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Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies presents a major clinical problem. Although preclinical studies have identified a number of possible mechanisms, clinical validation has been difficult. This is most likely to reflect the reliance on cell-line models that do not recapitulate the complexity and heterogeneity seen in human tumours. Here, we show the utility of a genetically engineered mouse model of HER2-driven breast cancer (MMTV-NIC) to define mechanisms of resistance to the pan-HER family inhibitor AZD8931. Genetic manipulation of MMTV-NIC mice demonstrated that loss of phosphatase and tensin homologue (PTEN) conferred de novo resistance to AZD8931, and a tumour fragment transplantation model was established to assess mechanisms of acquired resistance. Using this approach, 50% of tumours developed resistance to AZD8931. Analysis of the resistant tumours showed two distinct patterns of resistance: tumours in which reduced membranous HER2 expression was associated with an epithelial-to-mesenchymal transition (EMT) and resistant tumours that retained HER2 expression and an epithelial morphology. The plasticity of the EMT phenotype was demonstrated upon re-implantation of resistant tumours that then showed a mixed epithelial and mesenchymal phenotype. Further AZD8931 treatment resulted in the generation of secondary resistant tumours that again had either undergone EMT or retained their original epithelial morphology. The data provide a strong rationale for basing therapeutic decisions on the biology of the individual resistant tumour, which can be very different from that of the primary tumour and will be specific to individual patients.

In this note, we consider a two-class priority queueing system with Poisson arrivals, general service time distribution and one server, in which customers that are not currently being served may leave the queue according to exponentially distributed patience times, i.e., a M 1 , M 2 / G /1 + M system using a generalised Kendall’s notation. We expand the classic methodology to derive analytical formulas for the completion times in such a system, using preemptive repeat different and preemptive repeat identical disciplines. Known average completion times for priority queues without impatience are retrieved as limit cases.

With an ageing population and the constant need towards improving the quality of life for older people in our society, there comes an urgent challenge to support people where they live in an environment that adapts to their needs as they age. While much research on ubiquitous sensor systems and telehealth devices focuses on this need, many of these solutions operate at less than full capacity, and with little scope at present to assess everyday aspects of wellbeing. They focus on detecting sudden critical physiological and behavioural changes and offer few mechanisms to support preventative actions. The challenge of predicting changes and prompting positive preventative intervention measures, aiding the avoidance of severe physical or mental harm, has not adequately been addressed. This paper discusses our experiences of designing, deploying and testing an integrated home-based ambient assisted living (AAL) system for older adults, consisting of ambient monitoring, behaviour recognition and feedback to support self-management of wellness, in addition to providing feedback on home security and home energy. It offers a complete system overview of an AAL solution in smart environments and discusses our lessons learned with the goal of assisting other researchers in the field in designing and deploying similar environments.

AbstractExposure to ambient air pollution has been consistently associated with respiratory and cardiovascular disease. However, the neurological effects of air pollution have received little attention. It is suggested that the components of air pollution, such as particulate matter (PM) and specifically ultrafine particulate matter (UFP), may have the potential to extend beyond pulmonary organs to the central nervous system (CNS) and, ultimately, the brain. The transport mechanisms are not clear, although at least four possible routes have been proposed implicating PM and UFP in neurological disease processes. A limited number of studies have been undertaken to assess the role of PM and UFP in CNS diseases, including migraine, headache, stroke, Alzheimer’s disease, and Parkinson’s disease. Considering the high prevalence of such CNS diseases, along with the frequent and increasing exposure to ambient air pollution, it is important to highlight possible associations with regards to preventative, monitoring, and control measures. This article aimed to review the literature in relation to translocation routes of PM and UFP and their potential role in neurological disease processes.

The nature of compensation for women who donate eggs (oocytes) for research remains a contentious issue internationally. This position paper lays out the arguments for, and discusses the arrangements in which, a modest payment might be ethically justifiable.

Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time.

Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs).

