LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer.

Lysine-specific demethylase 1 (LSD1 or KDM1A ) has emerged as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Among mCRPC subtypes, neuroendocrine prostate cancer (NEPC) is an exceptionally aggressive variant driven by lineage plasticity, an adaptive resistance mechanism to androgen receptor axis-targeted therapies. Our study shows that LSD1 expression is elevated in NEPC and associated with unfavorable clinical outcomes. Using genetic approaches, we validated the on-target effects of LSD1 inhibition across various models. We investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor with low nanomolar potency. Our findings demonstrate potent antitumor activity against CRPC models, including tumor regressions in NEPC patient-derived xenografts. Mechanistically, our study uncovers that LSD1 inhibition suppresses the neuronal transcriptional program by downregulating ASCL1 through disrupting LSD1:INSM1 interactions and de-repressing YAP1 silencing. Our data support the clinical development of LSD1 inhibitors for treating CRPC - especially the aggressive NE phenotype. Statement of Significance: Neuroendocrine prostate cancer presents a clinical challenge due to the lack of effective treatments. Our research demonstrates that bomedemstat, a potent and selective LSD1 inhibitor, effectively combats neuroendocrine prostate cancer by downregulating the ASCL1- dependent NE transcriptional program and re-expressing YAP1.

Frailty among Older Adults and Its Distribution in England.

BACKGROUND: Information on the spatial distribution of the frail population is crucial to inform service planning in health and social care. OBJECTIVES: To estimate small-area frailty prevalence among older adults using survey data. To assess whether prevalence differs between urban, rural, coastal and inland areas of England. DESIGN: Using data from the English Longitudinal Study of Ageing (ELSA), ordinal logistic regression was used to predict the probability of frailty, according to age, sex and area deprivation. Probabilities were applied to demographic and economic information in 2020 population projections to estimate the district-level prevalence of frailty. RESULTS: The prevalence of frailty in adults aged 50+ (2020) in England was estimated to be 8.1 [95% CI 7.3-8.8]%. We found substantial geographic variation, with the prevalence of frailty varying by a factor of 4.0 [3.5-4.4] between the most and least frail areas. A higher prevalence of frailty was found for urban than rural areas, and coastal than inland areas. There are widespread geographic inequalities in healthy ageing in England, with older people in urban and coastal areas disproportionately frail relative to those in rural and inland areas. CONCLUSIONS: Interventions aimed at reducing inequalities in healthy ageing should be targeted at urban and coastal areas, where the greatest benefit may be achieved.

Closing the UK care home data gap - methodological challenges and solutions.

UK care home residents are invisible in national datasets. The COVID-19 pandemic has exposed data failings that have hindered service development and research for years. Fundamental gaps, in terms of population and service demographics coupled with difficulties identifying the population in routine data are a significant limitation. These challenges are a key factor underpinning the failure to provide timely and responsive policy decisions to support care homes. In this commentary we propose changes that could address this data gap, priorities include: (1) Reliable identification of care home residents and their tenure; (2) Common identifiers to facilitate linkage between data sources from different sectors; (3) Individual-level, anonymised data inclusive of mortality irrespective of where death occurs; (4) Investment in capacity for large-scale, anonymised linked data analysis within social care working in partnership with academics; (5) Recognition of the need for collaborative working to use novel data sources, working to understand their meaning and ensure correct interpretation; (6) Better integration of information governance, enabling safe access for legitimate analyses from all relevant sectors; (7) A core national dataset for care homes developed in collaboration with key stakeholders to support integrated care delivery, service planning, commissioning, policy and research. Our suggestions are immediately actionable with political will and investment. We should seize this opportunity to capitalise on the spotlight the pandemic has thrown on the vulnerable populations living in care homes to invest in data-informed approaches to support care, evidence-based policy making and research.

Impact of social care supply on healthcare utilisation by older adults: a systematic review and meta-analysis.

