Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants

Background: The vast majority of BRCA1 missense sequence variants remain uncharacterised for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene. Objective: To elucidate the effect of two BRCA1 variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in BRCA genes. Methods and Results: Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype BRCA1 in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with BRCA1 related tumours. Conclusions: A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of BRCA1 unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as "benign". In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in BRCA1 and BRCA2.

Benefits of blended learning for the first year medical imaging students in preparation for clinical placement

Although there is a plethora of definitions of blended learning, the underlying distinguishing feature is the combination of traditional content delivery and the utilisation of technology. Within Medical Imaging undergraduate education there is evidence of advantages and increased student engagement when utilising a blended learning approach. Although the embedding of technology has been proven to be a useful teaching tool, “Educators should tailor their teaching media to learner’s needs rather than assume that web based learning is intrinsically superior”. This study aims to determine which clinical learning tools are perceived to be the most useful to the student in preparing them for placements.

Medical negligence, causation and 'exceptional cases' under the civil liability legislation

Under the civil liability legislation enacted in most Australian jurisdictions, factual causation will be established if, on the balance of probabilities, the claimant can prove that the defendant's negligence was 'a necessary condition of the occurrence of the [claimant's] harm'. Causation will then be satisfied by showing that the harm would not have occurred 'but for' the defendant's breach of their duty of care. However, in an exceptional or appropriate case, sub-section 2 of the legislation provides that if the 'but for' test is not met, factual causation may instead be determined in accordance with other 'established principles'. In such a case, 'the court is to consider (amongst other relevant things) whether or not and why responsibility for the harm should be imposed' on the negligent party.

Reduced graphene oxide growth on 316L stainless steel for medical applications

We report a new method for the growth of reduced graphene oxide (rGO) on the 316L alloy of stainless steel (SS) and its relevance for biomedical applications. We demonstrate that electrochemical etching increases the concentration of metallic species on the surface and enables the growth of rGO. This result is supported through a combination of Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), scanning electron microscopy (SEM), density functional theory (DFT) calculations and static water contact angle measurements. Raman spectroscopy identifies the G and D bands for oxidized species of graphene at 1595 cm(-1) and 1350 cm(-1), respectively, and gives an ID/IG ratio of 1.2, indicating a moderate degree of oxidation. XPS shows -OH and -COOH groups in the rGO stoichiometry and static contact angle measurements confirm the wettability of rGO. SEM and AFM measurements were performed on different substrates before and after coronene treatment to confirm rGO growth. Cell viability studies reveal that these rGO coatings do not have toxic effects on mammalian cells, making this material suitable for biomedical and biotechnological applications.

What’s law got to do with it?: Medical negligence, causation and the use of policy

In a medical negligence context, and under the causation provisions enacted pursuant to Civil Liability Legislation in most Australian jurisdictions, the normative concept of “scope of liability” requires a consideration of whether or not and why a medical practitioner should be responsible for a patient’s harm. As such, it places a limit on the extent to which practitioners are deemed liable for a breach of the duty of care owed by them, in circumstances where a legal factual connection between that breach and the causation of a patient’s harm has already been shown. It has been said that a determination of causation requires ‘the identification and articulation of an evaluative judgement by reference to “the purposes and policy of the relevant part of the law”’: Wallace v Kam (2013) 297 ALR 383, 388. Accordingly, one of the normative factors falling within scope of liability is an examination of the content and purpose of the rule or duty of care violated – that is, its underlying policy and whether this supports an attribution of legal responsibility upon a practitioner. In this context, and with reference to recent jurisprudence, this paper considers: the policy relevant to a practitioner’s duty of care in each of the areas of diagnosis, treatment and advice; how this has been used to determine an appropriate scope of liability for the purpose of the causation inquiry in medical negligence claims; and whether such an approach is problematic for medical standards or decision-making.