Purpose:The aim of this study was to investigate the uptake of genetic testing by at-risk family members for four genetic conditions: chromosomal translocations, fragile X syndrome, Huntington disease, and spinal muscular atrophy.Methods:A clinical audit was undertaken using genetics files from Genetic Health Services Victoria. Data were extracted from the files regarding the number of at-risk family members and the proportion tested. Information was also collected about whether discussion of at-risk family members and family communication during the genetic consultation was recorded.Results:The proportion of at-risk family members who had genetic testing ranged from 11% to 18%. First-degree family members were most frequently tested and the proportion of testing decreased by degree of relatedness to the proband. Smaller families were significantly more likely to have genetic testing for all conditions except Huntington disease. Female at-risk family members were significantly more likely to have testing for fragile X syndrome.Conclusion:The majority of at-risk family members do not have genetic testing. Family communication is likely to influence the uptake of genetic testing by at-risk family members and therefore it is important that families are supported while communicating to ensure that at-risk family members are able to make informed decisions about genetic testing.Genet Med 2012:14(1):122–128

The communication of genetic information in families is an important process which can inform family members that they are at risk. However, evidence suggests that atrisk family members are often uninformed. Genetic health professionals have a role to assist consultands to communicate genetic information to their family members. Therefore, the aim of this study was to investigate genetic health professionals practice with regard to the familial implications of a genetic diagnosis and subsequent family communication. An online survey resulted in 626 responses from genetic health professionals internationally. The results indicated that over 90 of genetic health professionals consistently counsel consultands about the familial implications of a genetic diagnosis during a consultation. Also there were no major differences in practice between clinical geneticists and genetic counselors. An average of 79 of genetic health professionals always send a summary letter to the consultand after a consultation. In contrast, 41 of genetic health professionals never write letters for atrisk family members. Other support is available to consultands after a consultation, but the availability of support relies on consultands and family members acting proactively and seeking out assistance from genetic health professionals for family communication. This may result in family members who are unaware that they are at risk of carrying andor developing a genetic condition. This study is limited by the selfselection and selfreporting of the respondents practice. © 2010 WileyLiss, Inc.

ObjectiveWe investigated pathological emotionalism in a large cohort of patients that had presented with autoimmune limbic encephalitis(a-LE).Methods38 patients in the post-acute phase of a-LE completed questionnaires probing emotion regula- tion. They all underwent structural/functional MRI post-acutely, along with age- and sex-matched healthy controls. We investigated correlations of questionnaire scores with demographic, clinical, neuropsycho- logical and brain MRI data across patients. We also compared patients with pathological emotionalism and those without, along with healthy controls, on grey matter volume, resting-state functional connec- tivity and activity.ResultsPathological emotionalism was reported by 50% of the patients. It was not associated with depres- sion, impulsiveness, or memory impairment. However, it correlated with abnormalities in specific emotional brain networks: volume reduction in the anterior hippocampus, fusiform gyrus and cerebellum, abnormal hippocampal resting-state functional connectivity with the posteromedial cortex and middle frontal gyrus, and abnormal hemodynamic activity in the fusiform gyrus, inferior parietal lobule, and ventral pons.ConclusionsPathological emotionalism is common following a-LE, is not a manifestation of other neu- ropsychiatric disorders, and reflects abnormalities in networks of emotion regulation including, but not limited to the acute hippocampal focus. This condition provides novel insights into the neural basis of emotion regulation and its dysfunction in disease.christopher.butler@imperial.ac.uk

To investigate whether first trimester exposure to lamotrigine (LTG) monotherapy is specifically associated with an increased risk of orofacial clefts (OCs) relative to other malformations, in response to a signal regarding increased OC risk.

AbstractObjective:There is a paucity of literature on the content of referral letters to psychiatric services and few relating specifically to referrals to a department of old age psychiatry. There has been a significant increase in referrals over the last five years to this service, which may reflect the ageing population and a greater awareness of the service. Our objective was to evaluate the quality and legibility of information received, clarity of reason for referral and details of pre-referral management.Methodology:The clinical records of the first 100 referrals in 2002 to this department were analysed. The referral letters were examined for the documentation of a number of demographic variables, reason for referral, interventions to date and level of urgency.Results:The clinical records of nine patients did not have an identifiable referral letter at the time of this analysis. Of the remaining 91 analysed, 59% were referred by their GP, 33% were inpatient liaison referrals and 8% from outpatient departments. In the majority, patients' details were given, however, only 30% included a phone number. Next-of-kin was mentioned in 29%. GP's name was included in 71% of referrals from OPD and 7% of liaison referrals. The level of urgency was stated in 19%. Whether a domiciliary or OPD visit would be more appropriate was stated in 22%. The reason for referral was clear in 75%, with 43% including some aspect of Mental State Examination, 7% had included a MMSE score, 1% mentioned level of suicide risk.Thirty-one per cent had pre-referral investigations and 45% had pre-referral treatment documented. The letters were clearly legible in 73%.Conclusion:The information in the referral letter in many cases was insufficient to prioritise and expedite appropriate assessment. It is planned to introduce a proforma referral form, specific to old age psychiatry, which would include the information which is required and which would, hopefully, lead to a more efficient service.