Objective: to investigate the impact of the availability and supply of social care on healthcare utilisation (HCU) by older adults in high income countries. Design: systematic review and meta-analysis. Data sources: medline, EMBASE, Scopus, Health Management Information Consortium, Cochrane Database of Systematic Reviews, NIHR Health Technology Assessment, NHS Economic Evaluation Database, Database of Abstracts of Reviews of Effectiveness, SCIE Online and ASSIA. Searches were carried out October 2016 (updated April 2017 and May 2018). (PROSPERO CRD42016050772). Study selection: observational studies from high income countries, published after 2000 examining the relationship between the availability of social care (support at home or in care homes with or without nursing) and healthcare utilisation by adults >60 years. Studies were quality assessed. Results: twelve studies were included from 11,757 citations; ten were eligible for meta-analysis. Most studies (7/12) were from the UK. All reported analysis of administrative data. Seven studies were rated good in quality, one fair and four poor. Higher social care expenditure and greater availability of nursing and residential care were associated with fewer hospital readmissions, fewer delayed discharges, reduced length of stay and expenditure on secondary healthcare services. The overall direction of evidence was consistent, but effect sizes could not be confidently quantified. Little evidence examined the influence of home-based social care, and no data was found on primary care use. Conclusions: adequate availability of social care has the potential to reduce demand on secondary health services. At a time of financial stringencies, this is an important message for policy-makers.

Making the most of routine data in palliative care research--a case study analysis of linked hospital and mortality data on cancer and heart failure patients in Scotland and Oxford.

The research base of palliative care is growing rapidly, but despite methodological advances, some of the practical challenges of working with people at the end of life will persist. This means that analysis of routine data is arguably more important in studying palliative care than it is in other aspects of health services research. End-of-life researchers have been using the high-quality linked data from cancer registries for many years. This paper explores the value of a less well-known resource for palliative care research: linked mortality and hospital activity data. Two case studies are presented using information from Scotland (population 5.1 million) and the former Oxford region of England (population 2.5 million). The advantages and limitations of linked hospital and mortality data for research and service planning in palliative care are drawn out through analyses investigating hospital bed utilisation by people with cancer and heart failure and the influence of social deprivation on the use of hospital services in the last year of life. The use of such data deserves a higher profile.

Socioeconomic differences in service use, payment and receipt of illness-related benefits in the last year of life: findings from the British Household Panel Survey.

BACKGROUND: Terminal illness presents a financial challenge to many households, but in Britain the situation should be eased by state benefits, such as attendance allowance, which is available to everyone in the last six months of life without means testing. AIM: To investigate the use of health and social services, payments and benefit receipt by individuals in differing financial circumstances in the year before death. METHODS: Analysis of individual level panel data for 1652 community-dwelling decedents from 12 waves of the British Household Panel Study (1991-2003). RESULTS: In the year before death, over 90% of decedents saw their GP, and around one-third spent some time in hospital. More than 80% paid no fees for any services. Over a third of decedents aged over 65 reported financial strain, but only 13.9% of these were receiving attendance allowance. People who felt that they were having financial difficulties were more likely to be frequent attenders in primary care, taking age, health status and other factors into account (adjusted OR=1.9, 95% CI=1.3-2.6, P<0.001). Older age was associated with less use of primary, but not secondary care. CONCLUSIONS: Financial strain was common, but benefit uptake low. Primary health care professionals saw nearly all decedents in their last year, and could play an important role in ensuring that the elderly and the less well off are aware of the services and benefits available to them.

A case of pseudoarthrosis of the lateral talar process and distal fibula in a professional athlete.

We report a case of osteoarthritis of a pseudoarthrosis between the tip of the fibula and the lateral process of the talus. This was treated by excision of pseudoarthrosis with lateral ligament reconstruction.

The influence of posterior condylar offset on knee flexion after total knee replacement using a cruciate-sacrificing mobile-bearing implant.

We have studied the concept of posterior condylar offset and the importance of its restoration on the maximum range of knee flexion after posterior-cruciate-ligament-retaining total knee replacement (TKR). We measured the difference in the posterior condylar offset before and one year after operation in 69 patients who had undergone a primary cruciate-sacrificing mobile bearing TKR by one surgeon using the same implant and a standardised operating technique. In all the patients true pre- and post-operative lateral radiographs had been taken. The mean pre- and post-operative posterior condylar offset was 25.9 mm (21 to 35) and 26.9 mm (21 to 34), respectively. The mean difference in posterior condylar offset was + 1 mm (-6 to +5). The mean pre-operative knee flexion was 111 degrees (62 degrees to 146 degrees) and at one year postoperatively, it was 107 degrees (51 degrees to 137 degrees). There was no statistical correlation between the change in knee flexion and the difference in the posterior condylar offset after TKR (Pearson correlation coefficient r = -0.06, p = 0.69).

The cemented custom femoral stem--a 10 year review.

