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1.  Ovine neuronal ceroid lipofuscinosis: a large animal model syntenic with the human neuronal ceroid lipofuscinosis variant CLN6. 
Journal of Medical Genetics  1998;35(9):717-721.
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited degenerative neurological diseases affecting children. A number of non-allelic variants have been identified within the human population and the genes for some of these have recently been identified. The underlying mechanism for the neuropathology remains an enigma; however, pioneering studies with the naturally occurring ovine model (OCL) have led to the proposal that these diseases represent lesions in specific hydrophobic protein degradation pathways. In this study, we show linkage between OCL and microsatellite markers on OAR 7q13-15. Using interspecies chromosome painting we establish that OAR 7q13-15 is syntenic with human chromosome 15q21-23, the region which was recently defined as the location of a newly identified late infantile variant (CLN6). We propose that our ovine model represents a mutation in the gene orthologous to that mutated in the human late infantile variant CLN6. The ovine linkage flock, consisting of 56 families, represents a powerful resource for positional cloning of this NCL gene. The availability of such a large animal model will have important implications for experimentation in downstream corrective therapies.
Images
PMCID: PMC1051422  PMID: 9733028
2.  Key considerations for the experimental training and evaluation of cancer odour detection dogs: lessons learnt from a double-blind, controlled trial of prostate cancer detection 
BMC Urology  2014;14:22.
Background
Cancer detection using sniffer dogs is a potential technology for clinical use and research. Our study sought to determine whether dogs could be trained to discriminate the odour of urine from men with prostate cancer from controls, using rigorous testing procedures and well-defined samples from a major research hospital.
Methods
We attempted to train ten dogs by initially rewarding them for finding and indicating individual prostate cancer urine samples (Stage 1). If dogs were successful in Stage 1, we then attempted to train them to discriminate prostate cancer samples from controls (Stage 2). The number of samples used to train each dog varied depending on their individual progress. Overall, 50 unique prostate cancer and 67 controls were collected and used during training. Dogs that passed Stage 2 were tested for their ability to discriminate 15 (Test 1) or 16 (Tests 2 and 3) unfamiliar prostate cancer samples from 45 (Test 1) or 48 (Tests 2 and 3) unfamiliar controls under double-blind conditions.
Results
Three dogs reached training Stage 2 and two of these learnt to discriminate potentially familiar prostate cancer samples from controls. However, during double-blind tests using new samples the two dogs did not indicate prostate cancer samples more frequently than expected by chance (Dog A sensitivity 0.13, specificity 0.71, Dog B sensitivity 0.25, specificity 0.75). The other dogs did not progress past Stage 1 as they did not have optimal temperaments for the sensitive odour discrimination training.
Conclusions
Although two dogs appeared to have learnt to select prostate cancer samples during training, they did not generalise on a prostate cancer odour during robust double-blind tests involving new samples. Our study illustrates that these rigorous tests are vital to avoid drawing misleading conclusions about the abilities of dogs to indicate certain odours. Dogs may memorise the individual odours of large numbers of training samples rather than generalise on a common odour. The results do not exclude the possibility that dogs could be trained to detect prostate cancer. We recommend that canine olfactory memory is carefully considered in all future studies and rigorous double-blind methods used to avoid confounding effects.
doi:10.1186/1471-2490-14-22
PMCID: PMC3945616  PMID: 24575737
Prostate cancer; Cancer detection dogs; Cancer odour; Olfactory memory; Multiple sample learning
3.  Bagged gene shaving for the robust clustering of high-throughput data 
The analysis of high-throughput data sets, such as microarray data, often requires that individual variables (genes, for example) be grouped into clusters of variables with highly correlated values across all samples. Gene shaving is an established method for generating such clusters, but is overly sensitive to the input data: changing just one sample can determine whether or not an entire cluster is found. This paper describes a clustering method based on the bootstrap aggregation of gene shaving clusters, which overcomes this and other problems, and applies the new method to a large gene expression microarray dataset from brain tumour samples.
PMCID: PMC3879957  PMID: 20940121
bootstrap aggregation; clustering; gene shaving; glioblastoma
4.  Health Care Utilisation and Out-of-Pocket Expenditure Associated with Back Pain: A Nationally Representative Survey of Australian Women 
PLoS ONE  2013;8(12):e83559.
Background
Back pain impacts on a significant proportion of the Australian population over the life course and has high prevalence rates among women, particularly in older age. Back pain care is characterised by multiple practitioner and self-prescribed treatment options, and the out-of-pocket costs associated with consultations and self-prescribed treatments have not been examined to date.
Objective
To analyse the extent of health care practitioner consultations and self-prescribed treatment for back pain care among Australian women, and to assess the self-reported costs associated with such usage.
