The cancer stem-cell hypothesis : its emerging role in lung cancer biology and its relevance for future therapy

The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review.

Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure

Critically ill patients receiving extracorporeal membrane oxygenation (ECMO) are often noted to have increased sedation requirements. However, data related to sedation in this complex group of patients is limited. The aim of our study was to characterise the sedation requirements in adult patients receiving ECMO for cardiorespiratory failure. A retrospective chart review was performed to collect sedation data for 30 consecutive patients who received venovenous or venoarterial ECMO between April 2009 and March 2011. To test for a difference in doses over time we used a regression model. The dose of midazolam received on ECMO support increased by an average of 18 mg per day (95% confidence interval 8, 29 mg, P=0.001), while the dose of morphine increased by 29 mg per day (95% confidence interval 4, 53 mg, P=0.021) The venovenous group received a daily midazolam dose that was 157 mg higher than the venoarterial group (95% confidence interval 53, 261 mg, P=0.005). We did not observe any significant increase in fentanyl doses over time (95% confidence interval 1269, 4337 µg, P=0.94). There is a significant increase in dose requirement for morphine and midazolam during ECMO. Patients on venovenous ECMO received higher sedative doses as compared to patients on venoarterial ECMO. Future research should focus on mechanisms behind these changes and also identify drugs that are most suitable for sedation during ECMO.

Suspected child abuse and neglect reporting behaviour

Executuve Summary Background and Aims Child abuse and neglect is a tragedy within our community, with over 10,000 substantiated reports of abuse and neglect in Queensland in the past year. The considerable consequences of child abuse and neglect are far-reaching, substantial and can be fatal. The reporting of suspicions of child abuse or neglect is often the first step in preventing further abuse or neglect. In the State of Queensland, medical practitioners are mandated by law to report their suspicions of child abuse and neglect. However, despite this mandate many still do not report their suspicions. A 1998 study indicated that 43% of medical practitioners had, at some time, made a conscious decision to not report suspected abuse or neglect (Van Haeringen, Dadds & Armstrong, 1998). The aim of this study was to gain a better understanding of beliefs about reporting suspected child abuse and neglect and the barriers to reporting suspected abuse and neglect by medical practitioners and parents and students. The findings have the potential to inform the training and education of members of the community who have a shared responsibility to protect the wellbeing of its most vulnerable members. Method In one of the largest studies of reporting behaviour in relation to suspected child abuse and neglect in Australia, we examined and compared medical practitioners’ responses with members of the community, namely parents and students. We surveyed 91 medical practitioners and 214 members of the community (102 parents and 112 students) regarding their beliefs and reporting behaviour related to suspected child abuse and neglect. We also examined reasons for not reporting suspected abuse or neglect, as well as awareness of responsibilities and the appropriate reporting procedures. To obtain such information, participants anonymously completed a comprehensive questionnaire using items from previous studies of reporting attitudes and behaviour. Executive Summary Abused Child Trust Report August 2003 5 Findings Key findings include: • The majority of medical practitioners (97%) were aware of their duty to report suspected abuse and neglect and believed they had a professional and ethical duty to do so. • A majority of parents (82%) and students (68%) also believed that they had a professional and ethical duty to report suspected abuse and neglect. • In accord with their statutory duty to report suspected abuse and neglect, 69% of medical practitioners had made a report at some point. • Sixteen percent of parents and 9% of students surveyed indicated that they had reported their suspicions of neglect and abuse. • The most endorsed belief associated with not reporting suspected child abuse and neglect was that, ‘unpleasant events would follow reporting’. • Over a quarter of medical practitioners (26%) admitted to making a decision not to report their suspicions of child abuse or neglect on at least one occasion. • Compared with previous research, there has been a decline in the number of medical practitioners who decided not to report suspected abuse or neglect from 43% (Van Haeringen et al., 1998) to 26% in the current study. • Fourteen percent of parents and 15% of students surveyed had also chosen not to report a case of suspected abuse or neglect. • Attitudes that most strongly influenced the decision to report or not report suspected abuse or neglect differed between groups (medical practitioners, parents, or students). A belief that, ‘the abuse was a single incident’ was the best predictor of non-reporting by medical practitioners, while having ‘no time to follow-up the report’ or failing to be ‘convinced of evidence of abuse’ best predicted failure to report abuse by students. A range of beliefs predicted non-reporting by parents, including the beliefs that reporting suspected abuse was ‘not their responsibility’ and ‘knowing the child had retracted their statement’. Conclusions Of major concern is that approximately 25% of medical practitioners with a mandated responsibility to report, as well as some members of the general public, revealed that they have suspected child neglect or abuse but have made the decision not to report their suspicions. Parents and students perceived the general community as having responsibility for reporting suspicions of abuse or neglect. Despite this perception, they felt that lodging a report may be overly demanding in terms of time and they had the confidence in their ability to identify child abuse and neglect. An explanation for medical practitioners deciding not to report may be based upon their optimistic belief that suspected abuse or neglect was a single incident. Our findings may best be understood from the ‘inflation of optimism’ hypothesis put forward by the Nobel Laureate, Daniel Kahneman. He suggests that in spite of rational evidence, human beings tend to make judgements based on an optimistic view rather than engaging in a rational decision-making process. In this case, despite past behaviour of abuse or neglect being the best predictor of future behaviour, medical practitioners have taken an optimistic view, choosing to believe that their suspicion of child abuse or neglect represents a single incident. The clear implication of findings in the current research is the need for the members of the general community and medical practitioners to be better appraised of the consequences of their decision-making in relation to suspicionsof child abuse and neglect. Finally findings from parents and students relating to their reporting behaviour suggest that members of the larger community represent an untapped resourcewho might, with appropriate awareness, play a more significant role in theidentification and reporting of suspected child abuse and neglect.

