Drugs, labels and (p)ill-fitting boxes : ADHD and children who are hard to teach

In offering a critical review of the problem we call “ADHD” this paper progresses in three stages. The first two parts juxtapose the dominant voices emanating from the literature in medicine and psychology, highlighting some interdependency between these otherwise competing interest groups. In part three, the nature of the relationship between these groups and the institution of the school is considered, as is the role that the school may play in the psycho-pathologisation of fidgety, distractible, active children who prove hard to teach. In so doing, the author provides an insight as to why the problem we call “ADHD” has achieved celebrity status in Australia and what the effects of that may be for children who come to be described in these ways.

Tenofovir-associated proteinuria

Proteinuria was observed in 27% of 153 patients taking tenofovir for more than 1 year. Concomitant protease inhibitor therapy and cumulative tenofovir exposure were independently associated with proteinuria in this cohort. Proteinuria was reversible in 11 of 12 patients who ceased tenofovir because of proteinuria without altering other medications. Clinicians should be aware that tenofovir can cause reversible proteinuria in patients with HIV.

Who drives E&P innovation?

Few would argue that the upstream oil and gas industry has become more technology- intensive over the years. At the same time, the increasing costs and complexity of today’s exploration and production (E&P) technologies are making it increasingly difficult for any one company to support an aggressive research and development (R&D) agenda single handedly. The coming together of these two evolutionary forces gives rise to important questions. How does innovation happen in the E&P industry? Specifically, what ideas and inputs flow from which parts of the industry’s value network, and where do these inputs go? And how do firms and organizations from different countries contribute differently to this process? This survey was designed to shed light on these issues.

The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib and ponatinib ATP-competitive inhibitors

We sought to identify fibroblast growth factor receptor 2 (FGFR2) kinase domain mutations that confer resistance to the pan-FGFR inhibitor, dovitinib, and explore the mechanism of action of the drug-resistant mutations. We cultured BaF3 cells overexpressing FGFR2 in high concentrations of dovitinib and identified fourteen dovitinib-resistant mutations, including the N550K mutation observed in 25% of FGFR2mutant endometrial cancers (EC). Structural and biochemical in vitro kinase analyses, together with BaF3 proliferation assays, showed that the resistance mutations elevate the intrinsic kinase activity of FGFR2. BaF3 lines were used to assess the ability of each mutation to confer cross-resistance to PD173074 and ponatinib. Unlike PD173074, ponatinib effectively inhibited all the dovitinib-resistant FGFR2 mutants except the V565I gatekeeper mutation, suggesting ponatinib but not dovitinib targets the active conformation of FGFR2 kinase. EC cell lines expressing wild-type FGFR2 were relatively resistant to all inhibitors. Whereas EC cell lines expressing mutated FGFR2 showed differential sensitivity. Within the FGFR2mutant cell lines, 3/7 showed marked resistance to PD173074 and relative resistance to dovitinib and ponatinib. This suggests that alternative mechanisms distinct from kinase domain mutations are responsible for intrinsic resistance in these three EC lines. Finally, overexpression of FGFR2N550K in JHUEM-2 cells (FGFR2C383R) conferred resistance (~5 fold) to PD173074, providing independent data that FGFR2N550K can be associated with drug resistance. Biochemical in vitro kinase analyses also shows ponatinib is more effective than dovitinib at inhibiting FGFR2N550K. We propose tumors harboring mutationally activated FGFRs should be treated with FGFR inhibitors that specifically bind the active kinase.

P.I.C.U., H.D.U., A.O.A. What treatment do we provide?: Current descriptions of the function of intensive care for inpatient Psychiatric Health Care.