Methods
Survey of 1,310 women (response rate 80.9%) who reported seeking help for back pain from the ‘1946-51 cohort’ of the Australian Longitudinal Study on Women’s Health. Women were asked about their use of health care practitioners and self-prescribed treatments for back pain and the costs associated with such usage.
Results
In the past year 76.4% consulted a complementary and alternative practitioner, 56% an allied health practitioner and 59.2% a GP/medical specialist. Overall, women consulted with, on average, 3.0 (SD = 2.0) different health care practitioners, and had, on average, 12.2 (SD = 9.7) discrete health care practitioner consultations for back pain. Average self-reported out-of-pocket expenditure on practitioners and self-prescribed treatments for back pain care per annum was AU$873.10.
Conclusions
Multiple provider usage for various but distinct purposes (i.e. pain/mobility versus anxiety/stress) points to the need for further research into patient motivations and experiences of back pain care in order to improve and enhance access to and continuity of care. Our results suggest that the cost of back pain care represents a significant burden, and may ultimately limit women’s access to multiple providers. We extrapolate that for Australian working-age women, total out-of-pocket expenditure on back pain care per annum is in excess of AU$1.4billion, thus indicating the prominence of back pain as a major economic, social and health burden.
doi:10.1371/journal.pone.0083559
PMCID: PMC3869794  PMID: 24376716
5.  Sustainable, efficient livestock production with high biodiversity and good welfare for animals 
What is the future for livestock agriculture in the world? Consumers have concerns about sustainability but many widely used livestock production methods do not satisfy consumers' requirements for a sustainable system. However, production can be sustainable, occurring in environments that: supply the needs of the animals resulting in good welfare, allow coexistence with a wide diversity of organisms native to the area, minimize carbon footprint and provide a fair lifestyle for the people working there. Conservation need not just involve tiny islands of natural vegetation in a barren world of agriculture, as there can be great increases in biodiversity in farmed areas. Herbivores, especially ruminants that consume materials inedible by humans, are important for human food in the future. However, their diet should not be just ground-level plants. Silvopastoral systems, pastures with shrubs and trees as well as herbage, are described which are normally more productive than pasture alone. When compared with widely used livestock production systems, silvopastoral systems can provide efficient feed conversion, higher biodiversity, enhanced connectivity between habitat patches and better animal welfare, so they can replace existing systems in many parts of the world and should be further developed.
doi:10.1098/rspb.2013.2025
PMCID: PMC3790492  PMID: 24068362
sustainability; silvopastoral; livestock; biodiversity; animal welfare; conservation
6.  Feasibility and Effectiveness of an Automated Bilingual Text Message Intervention for Weight Loss: Pilot Study 
JMIR Research Protocols  2013;2(2):e48.
Background
Little is known about the feasibility and acceptability of tailored text message based weight loss programs for English and Spanish-language speakers.
Objective
This pilot study evaluated the feasibility, acceptability, and estimated impact of a tailored text message based weight loss program for English and Spanish-language speakers. The purpose of this pilot study was to inform the development of a full-scale randomized trial.
Methods
There were 20 overweight or obese participants (mean age 40.10, SD 8.05; 8/20, 40% male; 9/20, 45% Spanish-speakers) that were recruited in San Diego, California, from March to May 2011 and evaluated in a one-group pre/post clinical trial. For 8 weeks, participants received and responded to 3-5 text messages daily sent from a fully automated text messaging system. They also received printed weight loss materials and brief 10-15 minute weekly counseling calls. To estimate the impact of the program, the primary outcome was weight (kg) measured during face-to-face measurement visits by trained research staff. Pre and post differences in weight were analyzed with a one-way repeated measures analysis of variance. Differences by language preference at both time points were analyzed with t tests. Body mass index and weight management behaviors also were examined. Feasibility and acceptability were determined by recruitment success, adherence (ie, percentage of replies to interactive text messages and attrition), and participant satisfaction.
Results
Participants who completed the final assessment (N=18) decreased body weight by 1.85 kg (F 1,17=10.80, P=.004, CI∆ 0.66-3.03, η2=0.39). At both time points, there were no differences in weight by language preference. Participants responded to 88.04% (986/1120) of interactive text messages, attrition rate was 10% (2/20), and 94% (19/20) of participants reported satisfaction with the program.
Conclusions
This fully automated text message based weight program was feasible with English and Spanish-speakers and may have promoted modest weight loss over an 8-week period.