ADAMIS: a database for medical information systems

This paper describes the design and implementation of ADAMIS (‘A database for medical information systems’). ADAMIS is a relational database management system for a general hospital environment. Apart from the usual database (DB) facilities of data definition and data manipulation, ADAMIS supports a query language called the ‘simplified medical query language’ (SMQL) which is completely end-user oriented and highly non-procedural. Other features of ADAMIS include provision of facilities for statistics collection and report generation. ADAMIS also provides adequate security and integrity features and has been designed mainly for use on interactive terminals.

Growth and meaning from negotiating the complex journey of being an Emergency Medical Dispatcher

Emergency Medical Dispatchers (EMDs) are charged with taking the calls of those who ring the national emergency number for urgent medical assistance, for dispatching paramedical crews, and for providing as much assistance as can be offered remotely until paramedics arrive. In a job role which is filled with vicarious trauma, emergency situations, pressure, abuse, grief and loss, EMDs are often challenged in maintaining their mental health. The seemingly senseless death of a teenager who commits suicide, the devastating loss of a baby to Sudden Infant Death Syndrome, lives lost through natural disasters, and multiple vehicle fatalities are only a few of the types of experiences EMDs are faced with in the course of their work. However, amongst the horror are positive stories such as coaching a caller to negotiate the birth of a baby and saving a life in jeopardy from heart failure. EMD’s need to cope with the daily challenges of the role; make sense of their work and create meaning in order to have a fulfilled and sustainable career. Although some people in this work struggle greatly to withstand the impacts of vicarious trauma, there are also stories of personal growth. In this Chapter we use a case study to explore how meaning is made for those who are an auditory witness to a continual flux of trauma for others and how the traumatic experiences EMDs bear witness to can also be a catalyst for posttraumatic growth.

Multidisciplinary review of teaching and assessing competency attainment by non-medical prescribers

Background Prescribing is a complex task, requiring specific knowledge and skills, and the execution of effective, context-specific clinical reasoning. Systematic reviews indicate medical prescribing errors have a median rate of 7% [IQR 2%-14%] of medication orders [1-3]. For podiatrists pursuing prescribing rights, a clear need exists to ensure practitioners develop a well-defined set of prescribing skills, which will contribute to competent, safe and appropriate practice. Aim To investigate the methods employed to teach and assess the principles of effective prescribing in the undergraduate podiatry program and compare and contrast these findings with four other non-medical professions who undertake prescribing after training at Queensland University of Technology. Method The NPS National Prescribing Competency Standards were employed as the prescribing standard. A curriculum mapping exercise was undertaken to determine whether the prescribing principles articulated in the competency standards were addressed by each profession. Results A range of methods are currently utilised to teach prescribing across disciplines. Application of prescribing competencies to the context of each profession appears to influence the teaching methods used. Most competencies were taught using a multimodal format, including interactive lectures, self-directed learning, tutorial sessions and clinical placement. In particular clinical training was identified as the most consistent form of educating safe prescribers across all five disciplines. Assessment of prescribing competency utilised multiple techniques including written and oral examinations and research tasks, case studies, objective structured clinical examination exercises and the assessment of clinical practice. Effective and reliable assessment of prescribing undertaken by students in diverse settings remains challenging e.g. that occurring in the clinical practice environment. Conclusion Recommendations were made to refine curricula and to promote efficient cross-discipline teaching by staff from the disciplines of podiatry, pharmacy, nurse practitioner, optometry and paramedic science. Students now experience a sophisticated level of multidisciplinary learning in the clinical setting which integrates the expertise and skills of experience prescribers combined with innovative information technology platforms (CCTV and live patient assessments). Further work is required to establish a practical, effective approach to the assessment of prescribing competence especially between the university and clinical settings.

