Multiomics analysis of adaptation to repeated DNA damage in prostate cancer cells.

DNA damage is frequently utilized as the basis for cancer therapies; however, resistance to DNA damage remains one of the biggest challenges for successful treatment outcomes. Critically, the molecular drivers behind resistance are poorly understood. To address this question, we created an isogenic model of prostate cancer exhibiting more aggressive characteristics to better understand the molecular signatures associated with resistance and metastasis. 22Rv1 cells were repeatedly exposed to DNA damage daily for 6 weeks, similar to patient treatment regimes. Using Illumina Methylation EPIC arrays and RNA-seq, we compared DNA methylation and transcriptional profiles between the parental 22Rv1 cell line and the lineage exposed to prolonged DNA damage. Here we show that repeated DNA damage drives the molecular evolution of cancer cells to a more aggressive phenotype and identify molecular candidates behind this process. Total DNA methylation was increased while RNA-seq demonstrated these cells had dysregulated expression of genes involved in metabolism and the unfolded protein response (UPR) with Asparagine synthetase (ASNS) identified as central to this process. Despite the limited overlap between RNA-seq and DNA methylation, oxoglutarate dehydrogenase-like (OGDHL) was identified as altered in both data sets. Utilising a second approach we profiled the proteome in 22Rv1 cells following a single dose of radiotherapy. This analysis also highlighted the UPR in response to DNA damage. Together, these analyses identified dysregulation of metabolism and the UPR and identified ASNS and OGDHL as candidates for resistance to DNA damage. This work provides critical insight into molecular changes which underpin treatment resistance and metastasis.

The Griffiths Development Scales-Chinese (GDS-C): A cross-cultural comparison of developmental trajectories between Chinese and British children.

BACKGROUND: The Griffiths Mental Development Scales (GMDS) are used in many countries to assess the development of children from birth to 8 years. There is a need for accurate and culturally appropriate developmental assessment tools for Chinese children. Here, we adapted the GMDS for use in Chinese children and compare the developmental trajectories between Chinese and British children. METHODS: Children with typical development were recruited from 7 urban cities in China between 2009 and 2013. The Griffiths Mental Development Scales-Chinese (GDS-C) were adapted and used to assess the development of urban Chinese children. Developmental curves were computed for 6 subscales using learning management system methods and compare against the British curves from the Griffiths Mental Development Scales-Extended Revised (GMDS-ER). RESULTS: The GDS-C were used to assess the developmental status of 815 Chinese children. Plots of the 1st, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 99th percentiles, and full percentile tables were obtained, which showed similar trends to data from the British GMDS-ER. CONCLUSIONS: The Chinese developmental curves obtained from the GDS-C showed similarities and differences to the developmental curves from the British GMDS-ER. The development of urban Chinese children should be assessed with the culturally appropriate GDS-C.

Improving the mix of institutional and community care for older people with dementia: an application of the balance of care approach in eight European countries.

OBJECTIVES: To examine whether the mix of community and institutional long-term care (ILTC) for people with dementia (PwD) in Europe could be improved; assess the economic consequences of providing alternative services for particular groups of ILTC entrants and explore the transnational application of the 'Balance of Care' (BoC) approach. METHOD: A BoC study was undertaken in Estonia, Finland, France, Germany, the Netherlands, Spain, Sweden, and the UK as part of the RightTimePlaceCare project. Drawing on information about 2014 PwD on the margins of ILTC admission, this strategic planning framework identified people whose needs could be met in more than one setting, and compared the relative costs of the possible alternatives. RESULTS: The findings suggest a noteworthy minority of ILTC entrants could be more appropriately supported in the community if enhanced services were available. This would not necessarily require innovative services, but more standard care (including personal and day care), assuming quality was ensured. Potential cost savings were identified in all countries, but community care was not always cheaper than ILTC and the ability to release resources varied between nations. CONCLUSIONS: This is believed to be the first transnational application of the BoC approach, and demonstrates its potential to provide a consistent approach to planning across different health and social care systems. Better comparative information is needed on the number of ILTC entrants with dementia, unit costs and outcomes. Nevertheless, the findings offer important evidence on the appropriateness of current provision, and the opportunity to learn from different countries' experience.

Long term developmental outcomes of pre-school age children following laser surgery for twin-to-twin transfusion syndrome.