Trial Registration
Clinicaltrials.gov NCT01171586; http://clinicaltrials.gov/ct2/show/NCT01171586 (Archived by WebCite at http://www.webcitation.org/6Ksr6dl7n).
doi:10.2196/resprot.2789
PMCID: PMC3841356  PMID: 24200517
physical activity; diet; obesity; health behavior; Hispanic Americans; weight loss; cellular phone; text messaging
7.  The effect of very low-calorie diets on renal and hepatic outcomes: a systematic review 
Very low-calorie diets (VLCDs) are an effective means by which to induce clinically significant weight loss. However, their acceptance by health care practitioners and the public is generally lower than that for other nonsurgical weight loss methods. Whilst there is currently little evidence to suggest they have any detrimental effect on hepatic and renal health, data assessing these factors remain limited. We carried out a systematic review of the literature on randomized controlled trials that had a VLCD component and that reported outcomes for hepatic and renal health, published between January 1980 and December 2012. Cochrane criteria were followed, and eight out of 196 potential articles met the inclusion criteria. A total of 548 participants were recruited across the eight studies. All eight studies reported significant weight loss following the VLCD. Changes in hepatic and renal outcomes were variable but generally led to either no change or improvements in either of these. Due to the heterogeneity in the quality and methodology of the studies included, the effect of VLCDs on hepatic and renal outcomes remains unclear at this stage. Further standardized research is therefore required to fully assess the impact of VLCDs on these outcome measures, to better guide clinical practice.
doi:10.2147/DMSO.S51151
PMCID: PMC3798146  PMID: 24143118
obesity; liver; kidney; weight loss; health
8.  The Impact of Social Media on Medical Professionalism: A Systematic Qualitative Review of Challenges and Opportunities 
Background
The rising impact of social media on the private and working lives of health care professionals has made researchers and health care institutions study and rethink the concept and content of medical professionalism in the digital age. In the last decade, several specific policies, original research studies, and comments have been published on the responsible use of social media by health care professionals. However, there is no systematic literature review that analyzes the full spectrum of (1) social media–related challenges imposed on medical professionalism and (2) social media–related opportunities to both undermine and improve medical professionalism.
Objective
The aim of this systematic qualitative review is to present this full spectrum of social media–related challenges and opportunities.
Methods
We performed a systematic literature search in PubMed (restricted to English and German literature published between 2002 and 2011) for papers that address social media–related challenges and opportunities for medical professionalism. To operationalize “medical professionalism”, we refer to the 10 commitments presented in the physicians’ charter “Medical professionalism in the new millennium” published by the ABIM Foundation. We applied qualitative text analysis to categorize the spectrum of social media–related challenges and opportunities for medical professionalism.
Results
The literature review retrieved 108 references, consisting of 46 original research studies and 62 commentaries, editorials, or opinion papers. All references together mentioned a spectrum of 23 broad and 12 further-specified, narrow categories for social media–related opportunities (n=10) and challenges (n=13) for medical professionalism, grouped under the 10 commitments of the physicians’ charter.
Conclusions
The accommodation of the traditional core values of medicine to the characteristics of social media presents opportunities as well as challenges for medical professionalism. As a profession that is entitled to self-regulation, health care professionals should proactively approach these challenges and seize the opportunities. There should be room to foster interprofessional and intergenerational dialogue (and eventually guidelines and policies) on both challenges and opportunities of social media in modern health care. This review builds a unique source of information that can inform further research and policy development in this regard.
doi:10.2196/jmir.2708
PMCID: PMC3758042  PMID: 23985172
social media; professionalism; facebook; blogs; Twitter; health policy
9.  Can Social Semantic Web Techniques Foster Collaborative Curriculum Mapping In Medicine? 
Background
Curriculum mapping, which is aimed at the systematic realignment of the planned, taught, and learned curriculum, is considered a challenging and ongoing effort in medical education. Second-generation curriculum managing systems foster knowledge management processes including curriculum mapping in order to give comprehensive support to learners, teachers, and administrators. The large quantity of custom-built software in this field indicates a shortcoming of available IT tools and standards.
Objective
The project reported here aims at the systematic adoption of techniques and standards of the Social Semantic Web to implement collaborative curriculum mapping for a complete medical model curriculum.
Methods
A semantic MediaWiki (SMW)-based Web application has been introduced as a platform for the elicitation and revision process of the Aachen Catalogue of Learning Objectives (ACLO). The semantic wiki uses a domain model of the curricular context and offers structured (form-based) data entry, multiple views, structured querying, semantic indexing, and commenting for learning objectives (“LOs”). Semantic indexing of learning objectives relies on both a controlled vocabulary of international medical classifications (ICD, MeSH) and a folksonomy maintained by the users. An additional module supporting the global checking of consistency complements the semantic wiki. Statements of the Object Constraint Language define the consistency criteria. We evaluated the application by a scenario-based formative usability study, where the participants solved tasks in the (fictional) context of 7 typical situations and answered a questionnaire containing Likert-scaled items and free-text questions.