Purpose – This paper adds to growing research of psychiatric intensive care units (PICU) by recounting descriptions of psychiatric intensive care settings and discusses the perceptions held by nurses of the organisational interfaces, arrangements and provisions of care in these settings. Design/methodology/approach – Data gathered from focus groups held with nurses from two PICUs was used to establish terminology, defining attributes, related concepts, antecedents, values, processes and concepts related to current practices. A literature search was conducted to permit a review of the conceptual arrangements and contemporary understanding of intensive care for people experiencing acute psychiatric illness based on the perspectives held by the nurses from the focus groups. Findings – Dissonance between service needs and the needs and management of individual patients overshadow strategies to implement comprehensive recovery-oriented approaches. Three factors are reported in this paper that influence standards and procedural practice in PICU; organisational structures; physical structures; and subtype nomenclature. Practical implications – Acute inpatient care is an important part of a comprehensive approach to mental health services. Commonly intensive acute care is delivered in specialised wards or units co-located with acute mental health inpatient units mostly known as PICU. Evidence of the most effective treatment and approaches in intensive care settings that support comprehensive recovery for improved outcomes is nascent. Originality/value – Current descriptions from nurses substantiate wide variations in the provisions, design and classifications of psychiatric intensive care. Idiosyncratic and localised conceptions of psychiatric intensive care are not adequately entailing effective treatment and methods in support of recovery principles for improved and comprehensive outcomes. The authors suggest that more concrete descriptions, guidelines, training and policies for provision of intensive psychiatric health care encompassing the perspective of nursing professionals, would reinforce conceptual construction and thus optimum treatments within a comprehensive, recovery-oriented approach to mental health services.

Nutritional status of Ugandan women living with HIV/AIDS : anthropometry and body composition assessment

