Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer

Background: Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB 2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB 2levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC. © 2011 Cathcart et al; licensee BioMed Central Ltd.

Utilising hospital data to inform product safety prioritisation : the application of RAPEX severity rankings in ICD-coded burn data

Background The implementation of the Australian Consumer Law in 2011 highlighted the need for better use of injury data to improve the effectiveness and responsiveness of product safety (PS) initiatives. In the PS system, resources are allocated to different priority issues using risk assessment tools. The rapid exchange of information (RAPEX) tool to prioritise hazards, developed by the European Commission, is currently being adopted in Australia. Injury data is required as a basic input to the RAPEX tool in the risk assessment process. One of the challenges in utilising injury data in the PS system is the complexity of translating detailed clinical coded data into broad categories such as those used in the RAPEX tool. Aims This study aims to translate hospital burns data into a simplified format by mapping the International Statistical Classification of Disease and Related Health Problems (Tenth Revision) Australian Modification (ICD-10-AM) burn codes into RAPEX severity rankings, using these rankings to identify priority areas in childhood product-related burns data. Methods ICD-10-AM burn codes were mapped into four levels of severity using the RAPEX guide table by assigning rankings from 1-4, in order of increasing severity. RAPEX rankings were determined by the thickness and surface area of the burn (BSA) with information extracted from the fourth character of T20-T30 codes for burn thickness, and the fourth and fifth characters of T31 codes for the BSA. Following the mapping process, secondary data analysis of 2008-2010 Queensland Hospital Admitted Patient Data Collection (QHAPDC) paediatric data was conducted to identify priority areas in product-related burns. Results The application of RAPEX rankings in QHAPDC burn data showed approximately 70% of paediatric burns in Queensland hospitals were categorised under RAPEX levels 1 and 2, 25% under RAPEX 3 and 4, with the remaining 5% unclassifiable. In the PS system, prioritisations are made to issues categorised under RAPEX levels 3 and 4. Analysis of external cause codes within these levels showed that flammable materials (for children aged 10-15yo) and hot substances (for children aged <2yo) were the most frequently identified products. Discussion and conclusions The mapping of ICD-10-AM burn codes into RAPEX rankings showed a favourable degree of compatibility between both classification systems, suggesting that ICD-10-AM coded burn data can be simplified to more effectively support PS initiatives. Additionally, the secondary data analysis showed that only 25% of all admitted burn cases in Queensland were severe enough to trigger a PS response.

The role of epigenetics in resistance to cisplatin chemotherapy in lung cancer

Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20-30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC. © 2011 by the authors; licensee MDPI, Basel, Switzerland.

Utilising hospital data to inform product safety prioritisation : the application of RAPEX severity rankings in ICD-coded Burn Data

Background The implementation of the Australian Consumer Law in 2011 highlighted the need for better use of injury data to improve the effectiveness and responsiveness of product safety (PS) initiatives. In the PS system, resources are allocated to different priority issues using risk assessment tools. The rapid exchange of information (RAPEX) tool to prioritise hazards, developed by the European Commission, is currently being adopted in Australia. Injury data is required as a basic input to the RAPEX tool in the risk assessment process. One of the challenges in utilising injury data in the PS system is the complexity of translating detailed clinical coded data into broad categories such as those used in the RAPEX tool. Aims This study aims to translate hospital burns data into a simplified format by mapping the International Statistical Classification of Disease and Related Health Problems (Tenth Revision) Australian Modification (ICD-10-AM) burn codes into RAPEX severity rankings, using these rankings to identify priority areas in childhood product-related burns data. Methods ICD-10-AM burn codes were mapped into four levels of severity using the RAPEX guide table by assigning rankings from 1-4, in order of increasing severity. RAPEX rankings were determined by the thickness and surface area of the burn (BSA) with information extracted from the fourth character of T20-T30 codes for burn thickness, and the fourth and fifth characters of T31 codes for the BSA. Following the mapping process, secondary data analysis of 2008-2010 Queensland Hospital Admitted Patient Data Collection (QHAPDC) paediatric data was conducted to identify priority areas in product-related burns. Results The application of RAPEX rankings in QHAPDC burn data showed approximately 70% of paediatric burns in Queensland hospitals were categorised under RAPEX levels 1 and 2, 25% under RAPEX 3 and 4, with the remaining 5% unclassifiable. In the PS system, prioritisations are made to issues categorised under RAPEX levels 3 and 4. Analysis of external cause codes within these levels showed that flammable materials (for children aged 10-15yo) and hot substances (for children aged <2yo) were the most frequently identified products. Discussion and conclusions The mapping of ICD-10-AM burn codes into RAPEX rankings showed a favourable degree of compatibility between both classification systems, suggesting that ICD-10-AM coded burn data can be simplified to more effectively support PS initiatives. Additionally, the secondary data analysis showed that only 25% of all admitted burn cases in Queensland were severe enough to trigger a PS response.