Results
At present, ACLO contains roughly 5350 operational (ie, specific and measurable) objectives acquired during the last 25 months. The wiki-based user interface uses 13 online forms for data entry and 4 online forms for flexible searches of LOs, and all the forms are accessible by standard Web browsers. The formative usability study yielded positive results (median rating of 2 (“good”) in all 7 general usability items) and produced valuable qualitative feedback, especially concerning navigation and comprehensibility. Although not asked to, the participants (n=5) detected critical aspects of the curriculum (similar learning objectives addressed repeatedly and missing objectives), thus proving the system’s ability to support curriculum revision.
Conclusions
The SMW-based approach enabled an agile implementation of computer-supported knowledge management. The approach, based on standard Social Semantic Web formats and technology, represents a feasible and effectively applicable compromise between answering to the individual requirements of curriculum management at a particular medical school and using proprietary systems.
doi:10.2196/jmir.2623
PMCID: PMC3758046  PMID: 23948519
curriculum mapping; medical education; Semantic Web; Social Web
11.  Modulating microtubule stability enhances the cytotoxic response of cancer cells to paclitaxel 
Cancer research  2011;71(17):5806-5817.
The extracellular matrix protein TGFBI enhances the cytotoxic response of cancer cells to paclitaxel by affecting integrin signals that stabilize microtubules. Extending the implications of this knowledge, we tested the more general hypothesis that cancer cell signals which increase microtubule stability before exposure to paclitaxel may increase its ability to stablize microtubules and thereby enhance its cytotoxicity. Toward this end, we performed an siRNA screen to evaluate how genetic depletion affected microtubule stabilization, cell viability and apoptosis. High content microscopical analysis was performed in the absence or presence of paclitaxel. Kinase knockdowns that stabilized microtubules strongly enhanced the effects of paclitaxel treatment. Conversely, kinase knockdowns that enhanced paclitaxel-mediated cytotoxicity sensitized cells to microtubule stabilization by paclitaxel. The siRNA screen identified several genes that have not been linked previously to in microtubule regulation or paclitaxel response. Gene shaving and Bayesian resampling used to classify these genes suggested three pathways of paclitaxel-induced cell death related to apoptosis and microtubule stability, apoptosis alone, or neither process. Our results offer a functional classification of the genetic basis for paclitaxel sensitivity and they support the hypothesis that stablizing microtubules prior to therapy could enhance antitumor responses to paclitaxel treatment.
doi:10.1158/0008-5472.CAN-11-0025
PMCID: PMC3679477  PMID: 21775522
Microtubule stability; paclitaxel; ovarian cancer; targeted therapy; antimitotic therapy
12.  Gene Expression Profiling of Ampullary Carcinomas Classifies Ampullary Carcinomas into Biliary-Like and Intestinal-Like Subtypes That Are Prognostic of Outcome 
PLoS ONE  2013;8(6):e65144.
Background
Adenocarcinomas of the ampulla of Vater are classified as biliary cancers, though the exact epithelium of origin for these cancers is not known. We sought to molecularly classify ampullary adenocarcinomas in comparison to known adenocarcinomas of the pancreas, bile duct, and duodenum by gene expression analysis.
Methods
We analyzed 32 fresh-frozen resected, untreated periampullary adenocarcinomas (8 pancreatic, 2 extrahepatic biliary, 8 duodenal, and 14 ampullary) using the Affymetrix U133 Plus 2.0 genome array. Unsupervised and supervised hierarchical clustering identified two subtypes of ampullary carcinomas that were molecularly and histologically characterized.
Results
Hierarchical clustering of periampullary carcinomas segregated ampullary carcinomas into two subgroups, which were distinctly different from pancreatic carcinomas. Non-pancreatic periampullary adenocarcinomas were segregated into two subgroups with differing prognoses: 5 year RFS (77% vs. 0%, p = 0.007) and 5 year OS (100% vs. 35%, p = 0.005). Unsupervised clustering analysis of the 14 ampullary samples also identified two subgroups: a good prognosis intestinal-like subgroup and a poor prognosis biliary-like subgroup with 5 year OS of 70% vs. 28%, P = 0.09. Expression of CK7+/CK20- but not CDX-2 correlated with these two subgroups. Activation of the AKT and MAPK pathways were both increased in the poor prognostic biliary-like subgroup. In an independent 80 patient ampullary validation dataset only histological subtype (intestinal vs. pancreaticobiliary) was significantly associated with OS in both univariate (p = 0.006) and multivariate analysis (P = 0.04).