Strategically Pleading Intentional Torts in medical cases

The opportunities and challenges faced by litigants who strategically plead intentional torts are borne out by two recent medical cases. Both arose out of dental treatment. Dean v Phung established some key principles which were clarified in White v Johnston. Before considering those two cases it is worth examining the environment in which such intentional torts claims now exist. Following the Ipp Review of the Law of Negligence, non-uniform legislative changes to the law of negligence were introduced across Australia which have imposed limitations on liability and quantum of damages in cases where a person has been injured through the fault of another. While it seems that, given the limitation of the scope of the review and recommendations to negligently caused damage, the Ipp Review reforms were meant to be limited to injury resulting from negligent acts rather than intentional torts, the extent to which the civil liability legislation applies to intentional torts differs across Australia.

The effect of a self-development coaching program on the psychological health and the academic performance among medical and dental students in Saudi Arabia

Observational studies have shown that medical and dental students have poor psychological health worldwide; however, few interventional studies have been used to test approaches to help students. This thesis used a randomised control trial study design to evaluate the effect of a self-development coaching program on psychological health and the academic performance among medical and dental students in Saudi Arabia. The outcomes indicated that these medical and dental students in Saudi Arabia experienced high levels of depression, anxiety and stress, and that the self-development coaching program was a promising intervention to improve students' psychological health.

Guaiac versus immunochemical tests: Faecal occult blood test screening for colorectal cancer in a rural community

Objective: To describe patient participation and clinical performance in a colorectal cancer (CRC) screening program utilising faecal occult blood test (FOBT). Methods: A community-based intervention was conducted in a small, rural community in north Queensland, 2000/01. One of two FOBT kits – guaiac (Hemoccult-ll) or immunochemical (Inform) – was assigned by general practice and mailed to participants (3,358 patients aged 50–74 years listed with the local practices). Results: Overall participation in FOBT screening was 36.3%. Participation was higher with the immunochemical kit than the guaiac kit (OR=1.9, 95% Cl 1.6-2.2). Women were more likely to comply with testing than men (OR=1.4, 95% Cl 1.2-1.7), and people in their 60s were less likely to participate than those 70–74 years (OR=0.8, 95% Cl 0.6-0.9). The positivity rate was higher for the immunochemical (9.5%) than the guaiac (3.9%) test (χ2=9.2, p=0.002), with positive predictive values for cancer or adenoma of advanced pathology of 37.8% (95% Cl 28.1–48.6) for !nform and 40.0% (95% Cl 16.8–68.7) for Hemoccult-ll. Colonoscopy follow-up was 94.8% with a medical complication rate of 2–3%. Conclusions: An immunochemical FOBT enhanced participation. Higher positivity rates for this kit did not translate into higher false-positive rates, and both test types resulted in a high yield of neoplasia. Implications: In addition to type of FOBT, the ultimate success of a population-based screening program for CRC using FOBT will depend on appropriate education of health professionals and the public as well as significant investment in medical infrastructure for colonoscopy follow-up.

Travelling with medications and medical equipment across international borders

The international traveller needs to plan ahead to ensure medicines are available and used as directed for optimal therapeutic outcome. The planning needs to take account of legal and customs requirements for travelling with medicines for personal use. The standard advice by travel health providers is that travellers should check with the country of destination for requirements when travelling into the country with medicines for personal use. This is akin to introducing a barrier to care for this category of travellers. Innovative method of care for this group of traveller is needed.

Non-medical prescribing in Australia

The announcement in the 2009 federal budget to allow nurse practitioners and midwives access to the Pharmaceutical Benefits Scheme (PBS) and the Medicare Benefits Scheme,1and the subsequent announcement of a November 2010 start date,2has brought non-medical prescribing into the public arena. Non-medical prescribing is not a new concept in Australia as nurse practitioners, podiatrists and optometrists have been authorised to prescribe under various state legislations for some time. However, state legislation is not uniform in relation to authorisation or formulary. Midwives are currently seeking prescribing rights,3and other groups such as physiotherapists and pharmacists are likely to seek them in the future.

