Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma

We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer.

Renal and genitourinary emergencies

Genitourinary (GU) problems are a common complaint in the community and to the emergency department (ED). Urinary tract infections (UTIs) are the second most common bacterial disease. UTIs rank as the sixteenth most frequently reported problem to general practitioners in Australia1 and between 10% and 20% of women will experience at least one UTI in their lifetime. Over 1,000,000 Australians are currently suffering with nephrolithiasis (renal calculi) and it is hy-pothesised that Australia’s hot, dry climate causes more stone formation than many other coun-tries in the world. Acute kidney injury (AKI) is a common complication of any trauma. Hypovol-aemia results in severe hypotension and this precipitates the development of acute tubular necrosis and subsequent AKI. The incidence of chronic kidney disease (CKD) is rising across the world. CKD is classified into five stages with those in stage 5 being classified as being in end stage kidney disease (ESKD). It is estimated that there are over 1.5 million people in Australia with CKD and there were over 16,000 Australians and over 2900 individuals in New Zealand with ESKD.2 Indigenous populations from both countries (Aboriginals, Torres Strait Islanders, Maoris, and Pacific Islanders) are over-represented in the number of people with all stages of CKD in both countries. Patients with compromised renal function often require the assistance of paramedics and will arrive at the ED with life-threatening fluid and electrolyte imbalances. Spe-cific GU emergencies discussed in this chapter are acute renal failure, rhabdomyolysis, chronic kidney disease, UTIs, acute urinary retention, urinary calculi, testicular torsion, epididymitis, and priapism. Refer to Chapter 31 for discussion of sexually transmitted infections (STIs) in women and to Chapter X for discussion of genitourinary trauma.

Assessment of retinal structure and visual function in association with diabetic peripheral neuropathy

Diabetes is an increasingly prevalent disease worldwide. Providing early management of the complications can prevent morbidity and mortality in this population. Peripheral neuropathy, a significant complication of diabetes, is the major cause of foot ulceration and amputation in diabetes. Delay in attending to complication of the disease contributes to significant medical expenses for diabetic patients and the community. Early structural changes to the neural components of the retina have been demonstrated to occur prior to the clinically visible retinal vasculature complication of diabetic retinopathy. Additionally visual functionloss has been shown to exist before the ophthalmoscopic manifestations of vasculature damage. The purpose of this thesis was to evaluate the relationship between diabetic peripheral neuropathy and both retinal structure and visual function. The key question was whether diabetic peripheral neuropathy is the potential underlying factor responsible for retinal anatomical change and visual functional loss in people with diabetes. This study was conducted on a cohort with type 2 diabetes. Retinal nerve fibre layer thickness was assessed by means of Optical Coherence Tomography (OCT). Visual function was assessed using two different methods; Standard Automated Perimetry (SAP) and flicker perimetry were performed within the central 30 degrees of fixation. The level of diabetic peripheral neuropathy (DPN) was assessed using two techniques - Quantitative Sensory Testing and Neuropathy Disability Score (NDS). These techniques are known to be capable of detecting DPN at very early stages. NDS has also been shown as a gold standard for detecting 'risk of foot ulceration'. Findings reported in this thesis showed that RNFL thickness, particularly in the inferior quadrant, has a significant association with severity of DPN when the condition has been assessed using NDS. More specifically it was observed that inferior RNFL thickness has the ability to differentiate individuals who are at higher risk of foot ulceration from those who are at lower risk, indicating that RNFL thickness can predict late-staged DPN. Investigating the association between RNFL and QST did not show any meaningful interaction, which indicates that RNFL thickness for this cohort was not as predictive of neuropathy status as NDS. In both of these studies, control participants did not have different results from the type 2 cohort who did not DPN suggesting that RNFL thickness is not a marker for diagnosing DPN at early stages. The latter finding also indicated that diabetes per se, is unlikely to affect the RNFL thickness. Visual function as measured by SAP and flicker perimetry was found to be associated with severity of peripheral neuropathy as measured by NDS. These findings were also capable of differentiating individuals at higher risk of foot ulceration; however, visual function also proved not to be a maker for early diagnosis of DPN. It was found that neither SAP, nor flicker sensitivity have meaningful associations with DPN when neuropathy status was measured using QST. Importantly diabetic retinopathy did not explain any of the findings in these experiments. The work described here is valuable as no other research to date has investigated the association between diabetic peripheral neuropathy and either retinal structure or visual function.