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly/mental retardation syndrome consisting of characteristic dysmorphic features, microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay, and a variety of associated malformations. We present a population‐based epidemiological study of the classical form of CdLS. The data were extracted from the database of European Surveillance of Congenital Anomalies (EUROCAT) database, a European network of birth defect registries which follow a standard methodology. Based on 23 years of epidemiologic monitoring (8,558,346 births in the 1980–2002 period), we found the prevalence of the classical form of CdLS to be 1.24/100,000 births or 1:81,000 births and estimated the overall CdLS prevalence at 1.6–2.2/100,000. Live born children accounted for 91.5% (97/106) of cases, fetal deaths 2.8% (3/106), and terminations of pregnancy following prenatal diagnosis 5.7% (6/106). The most frequent associated congenital malformations were limb defects (73.1%), congenital heart defects (45.6%), central nervous system malformations (40.2%), and cleft palate (21.7%). In the last 11 years, as much as 68% of cases with major malformations were not detected by routine prenatal US. Live born infants with CdLS have a high first week survival (91.4%). All patients were sporadic. Maternal and paternal age did not seem to be risk factors for CdLS. Almost 70% of patients, born after the 37th week of gestation, weighed ≤2,500 g. Low birth weight correlated with a more severe phenotype. Severe limb anomalies were significantly more often present in males. © 2007 Wiley‐Liss, Inc.

To describe treatment, survival, and morbidity for liveborn infants with isolated transposition of great arteries (TGA).

There has been considerable recent interest in the literature on the impact of the internet on the internationalisation processes of SMEs. This contribution reports the findings of a four-country study on how internationalising Australian, Canadian, Irish and New Zealand firms utilise the internet. The findings suggest that SMEs in all countries use it extensively for communication purposes and make fairly widespread use of the internet for business processes, marketing and product development purposes, competitor analysis and market intelligence gathering. However, low usage is found in terms of online transactions and supply chain management. From these results, the authors conclude that many rapidly internationalising SMEs do not follow 'stages' of internet adoption suggested by many of the extant e-adoption models.

Over the last decade there has been escalating debate regarding the competency of patients with psychoses to give informed consent to participate in research. This debate has been made evermore complex by variations in the definition and evaluation of competency. Importantly, competency must meet both medical and legal standards, although the criteria for each of these are not always consistent and may be mediated by contextual factors. The matter of competency to give informed consent is further complicated in the case of patients with psychoses. As a result of their disorder, patients with psychoses develop a mental state where there is impairment of reality appreciation. The impact on competency however, is highly variable and can frequently be accommodated in the consent process. Establishing associations between particular psychotic symptoms and their severity, with competency to consent at different levels of risk is the central theme of research currently being conducted.

Examines some of the Australian legislative provisions that attempt to prohibit or to control the creation of human embryos by reproductive cloning. Commonwealth Gene Technology Act 2000; Victorian Infertility Treatment Act 1995; Western Australian Human Reproductive Technology Act 1991.

Aberrations in the components of cell‐cycle checkpoints are a common feature of many tumours and several have been shown to have prognostic significance in colorectal cancer. In this study, seven components of cell‐cycle control [cyclin D1, retinoblastoma (pRb), p21, p27, p16, p53, and proliferating cell nuclear antigen (PCNA)] were examined in a large series of well‐characterized colorectal adenocarcinomas using immunohistochemistry to ascertain co‐regulation and influence on survival. The majority (92%) of the tumours had abnormal staining of ⩾2 cell‐cycle control factors. Expression of cyclin D1 protein was correlated with both p21 (p<0.001) and p27 (p=0.033), suggesting co‐regulation of these proteins in colorectal tumours. Only cyclin D1 (p=0.048) and p53 (p=0.025) were directly associated with PCNA levels, suggesting a more important role in the proliferative capacity of tumour cells. Significant associations between cell cycle‐related proteins and clinicopathological data were observed: cyclin D1 and p53 proteins were correlated with patient age (p=0.042 and p<0.001, respectively) and p53 (p=0.01) and p21 (p=0.024) proteins were associated with tumour site. Expression of cyclin D1 protein was the only protein examined that was related to improved outcome in these patients (p=0.0266), but itwas not an independent predictor of survival. These results suggest that loss of control of cell‐cycle checkpoints is a common occurrence in colorectal tumours and may be an important therapeutic target. Copyright © 2002 John Wiley & Sons, Ltd.

