Katherine E Sleeman

CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells

IntroductionBreast cancer is thought to arise in mammary epithelial stem cells. There is, therefore, a large amount of interest in identifying these cells. The breast is a complex tissue consisting of two epithelial layers (an outer myoepithelial/basal layer and an inner luminal epithelial layer) as well as a large non-epithelial component (fibroblasts, endothelial cells, lymphocytes, adipocytes, neurons and myocytes). The definitive identification of a mammary epithelial stem cell population is critically dependent on its purity. To date, this has been hampered by the lack of suitable markers to separate out the two epithelial layers, and to remove contaminating non-epithelial cells.MethodsMouse mammary glands were dissociated and stained with CD24. Cells were sorted into separate populations based on CD24 expression and assessed for luminal epithelial and myoepithelial/basal markers by direct fluorescent microscopy and real time PCR. The stem/progenitor potential of these cell populations was assessed in vivo by cleared mammary fat pad transplantation.ResultsThree populations of CD24 expressing cells were identified: CD24Negative, CD24Low and CD24High. Staining of these cells with cytokeratin markers revealed that these populations correspond to non-epithelial, myoepithelial/basal and luminal epithelial cells, respectively. Cell identities were confirmed by quantitative PCR. Cleared mammary fat pad transplantation of these cell populations revealed that extensive mammary fat pad repopulation capacity segregates with the CD24Low cells, whilst CD24High cells have limited repopulation capacity.ConclusionDifferential staining of mammary epithelial cells for CD24 can be used to simultaneously isolate pure populations of non-epithelial, myoepithelial/basal and luminal epithelial cells. Furthermore, mammary fat pad repopulation capacity is enriched in the CD24Low population. As separation is achieved using a single marker, it will be possible to incorporate additional markers to further subdivide these populations. This will considerably facilitate the further analysis of mammary epithelial subpopulations, whilst ensuring high purity, which is key for understanding mammary epithelial stem cells in normal tissue biology and carcinogenesis.

Reversal of English trend towards hospital death in dementia: a population-based study of place of death and associated individual and regional factors, 2001–2010

BackgroundEngland has one of the highest rates of hospital death in dementia in Europe. How this has changed over time is unknown. This study aimed to analyse temporal trends in place of death in dementia over a recent ten year period.MethodsPopulation-based study linking Office for National Statistics mortality data with regional variables, in England 2001–2010. Participants were adults aged over 60 with a death certificate mention of dementia. Multivariable Poisson regression was used to determine the proportion ratio (PR) for death in care home (1) and home/hospice (1) compared to hospital (0). Explanatory variables included individual factors (age, gender, marital status, underlying cause of death), and regional variables derived at area level (deprivation, care home bed provision, urbanisation).Results388,899 deaths were included. Most people died in care homes (55.3%) or hospitals (39.6%). A pattern of increasing hospital deaths reversed in 2006, with a subsequent decrease in hospital deaths (−0.93% per year, 95% CI −1.08 to −0.79 p < 0.001), and an increase in care home deaths (0.60% per year, 95% CI 0.45 to 0.75 p < 0.001). Care home death was more likely with older age (PR 1.11, 1.10 to 1.13), and in areas with greater care home bed provision (PR 1.82, 1.79 to 1.85) and affluence (PR 1.29, 1.26 to 1.31). Few patients died at home (4.8%) or hospice (0.3%). Home/hospice death was more likely in affluent areas (PR 1.23, 1.18 to 1.29), for women (PR 1.61, 1.56 to 1.65), and for those with cancer as underlying cause of death (PR 1.84, 1.77 to 1.91), and less likely in the unmarried (PRs 0.51 to 0.66).ConclusionsTwo in five people with dementia die in hospital. However, the trend towards increasing hospital deaths has reversed, and care home bed provision is key to sustain this. Home and hospice deaths are rare. Initiatives which aim to support the end of life preferences for people with dementia should be investigated.

Place of death, and its relation with underlying cause of death, in Parkinson’s disease, motor neurone disease, and multiple sclerosis: A population-based study