Under the carpet : the politics and trauma of patient harm

Few studies have investigated iatrogenic outcomes from the viewpoint of patient experience. To address this anomaly, the broad aim of this research is to explore the lived experience of patient harm. Patient harm is defined as major harm to the patient, either psychosocial or physical in nature, resulting from any aspect of health care. Utilising the method of Consensual Qualitative Research (CQR), in-depth interviews are conducted with twenty-four volunteer research participants who self-report having been severely harmed by an invasive medical procedure. A standardised measure of emotional distress, the Impact of Event Scale (IES), is additionally employed for purposes of triangulation. Thematic analysis of transcript data indicate numerous findings including: (i) difficulties regarding patients‘ prior understanding of risks involved with their medical procedure; (ii) the problematic response of the health system post-procedure; (iii) multiple adverse effects upon life functioning; (iv) limited recourse options for patients; and (v) the approach desired in terms of how patient harm should be systemically handled. In addition, IES results indicate a clinically significant level of distress in the sample as a whole. To discuss findings, a cross-disciplinary approach is adopted that draws upon sociology, medicine, medical anthropology, psychology, philosophy, history, ethics, law, and political theory. Furthermore, an overall explanatory framework is proposed in terms of the master themes of power and trauma. In terms of the theme of power, a postmodernist analysis explores the politics of patient harm, particularly the dynamics surrounding the politics of knowledge (e.g., notions of subjective versus objective knowledge, informed consent, and open disclosure). This analysis suggests that patient care is not the prime function of the health system, which appears more focussed upon serving the interests of those in the upper levels of its hierarchy. In terms of the master theme of trauma, current understandings of posttraumatic stress disorder (PTSD) are critiqued, and based on data from this research as well as the international literature, a new model of trauma is proposed. This model is based upon the principle of homeostasis observed in biology, whereby within every cell or organism a state of equilibrium is sought and maintained. The proposed model identifies several bio-psychosocial markers of trauma across its three main phases. These trauma markers include: (i) a profound sense of loss; (ii) a lack of perceived control; (iii) passive trauma processing responses; (iv) an identity crisis; (v) a quest to fully understand the trauma event; (vi) a need for social validation of the traumatic experience; and (vii) posttraumatic adaption with the possibility of positive change. To further explore the master themes of power and trauma, a natural group interview is carried out at a meeting of a patient support group for arachnoiditis. Observations at this meeting and members‘ stories in general support the homeostatic model of trauma, particularly the quest to find answers in the face of distressing experience, as well as the need for social recognition of that experience. In addition, the sociopolitical response to arachnoiditis highlights how public domains of knowledge are largely constructed and controlled by vested interests. Implications of the data overall are discussed in terms of a cultural revolution being needed in health care to position core values around a prime focus upon patients as human beings.

Frequency response function based structural damage detection using artificial neural networks

Damage detection in structures has become increasingly important in recent years. While a number of damage detection and localization methods have been proposed, few attempts have been made to explore the structure damage with frequency response functions (FRFs). This paper illustrates the damage identification and condition assessment of a beam structure using a new frequency response functions (FRFs) based damage index and Artificial Neural Networks (ANNs). In practice, usage of all available FRF data as an input to artificial neural networks makes the training and convergence impossible. Therefore one of the data reduction techniques Principal Component Analysis (PCA) is introduced in the algorithm. In the proposed procedure, a large set of FRFs are divided into sub-sets in order to find the damage indices for different frequency points of different damage scenarios. The basic idea of this method is to establish features of damaged structure using FRFs from different measurement points of different sub-sets of intact structure. Then using these features, damage indices of different damage cases of the structure are identified after reconstructing of available FRF data using PCA. The obtained damage indices corresponding to different damage locations and severities are introduced as input variable to developed artificial neural networks. Finally, the effectiveness of the proposed method is illustrated and validated by using the finite element modal of a beam structure. The illustrated results show that the PCA based damage index is suitable and effective for structural damage detection and condition assessment of building structures.