Dying in hospital: medical failure or natural outcomes?

The purpose of this study was to describe patterns of medical and nursing practice in the care of patients dying of oncological and hematological malignancies in the acute care setting in Australia. A tool validated in a similar American study was used to study the medical records of 100 consecutive patients who died of oncological or hematological malignancies before August 1999 at The Canberra Hospital in the Australian Capital Territory. The three major indicators of patterns of end-of-life care were documentation of Do Not Resuscitate (DNR) orders, evidence that the patient was considered dying, and the presence of a palliative care intention. Findings were that 88 patients were documented DNR, 63 patients' records suggested that the patient was dying, and 74 patients had evidence of a palliative care plan. Forty-six patients were documented DNR 2 days or less prior to death and, of these, 12 were documented the day of death. Similar patterns emerged for days between considered dying and death, and between palliative care goals and death. Sixty patients had active treatment in progress at the time of death. The late implementation of end-of-life management plans and the lack of consistency within these plans suggested that patients were subjected to medical interventions and investigations up to the time of death. Implications for palliative care teams include the need to educate health care staff and to plan and implement policy regarding the management of dying patients in the acute care setting. Although the health care system in Australia has cultural differences when compared to the American context, this research suggests that the treatment imperative to prolong life is similar to that found in American-based studies.

A lawyer's duty of care : beware the failure to advise of contingencies and foreseeable risks

It is trite law that a lawyer owes their client a duty of care requiring the lawyer to take reasonable steps to avoid their client suffering foreseeable economiic loss: Hawkins v Clayton. In the context of a property transaction this will include a duty to warn the client of anything that is unusual or anything which may affect the client obtaining the full benefit of the contract entered into: Macindoe v Parbery.