Human immunodeficiency virus (HIV) that leads to acquired immune deficiency syndrome (AIDs) reduces immune function, resulting in opportunistic infections and later death. Use of antiretroviral therapy (ART) increases chances of survival, however, with some concerns regarding fat re-distribution (lipodystrophy) which may encompass subcutaneous fat loss (lipoatrophy) and/or fat accumulation (lipohypertrophy), in the same individual. This problem has been linked to Antiretroviral drugs (ARVs), majorly, in the class of protease inhibitors (PIs), in addition to older age and being female. An additional concern is that the problem exists together with the metabolic syndrome, even when nutritional status/ body composition, and lipodystrophy/metabolic syndrome are unclear in Uganda where the use of ARVs is on the increase. In line with the literature, the overall aim of the study was to assess physical characteristics of HIV-infected patients using a comprehensive anthropometric protocol and to predict body composition based on these measurements and other standardised techniques. The other aim was to establish the existence of lipodystrophy, the metabolic syndrome, andassociated risk factors. Thus, three studies were conducted on 211 (88 ART-naïve) HIV-infected, 15-49 year-old women, using a cross-sectional approach, together with a qualitative study of secondary information on patient HIV and medication status. In addition, face-to-face interviews were used to extract information concerning morphological experiences and life style. The study revealed that participants were on average 34.1±7.65 years old, had lived 4.63±4.78 years with HIV infection and had spent 2.8±1.9 years receiving ARVs. Only 8.1% of participants were receiving PIs and 26% of those receiving ART had ever changed drug regimen, 15.5% of whom changed drugs due to lipodystrophy. Study 1 hypothesised that the mean nutritional status and predicted percent body fat values of study participants was within acceptable ranges; different for participants receiving ARVs and the HIV-infected ART-naïve participants and that percent body fat estimated by anthropometric measures (BMI and skinfold thickness) and the BIA technique was not different from that predicted by the deuterium oxide dilution technique. Using the Body Mass Index (BMI), 7.1% of patients were underweight (<18.5 kg/m2) and 46.4% were overweight/obese (≥25.0 kg/m2). Based on waist circumference (WC), approximately 40% of the cohort was characterized as centrally obese. Moreover, the deuterium dilution technique showed that there was no between-group difference in the total body water (TBW), fat mass (FM) and fat-free mass (FFM). However, the technique was the only approach to predict a between-group difference in percent body fat (p = .045), but, with a very small effect (0.021). Older age (β = 0.430, se = 0.089, p = .000), time spent receiving ARVs (β = 0.972, se = 0.089, p = .006), time with the infection (β = 0.551, se = 0.089, p = .000) and receiving ARVs (β = 2.940, se = 1.441, p = .043) were independently associated with percent body fat. Older age was the greatest single predictor of body fat. Furthermore, BMI gave better information than weight alone could; in that, mean percentage body fat per unit BMI (N = 192) was significantly higher in patients receiving treatment (1.11±0.31) vs. the exposed group (0.99±0.38, p = .025). For the assessment of obesity, percent fat measures did not greatly alter the accuracy of BMI as a measure for classifying individuals into the broad categories of underweight, normal and overweight. Briefly, Study 1 revealed that there were more overweight/obese participants than in the general Ugandan population, the problem was associated with ART status and that BMI broader classification categories were maintained when compared with the gold standard technique. Study 2 hypothesized that the presence of lipodystrophy in participants receiving ARVs was not different from that of HIV-infected ART-naïve participants. Results showed that 112 (53.1%) patients had experienced at least one morphological alteration including lipohypertrophy (7.6%), lipoatrophy (10.9%), and mixed alterations (34.6%). The majority of these subjects (90%) were receiving ARVs; in fact, all patients receiving PIs reported lipodystrophy. Period spent receiving ARVs (t209 = 6.739, p = .000), being on ART (χ2 = 94.482, p = .000), receiving PIs (Fisher’s exact χ2 = 113.591, p = .000), recent T4 count (CD4 counts) (t207 = 3.694, p = .000), time with HIV (t125 = 1.915, p = .045), as well as older age (t209 = 2.013, p = .045) were independently associated with lipodystrophy. Receiving ARVs was the greatest predictor of lipodystrophy (p = .000). In other analysis, aside from skinfolds at the subscapular (p = .004), there were no differences with the rest of the skinfold sites and the circumferences between participants with lipodystrophy and those without the problem. Similarly, there was no difference in Waist: Hip ratio (WHR) (p = .186) and Waist: Height ratio (WHtR) (p = .257) among participants with lipodystrophy and those without the problem. Further examination showed that none of the 4.1% patients receiving stavudine (d4T) did experience lipoatrophy. However, 17.9% of patients receiving EFV, a non-nucleoside reverse transcriptase inhibitor (NNRTI) had lipoatrophy. Study 2 findings showed that presence of lipodystrophy in participants receiving ARVs was in fact far higher than that of HIV-infected ART-naïve participants. A final hypothesis was that the prevalence of the metabolic syndrome in participants receiving ARVs was not different from that of HIV-infected ART-naïve participants. Moreover, data showed that many patients (69.2%) lived with at least one feature of the metabolic syndrome based on International Diabetic Federation (IDF, 2006) definition. However, there was no single anthropometric predictor of components of the syndrome, thus, the best anthropometric predictor varied as the component varied. The metabolic syndrome was diagnosed in 15.2% of the subjects, lower than commonly reported in this population, and was similar between the medicated and the exposed groups (χ 21 = 0.018, p = .893). Moreover, the syndrome was associated with older age (p = .031) and percent body fat (p = .012). In addition, participants with the syndrome were heavier according to BMI (p = .000), larger at the waist (p = .000) and abdomen (p = .000), and were at central obesity risk even when hip circumference (p = .000) and height (p = .000) were accounted for. In spite of those associations, results showed that the period with disease (p = .13), CD4 counts (p = .836), receiving ART (p = .442) or PIs (p = .678) were not associated with the metabolic syndrome. While the prevalence of the syndrome was highest amongst the older, larger and fatter participants, WC was the best predictor of the metabolic syndrome (p = .001). Another novel finding was that participants with the metabolic syndrome had greater arm muscle circumference (AMC) (p = .000) and arm muscle area (AMA) (p = .000), but the former was most influential. Accordingly, the easiest and cheapest indicator to assess risk in this study sample was WC should routine laboratory services not be feasible. In addition, the final study illustrated that the prevalence of the metabolic syndrome in participants receiving ARVs was not different from that of HIV-infected ART-naïve participants.

Insights into the mechanism of the reaction between ttrachloro-p-bnzoquinone and hydrogen peroxide and their implications in the catalytic role of water molecules in producing the hydroxyl radial

Detailed mechanisms for the formation of hydroxyl or alkoxyl radicals in the reactions between tetrachloro-p-benzoquinone (TCBQ) and organic hydroperoxides are crucial for better understanding the potential carcinogenicity of polyhalogenated quinones. Herein, the mechanism of the reaction between TCBQ and H2O2 has been systematically investigated at the B3LYP/6-311++G** level of theory in the presence of different numbers of water molecules. We report that the whole reaction can easily take place with the assistance of explicit water molecules. Namely, an initial intermediate is formed first. After that, a nucleophilic attack of H2O2 onto TCBQ occurs, which results in the formation of a second intermediate that contains an OOH group. Subsequently, this second intermediate decomposes homolytically through cleavage of the O-O bond to produce a hydroxyl radical. Energy analyses suggest that the nucleophilic attack is the rate-determining step in the whole reaction. The participation of explicit water molecules promotes the reaction significantly, which can be used to explain the experimental phenomena. In addition, the effects of F, Br, and CH3 substituents on this reaction have also been studied.

Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines: targets for therapy

Indicators of mitochondrial function were studied in two different cell culture models of cis-diamminedichloroplatinum-II (CDDP) resistance: the intrinsically resistant human ovarian cancer cell line CI-80-13S, and resistant clones (HeLa-S1a and HeLa-S1b) generated by stable expression of the serine protease inhibitor—plasminogen activator inhibitor type-2 (PAI-2), in the human cervical cancer cell line HeLa. In both models, CDDP resistance was associated with sensitivity to killing by adriamycin, etoposide, auranofin, bis[1,2-bis(diphenylphosphino)ethane]gold(I) chloride {[Au(DPPE)2]Cl}, CdCl2 and the mitochondrial inhibitors rhodamine-123 (Rhl23), dequalinium chloride (DeCH), tetraphenylphosphonium (TPP), and ethidium bromide (EtBr) and with lower constitutive levels of ATP. Unlike the HeLa clones, CI-80-13S cells were additionally sensitive to chloramphenicol, 1-methyl-4-phenylpyridinium ion (MPP+), rotenone, thenoyltrifluoroacetone (TTFA), and antimycin A, and showed poor reduction of 1-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), suggesting a deficiency in NADH dehydrogenase and/or succinate dehydrogenase activities. Total platinum uptake and DNA-bound platinum were slightly lower in CI-80-13S than in sensitive cells. The HeLa-S1a and HeLa-S1b clones, on the other hand, showed poor reduction of triphenyltetrazolium chloride (TTC), indicative of low cytochrome c oxidase activity. Total platinum uptake by HeLa-S1a was similar to HeLa, but DNA-bound platinum was much lower than for the parent cell line. The mitochondria of CI-80-13S and HeLa-S1a showed altered morphology and were fewer in number than those of JAM and HeLa. In both models, CDDP resistance was associated with less platinum accumulation and with mitochondrial and membrane defects, brought about one case with expression of a protease inhibitor which is implicated in tumor progression. Such markers may identify tumors suitable for treatment with gold phosphine complexes or other mitochondrial inhibitors.

Protective effects of sweroside on human MG-63 cells and rat osteoblasts

Herbal Fructus Corni is a folk medicine with a long history of safe use for treating osteoporosis in postmenopausal women or elderly men in Asia. Sweroside is a bioactive herbal ingredient isolated from Fructus Corni, which has been widely used for the treatment of osteoporosis in traditional Chinese medicine (TCM). Unfortunately, the working mechanisms of this compound are difficult to determine and thus remain unclear. The aim of the study was performed to determine the potential molecular mechanism of the anti-osteoporotic effect of sweroside on the human MG-63 cells and rat osteoblasts. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used to observe the effect of sweroside on cell proliferation. The activity of alkaline phosphatase (ALP) and the amount of osteocalcin were also assayed the cell differentiation. Sweroside significantly increased the proliferation of human MG-63 cells and rat osteoblasts (P<0.01). It increased the activity of ALP, and osteocalcin was also elevated in response to sweroside (P<0.05). Of note, flowcytometer assay showed that sweroside can attenuate and inhibit apoptosis. Sweroside has a direct osteogenic effect on the proliferation and differentiation of cultured human MG-63 cells and rat osteoblasts in vitro. These data will help in understanding the molecular mechanisms of therapeutic efficacy of sweroside, and highlight insights into drug discovery. In the current study, sweroside has been suggested to be a promising osteoporosis therapeutic natural product.