This paper examines the law on the proprietary rights of people in respect of their bodies, body parts and tissue. Proprietary rights include rights of ownership and control, The paper argues that the context in which judicial decisions are made and policy recommendations are developed sometimes results in a patchwork of legal principles. Being aware of the context in which different aspects of the law have been developed enables us to understand why principles have been developed, what is needed to reconcile them and how we can establish a coherent regulatory regime. The paper then proposes such a scheme to deal with property and control rights in this area. It argues that people (or the personal representatives of people who have died) should have a personal autonomy right to be consulted about the use of their corpse or their excised body parts or tissue in teaching, research and commercialisation of biological inventions, and to refuse or to impose conditions. They should not, however, have a right of ultimate ownership in their corpse, body parts or tissue, except for the limited right of personal representatives to gain possession of bodies and body parts of people who have died for burial or cremation if they so wish. That right should not extend to tissue preserved on slides, in paraffin wax or similar format. That tissue should be subject to proprietary interests in favour only of the hospital, research institute, its staff or the people to whom they transfer it. The same rule should apply to bodies or body parts held by a hospital or research institute with the consent of the person concerned, though the bodies or body parts may ultimately have to be returned for burial or cremation. Tissue removed under a statutory requirement without consent, such as for coronial investigation or forensic tests, should be used only for the purposes prescribed by the relevant legislation.

AbstractTelehealth is an exciting new technique for improving access to specialist care, especially in underserviced areas. As with any new health care intervention, proper evaluations must be carried out to ensure that limited health care resources are employed appropriately. Evidence suggests that the most successful telehealth initiatives are those that have focussed on organisational and deployment issues, rather than on the technology itself. In the right circumstances, telehealth offers a cost-effective alternative to the traditional methods of health care delivery.Copyright © 2001 S. Karger AG, Basel

• We examine the ethical principles underpinning advance directives (ADs) and the legal duties of doctors in determining their validity. • A physician attending an incompetent patient with an acute life‐threatening illness, and an AD refusing treatment, should ensure that the AD is legally valid before making the treatment decision. • Treatment against a patient's wishes, as expressed in a valid AD, compromises patient autonomy and may constitute battery. Conversely, withholding treatment in accordance with an AD that is not legally valid risks substantial harm to the patient and may constitute breach of the duty of care and negligence. • Legally valid directives should be respected. If an AD is not legally valid, the patient should be treated in his or her best interests. If uncertain, the physician should treat according to the patient's best interests while seeking legal advice.

Although maternal death is rare in the UK, 90% (510 of 566 deaths) of women who died during or within a year after pregnancy in 2016–18 had multiple health and social problems (MBRRACE-UK). This study aims to estimate the prevalence of pre-existing multimorbidity in pregnant women in the UK.

Leaking blebs may be encountered in the early postoperative period, or months to years after filtering surgery. Early postoperative bleb leaks are most often related to surgical trauma to the conjunctiva and can be avoided by careful surgical technique. Spontaneous late bleb leaks occur more frequently in glaucoma filtering surgery following adjunctive use of antimetabolites and full-thickness procedures. As we endeavor to achieve better long-term success with filtering surgery, antimetabolites have gained increasing popularity. With this change in clinical practice, a higher rate of bleb leaks is being recognized. These leaks may be uncomplicated or may be associated with sight-threatening complications such as endophthalmitis. The plethora of treatment options for bleb leaks described in the literature reflects the widespread nature of this problem. It also reflects the failure of any one particular approach not only to resolve bleb leaks but also to prevent their recurrence. This paper reviews the contemporary surgical management of leaking blebs and formulates a practical approach to their management.