Background: Little is known about place of death in chronic neurological diseases. Mortality statistics are ideal for examining trends in place of death, but analyses are limited by coding rule changes. Aim: To examine the relationship between place of death and underlying cause of death in Parkinson’s disease, multiple sclerosis and motor neurone disease and the impact of coding rule changes on analysis of place of death. Design: Population-based study. Proportion ratios for death in hospice, home, care home and hospital were calculated according to underlying cause of death, using multivariable Poisson regression. Participants: Deaths in England (1993–2010) with any mention of Parkinson’s disease, multiple sclerosis or motor neurone disease as a cause of death, identified from national mortality data. Results: In this study, 125,242 patients with Parkinson’s disease, 23,501 with multiple sclerosis, and 27,030 with motor neurone disease were included. Home deaths ranged from 9.7% (Parkinson’s disease) to 27.1% (motor neurone disease), hospice deaths ranged from 0.6% (Parkinson’s disease) to 11.2% (motor neurone disease) and hospital deaths ranged from 43.4% (Parkinson’s disease) to 55.8% (multiple sclerosis). In Parkinson’s disease and multiple sclerosis, cancer as underlying cause of death increased likelihood of hospice death (proportion ratio (PR): 18.8, 95% confidence interval (CI) = 16.1–22.0; 8.88, 95% CI = 7.49–10.5) and home death (PR: 1.91, 95% CI = 1.80–2.04; 1.71, 95% CI = 1.56–1.88). Dementia as underlying cause of death increased likelihood of care home death in Parkinson’s disease (PR: 1.25, 95% CI = 1.19–1.32), multiple sclerosis (PR: 1.73, 95% CI = 1.22–2.45) and motor neurone disease (PR: 2.36, 95% CI = 1.31–4.27). Conclusions: Underlying cause of death has a marked effect on place of death. The effects of coding rule changes are an essential consideration for all research using underlying cause of death to study place of death.

The changing demographics of inpatient hospice death: Population-based cross-sectional study in England, 1993–2012

Background: Studies in the United Kingdom and elsewhere have suggested inequality of hospice provision with respect to factors such as age, diagnosis and socio-economic position. How this has changed over time is unknown. Aim: To describe the factors associated with inpatient hospice death in England and examine how these have changed over time. Design: Population-based study. Multivariable Poisson regression compared 1998–2002, 2003–2007 and 2008–2012, with 1993–1997. Explanatory variables included individual factors (age, gender, marital status, underlying cause of death) and area-based measures of deprivation. Setting: Adults aged 25 years and over who died in inpatient hospice units in England between 1993 and 2002 (n = 446,615). Results: The annual number of hospice deaths increased from 17,440 in 1993 to 26,032 in 2012, accounting for 3.4% of all deaths in 1993 and 6.0% in 2012. A total of 50.6% of hospice decedents were men; the mean age was 69.9 (standard deviation: 12.4) years. The likelihood of hospice decedents being in the oldest age group (>85 years) increased over time (proportion ratio: 1.43, 95% confidence interval: 1.39 to 1.48 for 2008–2012 compared to 1993–1997). Just 5.2% of all hospice decedents had non-cancer diagnoses, though the likelihood of non-cancer conditions increased over time (proportion ratio: 1.41, 95% confidence interval: 1.37 to 1.46 for 2008–2012 compared to 1993–1997). The likelihood of hospice decedents being resident in the least deprived quintile increased over time (proportion ratio: 1.25, 95% confidence interval: 1.22 to 1.29 for 2008–2012 compared to 1993–1997). Conclusion: The increase in non-cancer conditions among hospice decedents is encouraging although absolute numbers remain very small. Deprivation trends are concerning and require further exploration.

End-of-life communication: let's talk about death.

While some deaths occur suddenly, the majority of deaths are predictable, occurring after a period of chronic illness. All doctors will at some stage be required to care for patients who are dying and communication is the key to doing this well. Sadly, all too often this is not achieved. Indeed, more than half of NHS complaints are associated with care of the dying, many of them focused on information and communication. 2 Poor communication at the end of life can cause deep distress, both for the patient and their loved ones, and may adversely impact on post-bereavement outcomes. This was highlighted recently by the independent review into the Liverpool Care Pathway (LCP), an integrated care pathway designed to be used in the last days of life, and the subject of intensive media criticism following reports of poor end-of-life care. The independent review identified inadequate communication as responsible for much of the controversy and unhappiness surrounding care of the dying. 3 On the other hand, good communication allows patients and their families to make informed decisions about healthcare, to prepare for the future, and to express and meet their preferences for end-of-life care.

Reporting of clinically diagnosed dementia on death certificates: retrospective cohort study