An assessment of MMP and TIMP gene expression in cell lines and stroma : tumour differences in microdissected breast cancer biopsies

To examine matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinases (TIMP) mRNA levels in archival breast cancer biopsies, we employed microdissection to separate tumour tissue from the surrounding breast tissue, or stroma and RT-PCR to determine gross qualitative and small quantitative differences in the patterns of expression. In this study, a significant correlation (p < 0.05, by Mann-Whitney U analysis) between TIMP-2 expression and lymph node involvement was identified, while MMP-11 and TIMP-1 expression patterning also significantly (p < 0.05) differed between those tumours showing calcification and those that did not. When compared by Spearmans’ ρ correlation analysis, a significant association (p < 0.05, ρ = 0.404) was identified in the pattern of MMP-2 and MMP-9 gene expression. In this study, the use of microdissection and a systematic strategy of RT-PCR analysis have allowed us to investigate localized MMP and MMP inhibitor expression within breast tumours. We have identified patterns of gene expression that may further reveal aspects of breast carcinogenesis, and a robust method for examining changes in clinically important genes using archival biopsies and across stroma-tumour boundaries.

Simultaneous determination of aldrin, dieldrin, endrin, heptachlor, and p,p'-DDT in medicinal plant extracts using a novel high performance liquid chromatography method

A high performance liquid chromatographic method for the simultaneous determination of five organochlorine pesticides (aldrin, p,p’-DDT, dieldrin, endrin, and heptachlor) was developed. The method was used to determine the levels of these pesticides in medicinal plant samples. Analysis was carried out using a Merck LiChrospher 100 RP C18 (5 μm) column with a gradient solvent system of acetonitrile-water and PDA UV detection (224 nm). Quantification was carried out by the external standard method. The limit of detection for the utilized method was below the local legal limits (ANZFA) for similar plant materials for all 5 pesticides excepting endrin. Medicinal plant extracts were further analyzed by conventional GC-ECD and GC-NPD means using SPE and GPC cleanup as required.

Differences between provisionally licensed drivers who always display P plates and those who do not

Like most Australian states, the New South Wales Graduated Driver Licensing system requires all provisionally licensed drivers to display ‘P plates’ on their vehicle to indicate their licence status and facilitate enforcement. This paper examines whether the display of P plates increases compliance with driving laws in New South Wales. The driving behaviours of provisional drivers who reported always displaying their P plates were compared with those of drivers who sometimes drove without displaying their P plates. While no differences were found between the two groups on some behaviours, provisional drivers who did not always display their P plates indicated that they were less likely to obey the provisional speed limit and more likely to break the road rules if they knew they would not be caught. These results suggest that the requirement to display a P plate remains a priority to facilitate more general traffic law enforcement initiatives.

The association of single nucleotide polymorphisms with endometrial cancer risk and prognosis