Somatostatin, its receptors and analogs, in lung cancer

Despite developments in diagnosis and treatment, lung cancer is the commonest cause of cancer death in Europe and North America. Due to increasing cigarette consumption, the incidence of the disease and resultant mortality is rising dramatically in women. Novel approaches to the management of lung cancer are urgently required. Somatostatin is a tetradecapeptide first identified in the pituitary and subsequently throughout the body particularly in neuroendocrine cells of the pancreas and gastrointestinal tract and the nervous system. The peptide has numerous functions including inhibition of hormone release, immunomodulation and neurotransmission and is an endogenous inhibitor of cell proliferation and angiogenesis. Somatostatin and its analogs, including octreotide (SMS 201-995), somatuline (BIM 23014) and vapreotide (RC-160), act by binding to specific somatostatin receptors (SSTR) of which there are 5 principal subtypes, SSTR-1-5. Although elevated plasma somatostatin levels may be detected in 14-15% of patients, tumor cell expression appears rare. SSTR may be expressed by lung tumors, particularly small cell lung cancer and bronchial carcinoid disease. [111In]pentetreotide scintigraphy may have a role to play in the localization and staging of lung cancers both before and following treatment, and in detecting relapsed disease. The potential role of radiolabelled somatostatin analogs as radiotherapeutic agents in the management of lung cancer is currently being explored. Somatostatin analog therapy results in significant growth inhibition of both SSTR-positive and SSTR-negative lung tumors in vivo. Recent work indicates that these agents may enhance the efficacy of chemotherapeutic agents in the treatment of solid tumors including lung cancer. Copyright © 2001 S. Karger AG, Basel.

Associations of body mass index and waist circumference with: energy intake and percentage energy from macronutrients, in a cohort of Australian children

Background It is evident from previous research that the role of dietary composition in relation to the development of childhood obesity remains inconclusive. Several studies investigating the relationship between body mass index (BMI), waist circumference (WC) and/or skin fold measurements with energy intake have suggested that the macronutrient composition of the diet (protein, carbohydrate, fat) may play an important contributing role to obesity in childhood as it does in adults. This study investigated the possible relationship between BMI and WC with energy intake and percentage energy intake from macronutrients in Australian children and adolescents. Methods Height, weight and WC measurements, along with 24 h food and drink records (FDR) intake data were collected from 2460 boys and girls aged 5-17 years living in the state of Queensland, Australia. Results Statistically significant, yet weak correlations between BMI z-score and WC with total energy intake were observed in grades 1, 5 and 10, with only 55% of subjects having a physiologically plausible 24 hr FDR. Using Pearson correlations to examine the relationship between BMI and WC with energy intake and percentage macronutrient intake, no significant correlations were observed between BMI z-score or WC and percentage energy intake from protein, carbohydrate or fat. One way ANOVAs showed that although those with a higher BMI z-score or WC consumed significantly more energy than their lean counterparts. Conclusion No evidence of an association between percentage macronutrient intake and BMI or WC was found. Evidently, more robust longitudinal studies are needed to elucidate the relationship linking obesity and dietary intake.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK ) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.) Copyright © 2013 Massachusetts Medical Society.

Investigating the individual and organisational predictors of work-related driving crash involvement in Ethiopia

The rate of road traffic injury and death in Ethiopia is at a critical level when compared to rates in high-income countries. Considering the enormity of this issue, research is to identify groups of high-risk road users and the factors contributing to their crash involvement. This study focuses on work-related drivers. This study explores driving behaviour as a mediator of the relationship between organisational and individual attribute factors and self-reported crashes in a sample of 213 work-related drivers in Addis Ababa, Ethiopia. The hypothesised framework identifies driving behaviour as the most proximal determinant of self-reported crashes, and safety values, role overload and self-efficacy as antecedents of driving behaviour. With the exception of the relationship between self-efficacy and driving behaviour, all the hypothesised relationships were supported. We make recommendations for intervention approaches that are theoretically focused and sensitive to the cultural context.