Of tolerance in mice and men : studies in APECED and Aire

Autoimmune diseases affect 5 % of the population and come in many forms, such as diabetes, rheumatoid arthritis and MS. However, how and why autoimmune diseases arise are not yet fully resolved. In this thesis, the onset of autoimmunity was investigated using both patient samples and a mouse model of autoimmunity. Autoimmune diseases are usually complex, due to a number of different causative genes and environmental factors. However, a few monogenic autoimmune diseases have been described, which are caused by mutations in only one gene per disease. One of such disease is called APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) and is enriched in the Finnish population. The causative gene behind APECED is named AIRE from AutoImmune REgulator. How malfunction of just one gene product can cause the multitude of disease components found in APECED is not yet resolved. This thesis sought out to find out more about the functions of AIRE, in order to reveal why APECED and other autoimmune diseases arise and what goes wrong? Usually, immune cells are taught to distinguish between self and non-self during their development. That way, immune cells can fight off bacteria and microbes while leaving the tissues and organs of the host organism itself unharmed. In APECED, the development of immune cells called αβ T cells is incomplete. The cells are not able to fully distinguish between self and non-self. This leads to autodestruction of self tissues and autoimmune disease. One of the achievements of this thesis was the finding that the development of another set of T cells called γδ T cells is not affected by AIRE in mice or in men. Instead, we found that another type of immune cell important in tolerance, called the dendritic cell is defective in APECED patients and is not able to respond to microbial stimulus in a normal fashion. Finally, we studied Aire-deficient mice and found that autoantibodies expressed in the mice were not targeted against the same molecules as those found in APECED patients. This indicates differences in the autoimmune pathology in mice and men. More work is still required before we understand the mechanisms of tolerance and autoimmunity well enough to be able to cure APECED, let alone the more complex autoimmune diseases. Yet altogether, the findings of this thesis work bring us one step closer to finding out why and how APECED and common autoimmune diseases arise.

Cone beam computed tomography in oral radiology

In dentistry, basic imaging techniques such as intraoral and panoramic radiography are in most cases the only imaging techniques required for the detection of pathology. Conventional intraoral radiographs provide images with sufficient information for most dental radiographic needs. Panoramic radiography produces a single image of both jaws, giving an excellent overview of oral hard tissues. Regardless of the technique, plain radiography has only a limited capability in the evaluation of three-dimensional (3D) relationships. Technological advances in radiological imaging have moved from two-dimensional (2D) projection radiography towards digital, 3D and interactive imaging applications. This has been achieved first by the use of conventional computed tomography (CT) and more recently by cone beam CT (CBCT). CBCT is a radiographic imaging method that allows accurate 3D imaging of hard tissues. CBCT has been used for dental and maxillofacial imaging for more than ten years and its availability and use are increasing continuously. However, at present, only best practice guidelines are available for its use, and the need for evidence-based guidelines on the use of CBCT in dentistry is widely recognized. We evaluated (i) retrospectively the use of CBCT in a dental practice, (ii) the accuracy and reproducibility of pre-implant linear measurements in CBCT and multislice CT (MSCT) in a cadaver study, (iii) prospectively the clinical reliability of CBCT as a preoperative imaging method for complicated impacted lower third molars, and (iv) the tissue and effective radiation doses and image quality of dental CBCT scanners in comparison with MSCT scanners in a phantom study. Using CBCT, subjective identification of anatomy and pathology relevant in dental practice can be readily achieved, but dental restorations may cause disturbing artefacts. CBCT examination offered additional radiographic information when compared with intraoral and panoramic radiographs. In terms of the accuracy and reliability of linear measurements in the posterior mandible, CBCT is comparable to MSCT. CBCT is a reliable means of determining the location of the inferior alveolar canal and its relationship to the roots of the lower third molar. CBCT scanners provided adequate image quality for dental and maxillofacial imaging while delivering considerably smaller effective doses to the patient than MSCT. The observed variations in patient dose and image quality emphasize the importance of optimizing the imaging parameters in both CBCT and MSCT.