Endometrial cancer is one of the most common female diseases in developed nations and is the most commonly diagnosed gynaecological cancer in Australia. The disease is commonly classified by histology: endometrioid or non-endometrioid endometrial cancer. While non-endometrioid endometrial cancers are accepted to be high-grade, aggressive cancers, endometrioid cancers (comprising 80% of all endometrial cancers diagnosed) generally carry a favourable patient prognosis. However, endometrioid endometrial cancer patients endure significant morbidity due to surgery and radiotherapy used for disease treatment, and patients with recurrent disease have a 5-year survival rate of less than 50%. Genetic analysis of women with endometrial cancer could uncover novel markers associated with disease risk and/or prognosis, which could then be used to identify women at high risk and for the use of specialised treatments. Proteases are widely accepted to play an important role in the development and progression of cancer. This PhD project hypothesised that SNPs from two protease gene families, the matrix metalloproteases (MMPs, including their tissue inhibitors, TIMPs) and the tissue kallikrein-related peptidases (KLKs) would be associated with endometrial cancer susceptibility and/or prognosis. In the first part of this study, optimisation of the genotyping techniques was performed. Results from previously published endometrial cancer genetic association studies were attempted to be validated in a large, multicentre replication set (maximum cases n = 2,888, controls n = 4,483, 3 studies). The rs11224561 progesterone receptor SNP (PGR, A/G) was observed to be associated with increased endometrial cancer risk (per A allele OR 1.31, 95% CI 1.12-1.53; p-trend = 0.001), a result which was initially reported among a Chinese sample set. Previously reported associations for the remaining 8 SNPs investigated for this section of the PhD study were not confirmed, thereby reinforcing the importance of validation of genetic association studies. To examine the effect of SNPs from the MMP and KLK families on endometrial cancer risk, we selected the most significantly associated MMP and KLK SNPs from genome-wide association study analysis (GWAS) to be genotyped in the GWAS replication set (cases n = 4,725, controls n = 9,803, 13 studies). The significance of the MMP24 rs932562 SNP was unchanged after incorporation of the stage 2 samples (Stage 1 per allele OR 1.18, p = 0.002; Combined Stage 1 and 2 OR 1.09, p = 0.002). The rs10426 SNP, located 3' to KLK10 was predicted by bioinformatic analysis to effect miRNA binding. This SNP was observed in the GWAS stage 1 result to exhibit a recessive effect on endometrial cancer risk, a result which was not validated in the stage 2 sample set (Stage 1 OR 1.44, p = 0.007; Combined Stage 1 and 2 OR 1.14, p = 0.08). Investigation of the regions imputed surrounding the MMP, TIMP and KLK genes did not reveal any significant targets for further analysis. Analysis of the case data from the endometrial cancer GWAS to identify genetic variation associated with cancer grade did not reveal SNPs from the MMP, TIMP or KLK genes to be statistically significant. However, the representation of SNPs from the MMP, TIMP and KLK families by the GWAS genotyping platform used in this PhD project was examined and observed to be very low, with the genetic variation of four genes (MMP23A, MMP23B, MMP28 and TIMP1) not captured at all by this technique. This suggests that comprehensive candidate gene association studies will be required to assess the role of SNPs from these genes with endometrial cancer risk and prognosis. Meta-analysis of gene expression microarray datasets curated as part of this PhD study identified a number of MMP, TIMP and KLK genes to display differential expression by endometrial cancer status (MMP2, MMP10, MMP11, MMP13, MMP19, MMP25 and KLK1) and histology (MMP2, MMP11, MMP12, MMP26, MMP28, TIMP2, TIMP3, KLK6, KLK7, KLK11 and KLK12). In light of these findings these genes should be prioritised for future targeted genetic association studies. Two SNPs located 43.5 Mb apart on chromosome 15 were observed from the GWAS analysis to be associated with increased endometrial cancer grade, results that were validated in silico in two independent datasets. One of these SNPs, rs8035725 is located in the 5' untranslated region of a MYC promoter binding protein DENND4A (Stage 1 OR 1.15, p = 9.85 x 10P -5 P, combined Stage 1 and in silico validation OR 1.13, p = 5.24 x 10P -6 P). This SNP has previously been reported to alter the expression of PTPLAD1, a gene involved in the synthesis of very long fatty acid chains and in the Rac1 signaling pathway. Meta-analysis of gene expression microarray data found PTPLAD1 to display increased expression in the aggressive non-endometrioid histology compared with endometrioid endometrial cancer, suggesting that the causal SNP underlying the observed genetic association may influence expression of this gene. Neither rs8035725 nor significant SNPs identified by imputation were predicted bioinformatically to affect transcription factor binding sites, indicating that further studies are required to assess their potential effect on other regulatory elements. The other grade- associated SNP, rs6606792, is located upstream of an inferred pseudogene, ELMO2P1 (Stage 1 OR 1.12, p = 5 x 10P -5 P; combined Stage 1 and in silico validation OR 1.09, p = 3.56 x 10P -5 P). Imputation of the ±1 Mb region surrounding this SNP revealed a cluster of significantly associated variants which are predicted to abolish various transcription factor binding sites, and would be expected to decrease gene expression. ELMO2P1 was not included on the microarray platforms collected for this PhD, and so its expression could not be investigated. However, the high sequence homology of ELMO2P1 with ELMO2, a gene important to cell motility, indicates that ELMO2 could be the parent gene for ELMO2P1 and as such, ELMO2P1 could function to regulate the expression of ELMO2. Increased expression of ELMO2 was seen to be associated with increasing endometrial cancer grade, as well as with aggressive endometrial cancer histological subtypes by microarray meta-analysis. Thus, it is hypothesised that SNPs in linkage disequilibrium with rs6606792 decrease the transcription of ELMO2P1, reducing the regulatory effect of ELMO2P1 on ELMO2 expression. Consequently, ELMO2 expression is increased, cell motility is enhanced leading to an aggressive endometrial cancer phenotype. In summary, these findings have identified several areas of research for further study. The results presented in this thesis provide evidence that a SNP in PGR is associated with risk of developing endometrial cancer. This PhD study also reports two independent loci on chromosome 15 to be associated with increased endometrial cancer grade, and furthermore, genes associated with these SNPs to be differentially expressed according in aggressive subtypes and/or by grade. The studies reported in this thesis support the need for comprehensive SNP association studies on prioritised MMP, TIMP and KLK genes in large sample sets. Until these studies are performed, the role of MMP, TIMP and KLK genetic variation remains unclear. Overall, this PhD study has contributed to the understanding of genetic variation involvement in endometrial cancer susceptibility and prognosis. Importantly, the genetic regions highlighted in this study could lead to the identification of novel gene targets to better understand the biology of endometrial cancer and also aid in the development of therapeutics directed at treating this disease.