We report a series of 706 patients (759 hip implants) with an average follow up of 10.5 years (range, 10-11 years) following total hip replacement (THR) using a cemented custom-made femoral stem and a cemented HDP acetabular component. The fate of every implant is known. One hundred and seventy-four patients (23%) were deceased at the time of their 10-year review all died with a functioning THR in situ. Four hundred and sixty-two patients (61%) were subsequently reviewed. One hundred and twenty three patients (16%) were assessed by telephone review, as they were too ill or unwilling to attend. Kaplan-Meier survival analysis (all components) demonstrated a median survival at 10 years of 96.05% or 95% Confidence Intervals (CI) for median survival of (94.41% to 97.22%). Revision surgery occurred in 30 cases (3.9%). Seventeen had full revisions (2.2%) and 13 (1.7%) socket revisions only. Twenty-one out of 30 revisions were for infection or dislocation. There were 2 cases (0.3%) of revision for aseptic loosening of the stem. The 10-year results of the custom femoral titanium stem are encouraging and compare well with other cemented systems.

The effect of physical activity advice given in routine primary care consultations: a systematic review.

BACKGROUND: Recent evidence and recommendations suggest that physical activity health promotion should be aimed at persuading the whole population to adopt an active lifestyle. Intensive medical programmes aimed at promoting physical activity amongst those at risk are not effective at achieving this aim. Brief advice from primary care professionals to quit smoking has a small but, at a population level, important effect. Brief advice in primary care to adopt a more active lifestyle may be similarly effective. The aim of this review is to determine the effect of advice given in routine primary care consultations on levels of physical activity. METHODS: A systematic review was carried out of trials assessing the effectiveness of advice given in routine primary care consultations. Data sources were four electronic databases (MEDLINE, EMBASE, Sport discus, Cochrane Library), and bibliographies of retrieved papers were searched. Experts were contacted. RESULTS: Eight trials, with a total of 4747 participants, were identified; the majority were from the United States. Outcome measures varied considerably between trials, including continuous measures (e.g. duration of exercise) and dichotomous measures (e.g. being active), therefore statistical pooling was inappropriate. Two of the trials were cluster randomized controlled trials, the remainder were quasi-experimental. None of the trials fulfilled all of the predetermined quality criteria and selection bias in the nonrandomized studies may have exaggerated results. Four of the six trials that presented short-term (up to 8 weeks) results found advice to be effective; only one of the four trials with long-term follow-up (4-12 months) found a sustained effect. The two randomized controlled trials had negative short- and long-term results. CONCLUSIONS: From the available evidence it appears that advice in routine primary care consultations is not an effective means of producing sustained increases in physical activity. However, these results may not be applicable to the United Kingdom, where the structure of primary care is unique. Quality research in UK primary care would be valuable.

Invasive M-type 3 Streptococcus pyogenes affecting a family and a residential home.

This paper describes the first recognised United Kingdom outbreak of M-type 3 streptococci for 12 years. Four epidemiologically-linked invasive infections occurred in a residential home in northern England over two weeks. The index patient was admitted from home with necrotising fasciitis of the leg. Infection was subsequently detected in her husband (fatal pneumonia) another resident (fatal pneumonia) and a member of the care staff (parapharyngeal abscess). Screening of staff and residents in the home did not reveal any further infection or carriage. There is a substantial risk of serious secondary infection amongst the contacts of a patient with invasive Streptococcus pyogenes infection. Guidance is lacking, but needed, on the advisability of chemoprophylaxis in these circumstances.

UK measles outbreak in non-immune anthroposophic communities: the implications for the elimination of measles from Europe.

We describe the epidemiology of the first nationwide outbreak of measles infection in the UK since the implementation of a mass vaccination campaign. Notifications of infectious diseases, interview and postal questionnaire identified 293 clinical cases, 138 of which were confirmed by salivary IgM, measles virus isolation and PCR. Twelve were epidemiologically linked to confirmed cases. The outbreak began in London, after contact with measles infection probably imported from Italy. Measles genotyping determined by sequence analysis confirmed spread to other unimmunized anthroposophic communities in the north, south west and south coast of England. Only two cases had been vaccinated against measles infection, and 90% of cases were aged under 15 years. Measles virus can selectively target non-immune groups in countries with high vaccine uptake and broader herd immunity. Without harmonization of vaccination policies and uniform high coverage across Europe, the importation and spread of measles virus amongst non-immune groups may prevent the elimination of measles.

