osteoporosis interventions targeting older Australians and clinicians were conducted in 2008 and 2011 as part of a national quality improvement program underpinned by behavioural theory and stakeholder engagement. Uptake of bone mineral density (BMD) tests among targeted men and women increased after both interventions and sustained increases in osteoporosis treatment were observed among men targeted in 2008. PURPOSE: Educational interventions incorporating patient-specific prescriber feedback have improved osteoporosis screening and treatment among at-risk patients in clinical trials but have not been evaluated nationally. This study assessed uptake of BMD testing and osteoporosis medicines following two national Australian quality improvement initiatives targeting women (70-79 years) and men (75-85 years) at risk of osteoporosis. METHODS: Administrative health claims data were used to determine monthly rates of BMD testing and initiation of osteoporosis medicines in the 9-months post-intervention among targeted men and women compared to older cohorts of men and women. Log binomial regression models were used to assess differences between groups. RESULTS: In 2008 91,794 patients were targeted and 52,427 were targeted in 2011. There was a twofold increase in BMD testing after each intervention among targeted patients compared to controls (p < 0.001). Initiation of osteoporosis medicines increased by 21% among men targeted in 2008 and 34% among men targeted in 2011 compared to older controls (p < 0.01). Initiation of osteoporosis medicines among targeted women was similar to the older controls. CONCLUSION: Programs underpinned by behavioural theory and stakeholder engagement that target both primary care clinicians and patients can improve osteoporosis screening and management at the national level.

Update of mortality and cancer incidence in the Australian petroleum industry cohort.

OBJECTIVES: To update the analysis of the cohort mortality and cancer incidence study of employees in the Australian petroleum industry. METHODS: Employees of Australian Institute of Petroleum member companies were enrolled in the cohort in four industry-wide surveys between 1981 and 1999. Mortality of 16,547 males and 1356 females was determined up to 31 December 2001 and cancer incidence to 31 December 2000. Cause specific mortality and cancer incidence were compared with those of the Australian population by means of standardised mortality ratios (SMRs) and standardised incidence ratios (SIRs). Associations between increased incidence of specific cancers and employment in the petroleum industry were tested by trends according to period of first employment, duration of employment, latency, and hydrocarbon exposure, adjusting for personal smoking history where appropriate. RESULTS: There was a significant elevation of the incidence of mesothelioma (SIR 1.77, 95% CI 1.05 to 2.79), melanoma (SIR 1.37, 95% CI 1.19 to 1.58), and prostate cancer (SIR 1.18, 95% CI 1.04 to 1.34). The SIRs of all leukaemias and of acute non-lymphocytic leukaemia (ANLL) were not significantly different from unity, but all 11 ANLL cases were clustered in the middle to high hydrocarbon exposure categories. Tanker drivers had a significantly elevated incidence of kidney cancer (12 cases v 5.84 expected, SIR 2.05, 95% CI 1.06 to 3.59). Lung cancer incidence was significantly reduced (SIR 0.69, 95% CI 0.57 to 0.83) CONCLUSIONS: Most cases of mesothelioma are probably related to past exposure to asbestos in refineries. No occupational cause has been identified for the excess of melanoma, or prostatic or bladder cancer. The possibility of a causal relationship between cancer of the kidney and hydrocarbon exposure warrants further study. It is uncertain whether benzene exposures, particularly past levels of exposure, have been high enough to cause ANLL.

Construct Validity of Four Frailty Measures in an Older Australian Population: A Rasch Analysis.

Individuals identified as frail have been shown to be at an increased risk of adverse health outcomes. However, there is no gold standard frailty measure and frailty status can vary depending on the measure used, suggesting the measures perform differently. Construct validity can be used to assess a measure's performance. This study aimed to examine the construct validity of four frailty measures in an Australian older population using Rasch analysis. Frailty status among the 2087 participants aged 65 years and above from the Australian Longitudinal Study of Ageing (ALSA) was assessed using: frailty phenotype--FP, simplified frailty phenotype--SFP, frailty index--FI, and prognostic frailty score--PFS. Rasch analysis was used to assess the unidimensionality of the measures, which is the extent to which the underlying characteristic of frailty is assessed. The criteria for unidimensionality from principal component analysis of the residuals was when 50% or more of the raw variance was explained by the measures, and less than 5% was unexplained variance. Only FI meet the unidimensionality criteria with 74% of explained variance and 2.1% of unexplained variance. SFP did not show a unidimensional construct with 13.3% of explained variance and 47.1% of unexplained variance. FP and PFS had 39.6%, 18.1% and 46.5%, 8.7% of explained and unexplained variance, respectively. Our findings showed that FI has better construct validity than the other three measures in assessing frailty among the Australian older population.

p53 overexpression and downregulation of inter-alpha-inhibitor are associated with hyaluronidase enhancement of TNF cytotoxicity in L929 fibroblasts.

Degradation of extracellular matrix by hyaluronidase increases murine L929 cell sensitivity to tumor necrosis factor (TNF) cytotoxicity. Seeding and culturing L929 cells onto the matrix of serum fetuin and the hyaluronate-binding inter-alpha-inhibitor resulted in inhibition of hyaluronidase-enhanced TNF killing, suggesting that the release of these proteins from hyaluronidase-degraded matrix confers cellular TNF susceptibility. Metabolic labeling studies showed that hyaluronidase mediated de novo protein synthesis and down regulated several proteins in L929 cells. Specifically, hyaluronidase upregulated p53 protein expression (>200%) but down regulated a p85 inter-alpha-inhibitor-like protein (>90%) in L929 cells, whereas it had no effect on the protein levels of ICH-1, Bcl-xL, Bcl-2, Fas ligand, CAS (cellular apoptosis susceptible protein), TIAR (an RNA-binding protein) and alpha-tubulin. Conceivably, hyaluronidase enhancement of TNF sensitivity in L929 cells is p53-dependent and the matrix inter-alpha-inhibitor contributes a protective role against TNF cytotoxicity.

Role of the hypothalamic paraventricular nucleus in mediating stress-related litter deficits in the golden hamster.

Abstract Primiparous female hamsters (Mesocricetus auratus) were mated to proven breeders and stressed during early pregnancy. Females were housed singly throughout gestation except for Days 4, 5 and 6 when they were paired for ten-min intervals three times each day with another female matched for age, weight and day of pregnancy. Within each of the pairs, one female was consistently dominant to the other. Controls were exposed to a novel area instead of a conspecific. At parturition, all pups were counted, sexed and weighed. There were no significant differences between control and dominant females' litter sizes or sex ratios (defined as percentage male). Subordinate females produced significantly smaller litters than control or dominant dams and significantly lower sex ratios than control dams. Subordinates produced fewer males than control or dominant dams, but there were no differences in the number of females produced. The paraventricular nucleus (PVN) of the hypothalamus has been implicated as a relay center for the physiological response to stress. Bilateral lesions of the PVN were performed on another group of females and the same protocol described above was followed after the females recovered from surgery. When this 'stress relay center' was lesioned, subordinates did not show the significant deficits in litter size and sex ratio. Sham-operated females showed a similar response to social stress to that of intact females. These results suggest that subordinate dams produce smaller litters via selective resorption of males in utero and that the PVN may be a relay center for the mediation of this response.