Development and evaluation of a program to improve clinician and patient communication during a telehealth consultation : C.R.I.S.P. Telehealth

Introduction: The delivery of health care in the 21st century will look like no other in the past. The fast paced technological advances that are being made will need to transition from the information age into clinical practice. The phenomenon of e-Health is the over-arching form of information technology and telehealth is one arm of that phenomenon. The uptake of telehealth both in Australia and overseas, has changed the face of health service delivery to many rural and remote communities for the better, removing what is known as the tyranny of distance. Many studies have evaluated the satisfaction and cost-benefit analysis of telehealth across the organisational aspects as well as the various adaptations of clinical pathways and this is the predominant focus of most studies published to date. However, whilst comments have been made by many researchers about the need to improve and attend to the communication and relationship building aspects of telehealth no studies have examined this further. The aim of this study was to identify the patient and clinician experiences, concerns, behaviours and perceptions of the telehealth interaction and develop a training tool to assist these clinicians to improve their interaction skills. Methods: A mixed methods design combining quantitative (survey analysis and data coding) and qualitative (interview analysis) approaches was adopted. This study utilised four phases to firstly qualitatively explore the needs of clients (patients) and clinicians within a telehealth consultation then designed, developed, piloted and quantitatively and qualitatively evaluated the telehealth communication training program. Qualitative data was collected and analysed during Phase 1 of this study to describe and define the missing 'communication and rapport building' aspects within telehealth. This data was then utilised to develop a self-paced communication training program that enhanced clinicians existing skills, which comprised of Phase 2 of this study to develop the interactive program. Phase 3 included evaluating the training program with 26 clinicians and results were recorded pre and post training, whilst phase 4 was the pilot for future recommendations of this training program using a patient group within a Queensland Health setting at two rural hospitals. Results: Comparisons of pre and post training data on 1) Effective communication styles, 2) Involvement in communication training package, 3) satisfaction pre and post training, and 4) health outcomes pre and post training indicated that there were differences between pre and post training in relation to effective communication style, increased satisfaction and no difference in health outcomes between pre and post training for this patient group. The post training results revealed over half of the participants (N= 17, 65%) were more responsive to non-verbal cues and were better able to reflect and respond to looks of anxiousness and confusion from a 'patient' within a telehealth consultation. It was also found that during post training evaluations, clinicians had enhanced their therapeutic communication with greater detail to their own body postures, eye contact and presentation. There was greater time spent looking at the 'patient' with an increase of 35 second intervals of direct eye contact and less time spent looking down at paperwork which decreased by 20 seconds. Overall 73% of the clinicians were satisfied with the training program and 61% strongly agreed that they recognised areas of their communication that needed improving during a telehealth consultation. For the patient group there was significant difference post training in rapport with a mean score from 42 (SD = 28, n = 27) to 48 (SD = 5.9, n = 24). For communication comfort of the patient group there was a significant difference between the pre and post training scores t(10) = 27.9, p = .002, which meant that overall the patients felt less inhibited whilst talking to the clinicians and more understood. Conclusion: The aim of this study was to explore the characteristics of good patient-clinician communication and unmet training needs for telehealth consultations. The study developed a training program that was specific for telehealth consultations and not dependent on a 'trainer' to deliver the content. In light of the existing literature this is a first of its kind and a valuable contribution to the research on this topic. It was found that the training program was effective in improving the clinician's communication style and increased the satisfaction of patient's within an e-health environment. This study has identified some historical myths that telehealth cannot be part of empathic patient centred care due to its technology tag.