Sex differences in risk factors, treatment and mortality after acute myocardial infarction: an observational study.

BACKGROUND: Coronary heart disease is the major cause of death of postmenopausal women in industrialised countries. Although acute myocardial infarction (AMI) affects men in greater numbers, the short-term outcomes for women are worse. In the longer term, studies suggest that mortality risk for women is lower or similar to that of men. However, length of follow up and adjustment for confounding factors have varied and more importantly, the association between treatment and outcomes has not been examined. STUDY OBJECTIVE: To investigate the association between sex differences in risk factors and hospital treatment and mortality after AMI. DESIGN: A prospective observational study collecting demographic and clinical data on cases of AMI admitted to hospitals in Yorkshire. The main outcome measures were mortality status at discharge from hospital and two years later. SETTING: All district and university hospitals accepting emergency admissions in the former Yorkshire National Health Service (NHS) region of northern England. PARTICIPANTS: 3684 consecutive patients with a possible diagnosis of AMI admitted to hospitals in Yorkshire between 1 September and 30 November 1995. MAIN RESULTS: AMI was confirmed by the attending consultant for 2196 admissions (2153 people, 850 women and 1303 men). Women were older and less likely than men to be smokers or have a history of ischaemic heart disease. Crude inhospital mortality was higher for women (30% versus 19% for men, crude odds ratio of death before discharge for women 1.78, 95% confidence intervals 1.46, 2.18, p=0.00). This difference persisted after adjustment for age, risk factors and comorbidities (adjusted OR 1.29, 95% CI 1.04, 1.63, p=0.02), but was not significant when treatment was taken into account. Women were less likely to be given thrombolysis (37% versus 46%, p<0.01) and aspirin (83% versus 90%, p<0.01), discharged with beta blockers (33% versus 47%, p<0.01) and aspirin (82% versus 88% p<0.01) or be scheduled for angiography, exercise testing or revascularisation. Adjustment for age removed much of the disparity in treatment. Crude mortality rate at two years was higher for women (OR 1.81, 95%CI 1.41, 2.31, p=0.00). Age, existing risk factors and acute treatment accounted for most of this difference, with treatment on discharge having little additional influence. CONCLUSIONS: Patients admitted to hospital with AMI should be offered optimal treatment irrespective of age or sex. Women have a worse prognosis after AMI and under-treatment of older people with aspirin and thrombolysis may be contributing to this.

Palliative care provided by GPs: the carer's viewpoint.

As most terminal and palliative care is in the community, general practitioners (GPs) have an important role to play. This study presents bereaved carers' views of the palliative care provided by GPs. It suggests that symptom control may not be optimal.

Effective management of the elderly hearing impaired--a review.

In the United Kingdom, two and a half million people over 70 are thought to have hearing impairment that would benefit from an aid. Only one-third of these will possess one, and as many as 10 per cent probably never use their aid. Although it is important to examine the relative merits of different aids, there is also a need to look at how audiological services may reduce the unmet need that results from underuse of aids. This review examines the important question of 'what is the most effective way of providing hearing aids for the elderly affected by presbyacusis?' Extensive searching of four electronic databases and hand searching of relevant journals revealed the paucity of evidence to guide audiology practice. In particular there is little consensus on the best outcome measures for evaluating audiological rehabilitation or hearing aid fitting. Audiological services for the elderly are another example of an area where there is a need to fund research and development rather than continue to commission services that are variable and poorly evaluated.

Referrals to the Marie Curie nursing service in North Yorkshire.

District and Marie Curie nurses participated in a small-scale study to describe referrals to a Marie Curie service in one English health district over a 3-month period. The number of new patients referred was small; they were geographically clustered and had widely differing life expectancies. Anecdotal reports of difficulties with the 'Nurselink' referral system were not confirmed, and in situations where the system was in operation, Marie Curie nurses were more likely to speak directly to the referring nurse. The most frequently cited reason for referral was general nursing needs; however, Marie Curie nurses felt that they were most often involved to provide family support. These findings suggest that there may not be a shared understanding of the Marie Curie nurse's role, and that equity in community palliative nursing care merits examination. Defining and publicizing the role of the Marie Curie nurse, providing guidance for referrals and prioritizing communication between professionals are proposed not only to enhance the service locally but to ensure that the service is available to all. This article illustrates the value of research to identify ways to improve service delivery.