Conclusions
Gene expression analysis discriminated pancreatic adenocarcinomas from other periampullary carcinomas and identified two prognostically relevant subgroups of ampullary adenocarcinomas. Histological subtype was an independent prognostic factor in ampullary adenocarcinomas.
doi:10.1371/journal.pone.0065144
PMCID: PMC3679143  PMID: 23776447
13.  Further Insight into the Depth-Dependent Microstructural Response of Cartilage to Compression Using a Channel Indentation Technique 
Stress relaxation and structural analysis were used to investigate the zonally differentiated microstructural response to compression of the integrated cartilage-on-bone tissue system. Fifteen cartilage-on-bone samples were divided into three equal groups and their stress relaxation responses obtained at three different levels of axial compressive strain defined as low (~20%), medium (~40%) and high (~60%). All tests were performed using a channel indenter which included a central relief space designed to capture the response of the matrix adjacent to the directly loaded regions. On completion of each stress relaxation test and while maintaining the imposed axial strain, the samples were formalin fixed, decalcified, and then sectioned for microstructural analysis. Chondron aspect ratios were used to determine the extent of relative strain at different zonal depths. The stress relaxation response of cartilage to all three defined levels of axial strain displayed an initial highly viscous response followed by a significant elastic response. Chondron aspect ratio measurements showed that at the lowest level of compression, axial deformation was confined to the superficial cartilage layer, while in the medium and high axial strain samples the deformation extended into the midzone. The cells in the deep zone remained undeformed for all compression levels.
doi:10.1155/2013/358192
PMCID: PMC3638672  PMID: 24023589
14.  Silencing of microRNA families by seed-targeting tiny LNAs 
Nature genetics  2011;43(4):371-378.
The challenge of understanding the widespread biological roles of animal microRNAs (miRNAs) has prompted the development of genetic and functional genomics technologies for miRNA loss-of-function studies. However, tools for exploring the functions of entire miRNA families are still limited. We developed a method that enables antagonism of miRNA function using seed-targeting 8-mer locked nucleic acid (LNA) oligonucleotides, termed tiny LNAs. Transfection of tiny LNAs into cells resulted in simultaneous inhibition of miRNAs within families sharing the same seed with concomitant upregulation of direct targets. In addition, systemically delivered, unconjugated tiny LNAs showed uptake in many normal tissues and in breast tumors in mice, coinciding with long-term miRNA silencing. Transcriptional and proteomic profiling suggested that tiny LNAs have negligible off-target effects, not significantly altering the output from mRNAs with perfect tiny LNA complementary sites. Considered together, these data support the utility of tiny LNAs in elucidating the functions of miRNA families in vivo.
doi:10.1038/ng.786
PMCID: PMC3541685  PMID: 21423181
15.  Utilisation of complementary and alternative medicine (CAM) practitioners within maternity care provision: results from a nationally representative cohort study of 1,835 pregnant women 
Background
There is little known about women’s concurrent use of conventional and complementary health care during pregnancy, particularly consultation patterns with complementary and alternative medicine (CAM). This study examines health service utilisation among pregnant women including consultations with obstetricians, midwives, general practitioners (GPs) and CAM practitioners.
Methods
A sub-study of pregnant women (n=2445) was undertaken from the nationally-representative Australian Longitudinal Study on Women’s Health (ALSWH). Women’s consultations with conventional practitioners (obstetricians, GPs and midwives) and CAM practitioners for pregnancy-related health conditions were analysed. The analysis included Pearson chi-square tests to compare categorical variables.
Results
The survey was completed by 1835 women (response rate = 79.2%). A substantial number (49.4%) of respondents consulted with a CAM practitioner for pregnancy-related health conditions. Many participants consulted only with a CAM practitioner for assistance with certain conditions such as neck pain (74.6%) and sciatica (40.4%). Meanwhile, women consulted both CAM practitioners and conventional maternity health professionals (obstetricians, midwives and GPs) for back pain (61.8%) and gestational diabetes (22.2%). Women visiting a general practitioner (GP) 3–4 times for pregnancy care were more likely to consult with acupuncturists compared with those consulting a GP less often (p=<0.001, x2=20.5). Women who had more frequent visits to a midwife were more likely to have consulted with an acupuncturist (p=<0.001, x2=18.9) or a doula (p=<0.001, x2=23.2) than those visiting midwives less frequently for their pregnancy care.
Conclusions
The results emphasise the necessity for a considered and collaborative approach to interactions between pregnant women, conventional maternity health providers and CAM practitioners to accommodate appropriate information transferral and co-ordinated maternity care. The absence of sufficient clinical evidence regarding many commonly used CAM practices during pregnancy also requires urgent attention.
doi:10.1186/1471-2393-12-146
PMCID: PMC3534226  PMID: 23231765
Pregnancy; Complementary medicine; Health services; Interprofessional; Integrative medicine
16.  iBAG: integrative Bayesian analysis of high-dimensional multiplatform genomics data 
Bioinformatics  2012;29(2):149-159.
Motivation: Analyzing data from multi-platform genomics experiments combined with patients’ clinical outcomes helps us understand the complex biological processes that characterize a disease, as well as how these processes relate to the development of the disease. Current data integration approaches are limited in that they do not consider the fundamental biological relationships that exist among the data obtained from different platforms.