A pilot study exploring Australian general practice nurses roles, responsibilities and professional development needs in well and sick child care

Aim Explore practice nurses' (PNs) role in child health and development, and advising parents about child health issues. Background Introduction of the four-year-old child health check into general practice in 2008 placed additional responsibilities on PNs in child health and wellness. This study explores their readiness to expand their practice into this area. Design Integrated mixed method design, self-report survey. Method A purpose-developed questionnaire explored demographics, child health roles and responsibilities, difficulties encountered, professional development needs, barriers and facilitators, and professional development activities undertaken in the past year. Surveys were posted to 218 PNs in one rural Division of General Practice (DGP) in Queensland, Australia; 29 responded. Results PNs reported a significant role in well and sick child care (93.1%) though few had a paediatric/child health background (14.3%). Roles included immunisations (92.3%), child health checks (65.4%), general child health and development (26.9%), asthma (23.1%), feeding (15.4%), fever (11.5%), settling/sleeping (11.5%). PNs were interested in learning more about (81.5%) and incorporating more child health into their practice (81.5%). Professional development in childhood growth and development (80.0%), health and illness (60.0%) and advising new mothers (20.0%) was needed. Conclusions PNs play a substantial role in child health, are unprepared for the complexities of this role and have preferred methods for undertaking professional development to address knowledge deficits. Implications for practice PNs are unprepared for an advanced role in child health and wellness. Significant gaps in their knowledge to support this role were identified. This ever-expanding role requires close monitoring to ensure knowledge precedes expectations to practice.

Exploring differences in driving behaviour across age and years of education of taxi drivers in Addis Ababa, Ethiopia

Despite statistics indicating that the African region has the highest road traffic fatality rate globally, there is limited scientific literature identifying the determinants of driving behaviour. In this study, we explore differences in self-reported driving behaviour across age groups and years of education in a population of 213 drivers from Addis Ababa, Ethiopia. We hypothesize that younger, less educated drivers will report engaging in more unsafe driving behaviours compared to older, more educated drivers. Contrary to expectations, we found the opposite effect, whereby older, more educated drivers reported engaging in more unsafe driving behaviours than younger, less educated drivers. We explain these findings by describing key characteristics of the sample and cultural ideologies of the region. The findings of this study offer some practical guidance for intervention to address the burden of road traffic injury and death in the African region.

Evidence of effectiveness : high level synthesis of research to prevent obesity and increase physical activity in children

Background Prevention of childhood obesity is a public health priority for Malaysia and many other countries. Physical activity for children is also decreasing at an alarming rate. Both conditions are associated with non-communicable diseases and with significant morbidity and mortality in later life. Systematic reviews of public health interventions provide a useful summary to inform public health practice by combining the results of a range of research studies on a specific intervention into a single report. Systematic reviews are deemed most valuable for health program development and evidence based practice. Unfortunately, many policy makers and practitioners are simply unaware of the evidence: which strategies which are most likely to provide benefit; and which strategies are known to be harmful or useless. This presentation provides a “birds eye” overview based upon recent (since 2007 to present) high quality systematic reviews of public health interventions. Method HealthEvidece.org and the Cochrane Library were searched for systematic reviews which evaluated interventions targeting obesity prevention and increasing physical activity for children. The findings of the included reviews were themed and summarized. Results Seven reviews were identified addressing obesity in the early years, and fifteen reviews addressing obesity more broadly in childhood. Additional reviews were identified aimed at increasing physical activity. The synthesis shows several strategies to be effective, however many popular strategies clearly are not. Several of the reviews were inconclusive due to an absence of robust primary studies. Amongst the findings, interventions undertaken in the school setting appear very promising. Conclusions There is significant evidence from systematic reviews to guide public health practice and policy, and to inform future research.

MIA – Musings in appreciation

Stuart Cunningham has been a regular contributor to MIA since 1987, and was one of the six editors appointed to manage MIA after Henry Mayer’s death in 1991.