Scaling digital radiographs for templating in total hip arthroplasty using conventional acetate templates independent of calibration markers

We describe a scaling method for templating digital radiographs using conventional acetate templates independent of template magnification without the need for a calibration marker. The mean magnification factor for the radiology department was determined (119.8%, range117%-123.4%). This fixed magnification factor was used to scale the radiographs by the method described. 32 femoral heads on postoperative THR radiographs were then measured and compared to the actual size. The mean absolute accuracy was within 0.5% of actual head size (range 0 to 3%) with a mean absolute difference of 0.16mm (range 0-1mm, SD 0.26mm). Intraclass Correlation Coefficient (ICC) showed excellent reliability for both inter and intraobserver measurements with ICC scores of 0.993 (95% CI 0.988-0.996) for interobserver measurements and intraobserver measurements ranging between 0.990-0.993 (95% CI 0.980-0.997).

Corneal markers of diabetic neuropathy

Diabetic neuropathy is a significant clinical problem that currently has no effective therapy, and in advanced cases, leads to foot ulceration and lower limb amputation. The accurate detection, characterization and quantification of this condition are important in order to define at-risk patients, anticipate deterioration, monitor progression, and assess new therapies This review evaluates novel corneal methods of assessing diabetic neuropathy. Two new non-invasive corneal markers have emerged, and in cross-sectional studies have demonstrated their ability to stratify the severity of this disease. Corneal confocal microscopy allows quantification of corneal nerve parameters and non-contact corneal esthesiometry, the functional correlate of corneal structure, assesses the sensitivity of the cornea. Both these techniques are quick to perform, produce little or no discomfort for the patient, and are suitable for clinical settings. Each has advantages and disadvantages over traditional techniques for assessing diabetic neuropathy. Application of these new corneal markers for longitudinal evaluation of diabetic neuropathy has the potential to reduce dependence on more invasive, costly, and time-consuming assessments, such as skin biopsy.

An exploration of young students' ability to generalise function tasks

The Early Years Generalising Project involves Australian students, Years 1-4 (age 5-9), and explores how the students grasp and express generalisations. This paper focuses on the data collected from clinical interviews with Year 3 and 4 cohorts in an investigative study focusing on the identifications, prediction and justification of function rules. It reports on students' attempts to generalise from function machine contexts, describing the various ways students express generalisation and highlighting the different levels of justification given by students. Finally, we conjecture that there are a set of stages in the expression and justification of generalisations that assist students to reach generality within tasks.

Psycho-markers of weight loss. The roles of TFEQ Disinhibition and Restraint in exercise-induced weight management

Eating behaviour traits, namely Disinhibition and Restraint, have the potential to exert an effect on food intake and energy balance. The effectiveness of exercise as a method of weight management could be influenced by these traits. Fifty eight overweight and obese participants completed 12-weeks of supervised exercise. Each participant was prescribed supervised exercise based on an expenditure of 500 kcal/session, 5 d/week for 12-weeks. Following 12-weeks of exercise there was a significant reduction in mean body weight (-3.26 ± 3.63 kg), fat mass (FM: -3.26 ± 2.64 kg), BMI (-1.16 ± 1.17 kg/m2)and waist circumference (WC: -5.0 ± 3.23 cm). Regression analyses revealed a higher baseline Disinhibition score was associated with a greater reduction in BMI and WC, while Internal Disinhibition was associated with a larger decrease in weight, %FM and WC. Neither baseline Restraint or Hunger were associated with any of the anthropometric markers at baseline or after 12-weeks. Furthermore, after 12-weeks of exercise, a decrease in Disinhibition and increase in Restraint were associated with a greater reduction in WC, whereas only Restraint was associated with a decrease in weight. Post-hoc analysis of the sub-factors revealed a decrease in External Disinhibition and increase in Flexible Restraint were associated with weight loss. However, an increase in Rigid Restraint was associated with a reduction in %FM and WC. These findings suggest that exercise-induced weight loss is more marked in individuals with a high level of Disinhibition. These data demonstrate the important roles that Disinhibition and Restraint play in the relationship between exercise and energy balance.