Statistical Model: We propose an integrative Bayesian analysis of genomics data (iBAG) framework for identifying important genes/biomarkers that are associated with clinical outcome. This framework uses hierarchical modeling to combine the data obtained from multiple platforms into one model.
Results: We assess the performance of our methods using several synthetic and real examples. Simulations show our integrative methods to have higher power to detect disease-related genes than non-integrative methods. Using the Cancer Genome Atlas glioblastoma dataset, we apply the iBAG model to integrate gene expression and methylation data to study their associations with patient survival. Our proposed method discovers multiple methylation-regulated genes that are related to patient survival, most of which have important biological functions in other diseases but have not been previously studied in glioblastoma.
Availability: http://odin.mdacc.tmc.edu/∼vbaladan/.
Contact: veera@mdanderson.org
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts655
PMCID: PMC3546799  PMID: 23142963
17.  Long-Term Survival in HIV Positive Patients with up to 15 Years of Antiretroviral Therapy 
PLoS ONE  2012;7(11):e48839.
Background
Life expectancy has increased for newly diagnosed HIV patients since the inception of combination antiretroviral treatment (cART), but there remains a need to better understand the characteristics of long-term survival in HIV-positive patients. We examined long-term survival in HIV-positive patients receiving cART in the Australian HIV Observational Database (AHOD), to describe changes in mortality compared to the general population and to develop longer-term survival models.
Methods
Data were examined from 2,675 HIV-positive participants in AHOD who started cART. Standardised mortality ratios (SMR) were calculated by age, sex and calendar year across prognostic characteristics using Australian Bureau of Statistics national data as reference. SMRs were examined by years of duration of cART by CD4 and similarly by viral load. Survival was analysed using Cox-proportional hazards and parametric survival models.
Results
The overall SMR for all-cause mortality was 3.5 (95% CI: 3.0–4.0). SMRs by CD4 count were 8.6 (95% CI: 7.2–10.2) for CD4<350 cells/µl; 2.1 (95% CI: 1.5–2.9) for CD4 = 350–499 cells/µl; and 1.5 (95% CI: 1.1–2.0) for CD4≥500 cells/µl. SMRs for patients with CD4 counts <350 cells/µL were much higher than for patients with higher CD4 counts across all durations of cART. SMRs for patients with viral loads greater than 400 copies/ml were much higher across all durations of cART. Multivariate models demonstrated improved survival associated with increased recent CD4, reduced recent viral load, younger patients, absence of HBVsAg-positive ever, year of HIV diagnosis and incidence of ADI. Parametric models showed a fairly constant mortality risk by year of cART up to 15 years of treatment.
Conclusion
Observed mortality remained fairly constant by duration of cART and was modelled accurately by accepted prognostic factors. These rates did not vary much by duration of treatment. Changes in mortality with age were similar to those in the Australian general population.
doi:10.1371/journal.pone.0048839
PMCID: PMC3492258  PMID: 23144991
18.  A randomised controlled trial of Heparin versus EthAnol Lock THerapY for the prevention of Catheter Associated infecTion in Haemodialysis patients – the HEALTHY-CATH trial 
BMC Nephrology  2012;13:146.
Background
Tunnelled central venous dialysis catheter use is significantly limited by the occurrence of catheter-related infections. This randomised controlled trial assessed the efficacy of a 48 hour 70% ethanol lock vs heparin locks in prolonging the time to the first episode of catheter related blood stream infection (CRBSI).
Methods
Patients undergoing haemodialysis (HD) via a tunnelled catheter were randomised 1:1 to once per week ethanol locks (with two heparin locks between other dialysis sessions) vs thrice per week heparin locks.
Results
Observed catheter days in the heparin (n=24) and ethanol (n=25) groups were 1814 and 3614 respectively. CRBSI occurred at a rate of 0.85 vs. 0.28 per 1000 catheter days in the heparin vs ethanol group by intention to treat analysis (incident rate ratio (IRR) for ethanol vs. heparin 0.17; 95%CI 0.02-1.63; p=0.12). Flow issues requiring catheter removal occurred at a rate of 1.6 vs 1.4 per 1000 catheter days in the heparin and ethanol groups respectively (IRR 0.85; 95% CI 0.20-3.5 p =0.82 (for ethanol vs heparin).
Conclusions
Catheter survival and catheter-related blood stream infection were not significantly different but there was a trend towards a reduced rate of infection in the ethanol group. This study establishes proof of concept and will inform an adequately powered multicentre trial to definitively examine the efficacy and safety of ethanol locks as an alternative to current therapies used in the prevention of catheter-associated blood stream infections in patients dialysing with tunnelled catheters.