Background: mortality statistics are a frequently used source of information on deaths in dementia but are limited by concerns over accuracy. Objective: to investigate the frequency with which clinically diagnosed dementia is recorded on death certificates, including predictive factors. Methods: a retrospective cohort study assembled using a large mental healthcare database in South London, linked to Office for National Statistics mortality data. People with a clinical diagnosis of dementia, aged 65 or older, who died between 2006 and 2013 were included. The main outcome was death certificate recording of dementia. Results: in total, 7,115 people were identified. Dementia was recorded on 3,815 (53.6%) death certificates. Frequency of dementia recording increased from 39.9% (2006) to 63.0% (2013) (odds ratio (OR) per year increment 1.11, 95% CI 1.07–1.15). Recording of dementia was more likely if people were older (OR per year increment 1.02, 95% CI 1.01–1.03), and for those who died in care homes (OR 1.89, 95% CI 1.50–2.40) or hospitals (OR 1.14, 95% CI 1.03–1.46) compared with home, and less likely for people with less severe cognitive impairment (OR 0.95, 95% CI 0.94–0.96), and if the diagnosis was Lewy body (OR 0.30, 95% CI 0.15–0.62) or vascular dementia (OR 0.79, 95% CI 0.68–0.93) compared with Alzheimers disease. Conclusions: changes in certification practices may have contributed to the rise in recorded prevalence of dementia from mortality data. However, mortality data still considerably underestimate the population burden of dementia. Potential biases affecting recording of dementia need to be taken into account when interpreting mortality data.

Caring for a dying patient in hospital

Recognising the dying phase shifts focus of care from disease management to the patient’s priorities and symptoms

The Liverpool care pathway: a cautionary tale

Its fate should serve to warn us of the dangers of implementing tools that are not properly evidence based

Research into end-of-life cancer care - investment is needed

www.thelancet.com Vol 379 February 11, 2012 519 of the eff ect of immunoadsorption in patients with HUS is still necessary after our report and whether the signal can be clearly discriminated from background noise. We have addressed this valid comment by calculating the so called rate ratio—a test for the signal-tonoise ratio. In our 12 patients, the rate ratio for immunoadsorption was 2·65 when improvements in neurological symptoms from 3 days before to 3 days after treatment were used (p=0·0003). Glasziou and colleagues suggest that a rate ratio above 5 virtually excludes mere coincidence or confounding factors. Although our case series is too small to meet this highest standard of evidence, we additionally applied the Bradford-Hill criteria to strengthen the level of evidence and found that our cohort passed this test. First, there was a clear temporal relation between immunoadsorption and resolution of symptoms; second, immuno adsorption repeatedly resulted in improvement of symptoms in the same patient; third, immuno adsorption and its positive eff ect is pathophysiologically plausible; fourth, we found a dose–response relation because an increasing number of treatment sessions improved neurological out come. With regard to the fi fth Bradford-Hill criterion, the specifi city of the treatment, we have to await the results of ongoing studies on the molecular mechanisms. The conclusions of our report are further supported by the additional patient in France reported by Christian Combe and colleagues. As to the question of why immunoadsorption is more eff ective in symptom relief than plasmapheresis, we would like to point to the fact that immunoadsorption removes 85% of patients’ IgG, whereas plasmapheresis removes only 40%. We agree with Roukens and Vandenbroucke that only a comparison of outcomes between HUS patients treated by immunoadsorption and For the online database of HUS patients see http://mcmicm. limeask.com/78534 those in whom immunoadsorption was not used will allow a conclusive assessment. Since HUS is a rare disease, a randomised study is unfeasible and the fi nal answer might only be achieved by a multi centre, multinational approach. For this purpose we have installed an online database to enable other centres to enter characteristics and outcome data of their HUS patients. Researchers should contact the corresponding author for an access key.

'It doesn't do the care for you': a qualitative study of health care professionals' perceptions of the benefits and harms of integrated care pathways for end of life care

Objectives To understand healthcare professionals’ perceptions of the benefits and potential harms of integrated care pathways for end-of-life care, to inform the development of future interventions that aim to improve care of the dying. Design Qualitative interview study with maximum variation sampling and thematic analysis. Participants 25 healthcare professionals, including doctors, nurses and allied health professionals, interviewed in 2009. Setting A 950-bed South London teaching hospital. Results 4 main themes emerged, each including 2 subthemes. Participants were divided between (1) those who described mainly the benefits of integrated care pathways, and (2) those who talked about potential harms. Benefits focused on processes of care, for example, clearer, consistent and comprehensive actions. The recipients of these benefits were staff members themselves, particularly juniors. For others, this perceived clarity was interpreted as of potential harm to patients, where over-reliance on paperwork lead to prescriptive, less thoughtful care, and an absolution from decision-making. Independent of their effects on patient care, integrated care pathways for dying had (3) a symbolic value: they legitimised death as a potential outcome and were used as a signal that the focus of care had changed. However, (4) a weak infrastructure, including scanty education and training in end-of-life care and a poor evidence base, that appeared to undermine the foundations on which the Liverpool Care Pathway was built. Conclusions The potential harms of integrated care pathways for the dying identified in this study were reminiscent of criticisms subsequently published by the Neuberger review. These data highlight: (1) the importance of collecting, reporting and using qualitative data when developing and evaluating complex interventions; (2) that comprehensive education and training in palliative care is critical for the success of any new intervention; (3) the need for future interventions to be grounded in patient-centred outcomes, not just processes of care.