An objective study of acid reflux and cough in children using an ambulatory pHmetry-cough logger

Objective There are no objective ambulatory studies on the temporal relationship between reflux and cough in children. Commercial pHmetry loggers have slow capture rates (0.25 Hz) that limit objective quantification of reflux and cough. The authors aimed to evaluate if there is a temporal association between cough and acid pH in ambulatory children with chronic cough. setting and patients The authors studied children (aged <14 years) with chronic cough, suspected of acid reflux and considered for pHmetry using a specifically built ambulatory pHmetry–cough logger that enabled the simultaneous ambulatory recording of cough and pH with a fast (10 Hz) capture rate. Main outcome measures Coughs within (before and after) 10, 30, 60 and 120 s of a reflux episode (pH<4 for >0.5 s). Results Analysis of 5628 coughs in 20 children. Most coughs (83.9%) were independent of a reflux event. Cough–reflux (median 19, IQR 3–45) and reflux–cough (24.5, 13–51) sequences were equally likely to occur within 120 s. Within the 10 and 30 s time frame, reflux–cough (10 s=median 2.5, IQR 0–7.25; 30 s=6.5, 1.25–22.25) sequences were significantly less frequent than reflux–no cough (10 s=27, IQR 15–65; 30 s=24.5, 14.5–55.5) sequences, (p=0.0001 and p=0.001, respectively). No differences were found for 60 and 120 s time frame. Cough–reflux sequence (median 1.0, IQR 0–8) within 10 s was significantly less (p=0.0001) than no cough–reflux sequences (median 29.5, 15–67), within 30 s (p=0.006) and 60 s (p=0.048) but not within 120 s (p=0.47). Conclusions In children with chronic cough and suspected of having gastro-oesophageal reflux disease, the temporal relationship between acid reflux and cough is unlikely causal.

In-hospital mortality rates after a cemented femoral component for displaced neck of femur fractures

Aim This prospective cohort study investigated whether the use of preoperative anticoagulants is an independent risk factor for the outcomes of surgical treatment of patients with a neck of femur fracture. Methods Data was obtained from a prospectively collected database. All patients admitted for a neck of femur fracture between Nov 2010 and Oct 2011 were included. This resulted in three hundred twenty-eight patients with 330 neck of femur fractures. Four groups were defined; patients preoperatively (i) on aspirin (n = 105); (ii) on clopidogrel (n = 28); (iii) on warfarin (n = 30), and; (iv) without any anticoagulation history (n = 167, the control group). The non-warfarin group included the aspirin group, clopidogrel group and the control group. Primary outcome was the in-hospital mortality. Secondary outcomes were the postoperative complications, return to theatre and length of stay. Results Thirteen in-hospital deaths were identified, 4 deaths in the aspirin group, 1 death in the clopidogrel group, 2 deaths in the warfarin group and 6 deaths in the control group. No significant difference in the mortality rates was found between the different groups. Also in the secondary outcomes, no significant difference was found between the four groups. A trend to a higher wound complication rate for the warfarin group was detected. Conclusion The use of clopidrogel or aspirin pre operatively is not an influence on short term patient outcome for patients with a neck of femur fracture. Surgical procedures should not be delayed to reverse their influence.

Heat-related morbidity in Brisbane, Australia : spatial variation and area-level predictors

Background: Extreme heat is a leading weather-related cause of illness and death in many locations across the globe, including subtropical Australia. The possibility of increasingly frequent and severe heat waves warrants continued efforts to reduce this health burden, which could be accomplished by targeting intervention measures toward the most vulnerable communities. Objectives: We sought to quantify spatial variability in heat-related morbidity in Brisbane, Australia, to highlight regions of the city with the greatest risk. We also aimed to find area-level social and environmental determinants of high risk within Brisbane. Methods: We used a series of hierarchical Bayesian models to examine city-wide and intracity associations between temperature and morbidity using a 2007–2011 time series of geographically referenced hospital admissions data. The models accounted for long-term time trends, seasonality, and day of week and holiday effects. Results: On average, a 10°C increase in daily maximum temperature during the summer was associated with a 7.2% increase in hospital admissions (95% CI: 4.7, 9.8%) on the following day. Positive statistically significant relationships between admissions and temperature were found for 16 of the city’s 158 areas; negative relationships were found for 5 areas. High-risk areas were associated with a lack of high income earners and higher population density. Conclusions: Geographically targeted public health strategies for extreme heat may be effective in Brisbane, because morbidity risk was found to be spatially variable. Emergency responders, health officials, and city planners could focus on short- and long-term intervention measures that reach communities in the city with lower incomes and higher population densities, including reduction of urban heat island effects.