Trial Registration
Australian New Zealand Clinical Trials Registry ACTRN12609000493246
doi:10.1186/1471-2369-13-146
PMCID: PMC3531247  PMID: 23121768
Catheter related blood stream infection (CRBSI); Central venous catheter; Ethanol; Lock therapy; Haemodialysis (HD); Prophylaxis
19.  Soluble Axoplasm Enriched from Injured CNS Axons Reveals the Early Modulation of the Actin Cytoskeleton 
PLoS ONE  2012;7(10):e47552.
Axon injury and degeneration is a common consequence of diverse neurological conditions including multiple sclerosis, traumatic brain injury and spinal cord injury. The molecular events underlying axon degeneration are poorly understood. We have developed a novel method to enrich for axoplasm from rodent optic nerve and characterised the early events in Wallerian degeneration using an unbiased proteomics screen. Our detergent-free method draws axoplasm into a dehydrated hydrogel of the polymer poly(2-hydroxyethyl methacrylate), which is then recovered using centrifugation. This technique is able to recover axonal proteins and significantly deplete glial contamination as confirmed by immunoblotting. We have used iTRAQ to compare axoplasm-enriched samples from naïve vs injured optic nerves, which has revealed a pronounced modulation of proteins associated with the actin cytoskeleton. To confirm the modulation of the actin cytoskeleton in injured axons we focused on the RhoA pathway. Western blotting revealed an augmentation of RhoA and phosphorylated cofilin in axoplasm-enriched samples from injured optic nerve. To investigate the localisation of these components of the RhoA pathway in injured axons we transected axons of primary hippocampal neurons in vitro. We observed an early modulation of filamentous actin with a concomitant redistribution of phosphorylated cofilin in injured axons. At later time-points, RhoA is found to accumulate in axonal swellings and also colocalises with filamentous actin. The actin cytoskeleton is a known sensor of cell viability across multiple eukaryotes, and our results suggest a similar role for the actin cytoskeleton following axon injury. In agreement with other reports, our data also highlights the role of the RhoA pathway in axon degeneration. These findings highlight a previously unexplored area of axon biology, which may open novel avenues to prevent axon degeneration. Our method for isolating CNS axoplasm also represents a new tool to study axon biology.
doi:10.1371/journal.pone.0047552
PMCID: PMC3480358  PMID: 23115653
20.  Ecological theatre and the evolutionary game: how environmental and demographic factors determine payoffs in evolutionary games 
In the standard approach to evolutionary games and replicator dynamics, differences in fitness can be interpreted as an excess from the mean Malthusian growth rate in the population. In the underlying reasoning, related to an analysis of “costs” and “benefits”, there is a silent assumption that fitness can be described in some type of units. However, in most cases these units of measure are not explicitly specified. Then the question arises: are these theories testable? How can we measure “benefit” or “cost”? A natural language, useful for describing and justifying comparisons of strategic “cost” versus “benefits”, is the terminology of demography, because the basic events that shape the outcome of natural selection are births and deaths. In this paper, we present the consequences of an explicit analysis of births and deaths in an evolutionary game theoretic framework. We will investigate different types of mortality pressures, their combinations and the possibility of trade-offs between mortality and fertility. We will show that within this new approach it is possible to model how strictly ecological factors such as density dependence and additive background fitness, which seem neutral in classical theory, can affect the outcomes of the game. We consider the example of the Hawk–Dove game, and show that when reformulated in terms of our new approach new details and new biological predictions are produced.
doi:10.1007/s00285-012-0573-2
PMCID: PMC3766521  PMID: 22936541
Replicator dynamics; Mortality; Fertility; Eco-evolutionary feedback; Trade-off; Density dependence; 92D40
21.  Model averaging strategies for structure learning in Bayesian networks with limited data 
BMC Bioinformatics  2012;13(Suppl 13):S10.
Background
Considerable progress has been made on algorithms for learning the structure of Bayesian networks from data. Model averaging by using bootstrap replicates with feature selection by thresholding is a widely used solution for learning features with high confidence. Yet, in the context of limited data many questions remain unanswered. What scoring functions are most effective for model averaging? Does the bias arising from the discreteness of the bootstrap significantly affect learning performance? Is it better to pick the single best network or to average multiple networks learnt from each bootstrap resample? How should thresholds for learning statistically significant features be selected?
Results
The best scoring functions are Dirichlet Prior Scoring Metric with small λ and the Bayesian Dirichlet metric. Correcting the bias arising from the discreteness of the bootstrap worsens learning performance. It is better to pick the single best network learnt from each bootstrap resample. We describe a permutation based method for determining significance thresholds for feature selection in bagged models. We show that in contexts with limited data, Bayesian bagging using the Dirichlet Prior Scoring Metric (DPSM) is the most effective learning strategy, and that modifying the scoring function to penalize complex networks hampers model averaging. We establish these results using a systematic study of two well-known benchmarks, specifically ALARM and INSURANCE. We also apply our network construction method to gene expression data from the Cancer Genome Atlas Glioblastoma multiforme dataset and show that survival is related to clinical covariates age and gender and clusters for interferon induced genes and growth inhibition genes.