Systematic variation of the severity of motor vehicle accident-related traumatic brain injury vignettes produces different post-concussion symptom reports

This study investigated the specificity of the post-concussion syndrome (PCS) expectation-as-etiology hypothesis. Undergraduate students (n = 551) were randomly allocated to one of three vignette conditions. Vignettes depicted either a very mild (VMI), mild (MI), or moderate-to-severe (MSI) motor vehicle-related traumatic brain injury (TBI). Participants reported the PCS and PTSD symptoms that they imagined the depicted injury would produce. Secondary outcomes (knowledge of mild TBI, and the perceived undesirability of TBI) were also assessed. After data screening, the distribution of participants by condition was: VMI (n = 100), MI (n = 96), and MSI (n = 71). There was a significant effect of condition on PCS symptomatology, F(2, 264) = 16.55, p < .001. Significantly greater PCS symptomatology was expected in the MSI condition compared to the other conditions (MSI > VMI; medium effect, r = .33; MSI > MI; small-to-medium effect, r = .22). The same pattern of group differences was found for PTSD symptoms, F(2, 264) = 17.12, p < .001. Knowledge of mild TBI was not related to differences in expected PCS symptoms by condition; and the perceived undesirability of TBI was only associated with reported PCS symptomatology in the MSI condition. Systematic variation in the severity of a depicted TBI produces different PCS and PTSD symptom expectations. Even a very mild TBI vignette can elicit expectations of PCS symptoms.

Supply chain benefits expectation management framework

Organizations invest heavily in Supply Chain Management Systems expecting the benefits promised by the software vendors and the implementation partners. However, both academic and industry reports suggest that there is growing dissatisfaction among client organizations due to an increasing gap in benefits purported by the software vendors and benefits realised by the client. In order to better manage expectations of the client organization, this study proposes a Benefit Expectation Management Framework for Supply Chain Management Systems, based on Expectation-Confirmation Theory. This study derives 60 expected benefits of Supply Chain Management Systems through 41 vendor-reported customer stories and academic papers. Through comparing those benefits with the received benefits by a case organization that has implemented SAP Supply Chain Management Systems for seven years, two salient factors – long timetable and multiple stakeholders – have been identified as the controlling factors affecting the confirmation level of Supply Chain Management System expectations and further impacting the satisfaction of a client organization. The case study also highlights the likely causes for realized benefits and enduring issues in relation to the Supply Chain Management Systems.

Regression and hypothesis tests for multivariate GNSS state time series

A satellite based observation system can continuously or repeatedly generate a user state vector time series that may contain useful information. One typical example is the collection of International GNSS Services (IGS) station daily and weekly combined solutions. Another example is the epoch-by-epoch kinematic position time series of a receiver derived by a GPS real time kinematic (RTK) technique. Although some multivariate analysis techniques have been adopted to assess the noise characteristics of multivariate state time series, statistic testings are limited to univariate time series. After review of frequently used hypotheses test statistics in univariate analysis of GNSS state time series, the paper presents a number of T-squared multivariate analysis statistics for use in the analysis of multivariate GNSS state time series. These T-squared test statistics have taken the correlation between coordinate components into account, which is neglected in univariate analysis. Numerical analysis was conducted with the multi-year time series of an IGS station to schematically demonstrate the results from the multivariate hypothesis testing in comparison with the univariate hypothesis testing results. The results have demonstrated that, in general, the testing for multivariate mean shifts and outliers tends to reject less data samples than the testing for univariate mean shifts and outliers under the same confidence level. It is noted that neither univariate nor multivariate data analysis methods are intended to replace physical analysis. Instead, these should be treated as complementary statistical methods for a prior or posteriori investigations. Physical analysis is necessary subsequently to refine and interpret the results.

Disclosure obligations on ex parte application for freezing order - duty of practitioners to the court - failure to comply with duty - serious dereliction of duty to court - supplemental order for costs against solicitors personally

The decision of Applegarth J in Heartwood Architectural & Joinery Pty Ltd v Redchip Lawyers [2009] QSC 195 (27 July 2009) involved a costs order against solicitors personally. This decision is but one of several recent decisions in which the court has been persuaded that the circumstances justified costs orders against legal practitioners on the indemnity basis. These decisions serve as a reminder to practitioners of their disclosure obligations when seeking any interlocutory relief in an ex parte application. These obligations are now clearly set out in r 14.4 of the Legal Profession (Solicitors) Rule 2007 and r 25 of 2007 Barristers Rule. Inexperience or ignorance will not excuse breaches of the duties owed to the court.