Conclusions
For small data sets, our approach performs significantly better than previously published methods.
doi:10.1186/1471-2105-13-S13-S10
PMCID: PMC3426799  PMID: 23320818
22.  A fresh look at the nucleus-endplate region: new evidence for significant structural integration 
European Spine Journal  2011;20(8):1225-1232.
The disc nucleus is commonly thought of as a largely unstructured gel. However, exactly how the nucleus integrates structurally with the endplates remains somewhat ambiguous. The purpose of this study was to investigate whether a substantial level of structural/mechanical cohesion does, in fact, exist across the nucleus-endplate junction. Vertebra–nucleus–vertebra samples were obtained from mature ovine lumbar motion segments and subjected to a novel technique involving circumferential transverse severing (i.e. ring-severing) of the annulus fibrosus designed to eliminate its strain-limiting influence. These samples were loaded in tension and then chemically fixed in order to preserve the stretched nucleus material. Structural continuity across the nucleus-endplate junctions was sufficient for the samples to support, on average, 20 N before tensile failure occurred. Microscopic examination revealed nucleus fibres inserting into the endplates and the significant level of load carried by the nucleus material indicates that there is some form of structural continuity from vertebra to vertebra in the central nucleus region.
doi:10.1007/s00586-011-1704-y
PMCID: PMC3175834  PMID: 21327814
Disc nucleus; Cartilaginous endplate; Fibrosity; Tethering mechanisms
23.  Who Uses Glucosamine and Why? A Study of 266,848 Australians Aged 45 Years and Older 
PLoS ONE  2012;7(7):e41540.
Objectives
There has been a dramatic increase in the use of complementary medicines over recent decades. Glucosamine is one of the most commonly used complementary medicines in Western societies. An understanding of glucosamine consumption is of significance for public health and future health promotion. This paper, drawing upon the largest dataset to date with regards to glucosamine use (n = 266,844), examines the use and users of glucosamine amongst a sample of older Australians.
Design
Analysis of the self-reported data on use of glucosamine, demographics and health status as extracted from the dataset of the 45 and Up Study, which is the largest study of healthy ageing ever undertaken in the Southern Hemisphere involving over 265,000 participants aged 45 and over.
Results
Analysis reveals that 58,630 (22.0%) participants reported using glucosamine in the 4 weeks prior to the survey. Use was higher for those who were female, non-smokers, residing in inner/outer regional areas, with higher income and private health insurance. Of all the health conditions examined only osteoarthritis was positively associated with use of glucosamine, while cancer, heart attack or angina and other heart disease were all negatively associated with glucosamine use.
Conclusions
This study suggests that a considerable proportion of the Australia population aged 45 and over consume glucosamine. There is a need for health care practitioners to enquire with their patients about their use of glucosamine and for further attention to be directed to providing good quality information for patients and providers with regards to glucosamine products.
doi:10.1371/journal.pone.0041540
PMCID: PMC3408465  PMID: 22859995
24.  Use of complementary and alternative medicine by mid-age women with back pain: a national cross-sectional survey 
Background
The use of complementary and alternative medicine (CAM) has increased significantly in Australia over the past decade. Back pain represents a common context for CAM use, with increasing utilisation of a wide range of therapies provided within and outside conventional medical facilities. We examine the relationship between back pain and use of CAM and conventional medicine in a national cohort of mid-aged Australian women.
Methods
Data is taken from a cross-sectional survey (n = 10492) of the mid-aged cohort of the Australian Longitudinal Study on Women’s Health, surveyed in 2007. The main outcome measures were: incidence of back pain the previous 12 months, and frequency of use of conventional or CAM treatments in the previous 12 months.
Results
Back pain was experienced by 77% (n = 8063) of the cohort in the previous twelve month period. The majority of women with back pain only consulted with a conventional care provider (51.3%), 44.2% of women with back pain consulted with both a conventional care provider and a CAM practitioner. Women with more frequent back pain were more likely to consult a CAM practitioner, as well as seek conventional care. The most commonly utilised CAM practitioners were massage therapy (26.5% of those with back pain) and chiropractic (16.1% of those with back pain). Only 1.7% of women with back pain consulted with a CAM practitioner exclusively.
Conclusions
Mid-aged women with back pain utilise a range of conventional and CAM treatments. Consultation with CAM practitioners or self-prescribed CAM was predominantly in addition to, rather than a replacement for, conventional care. It is important that health professionals are aware of potential multiple practitioner usage in the context of back pain and are prepared to discuss such behaviours and practices with their patients.
doi:10.1186/1472-6882-12-98
PMCID: PMC3493383  PMID: 22809262
Back pain; Complementary medicine; Survey

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