BACKGROUND: Laser therapy is now a well recognised treatment for twin-to-twin transfusion syndrome (TTTS). We investigated the early childhood neurodevelopmental outcome of children post laser treatment for TTTS in our centre. METHODS: Children of women who had laser therapy for TTTS between March 2006 and June 2008 were assessed at 30-69 months of age with WPPSI-III and a general health questionnaire. Major neurodevelopmental impairment (NDI) was reported as IQ<70 or cerebral palsy (CP). Borderline cognitive impairment was defined by IQ 70-79. RESULTS: Amongst the 37 pregnancies treated, 62 infants were discharged home and the overall foetal survival rate was 84%. A total of 50 children (84%) from 31 pregnancies were assessed. Average age at assessment was 47 months. Two children with late treatment of congenital hypothyroidism were excluded. The majority of pregnancies were Quintero Stage III (74%). There was a significant trend for worse outcome with higher Quintero stage. The average gestational age at birth was 32 weeks. The majority (39, 78%) of children were found to be neurodevelopmentally normal; 9 (18%) had borderline cognitive development; and 2 (4%) had a major NDI, including one with cerebral palsy (2%). CONCLUSIONS: There was a modest level of neurocognitive impairment post laser therapy for TTTS, mainly borderline cognitive development, lesser so major NDI. There was a low incidence of cerebral palsy. Routine developmental and neurological follow-up of these children is recommended.

Variations in structures, processes and outcomes of community mental health teams for older people: a systematic review of the literature.

OBJECTIVES: In the UK and elsewhere, specialist community mental health teams (CMHTs) are central to the provision of comprehensive services for older people with mental ill health. Recent guidance documents suggest a core set of attributes that such teams should encompass. This article reports on a systematic literature review undertaken to collate existing evidence regarding the structures and processes of CMHTs for older people and to evaluate evidence linking approaches to effectiveness. METHOD: Relevant publications were identified via systematic searches, both electronic and manual. Searches were limited to the UK for descriptions of organisation and practice but included international literature where comparisons between different CMHT arrangements were evaluated. Empirical, peer-reviewed studies from 1989 onward were included, extended to non peer-reviewed nationally or regionally representative reports, published after 1998, for the descriptive element. RESULTS: Forty-five studies met inclusion criteria of which seven provided comparative outcome data. All but one were UK based. The most robust evidence related to research conducted in exemplar teams. Limited evidence was found regarding the effectiveness of many of the core attributes recommended in policy directives although their presence was reported in much of the literature. CONCLUSIONS: The contrast between presentation and evaluation of attributes is stark. Whilst some gaps can be filled from related fields, further research is required that moves beyond description to evaluation of the impact of team design on service user outcomes in order to inform future policy directives and practice guidance. A framework for an evidence-based model of CMHTs for older people is provided.

Immediate outcome of twin-twin transfusion syndrome following selective laser photocoagulation of communicating vessels at the NSW Fetal Therapy Centre.

OBJECTIVE: To audit the outcome for laser photocoagulation for twin-twin transfusion syndrome (TTTS) as managed by the New South Wales Fetal Therapy Centre (NSW FTC). METHODS: A retrospective cohort study. Outcome data were reviewed for referrals between June 2003 and June 2008.The outcome measures included the severity of TTTS at presentation, delivery details (gestational age at delivery, birth weight and Apgar score at 5 min) and perinatal outcome (spontaneous miscarriage, premature rupture of membranes, intrauterine death, placental abruption and neonatal death). RESULTS: Seventy-nine patients were treated with laser therapy for stage I-IV TTTS (median stage III). Median gestational age at treatment was 20 weeks (range 16-25). Median gestational age at delivery was 32 weeks (range 24-40). Survival of at least one baby in this study was 90.7% (88.9% for anterior and 92.1% for posterior placenta), and of both babies was 60.0%. Median birth weight was 1788 g (range 490-3695). Median Apgar score was nine at 5 min. Three women required repeat laser treatment for persistent TTTS. CONCLUSIONS: Selective laser photocoagulation of communicating vessels remains the treatment of choice for TTTS. Referrals to the NSW FTC have increased from five cases in the last half of 2003, to 18 cases in the first half of 2008. Local outcome figures at least equal any in the published international literature and support a continued policy of centralised care in Australia. A two-year follow-up study on neonatal outcome for survivors is underway.

Reliability of needs assessments in the community care of older people: impact of the single assessment process in England.

BACKGROUND: The single assessment process (SAP) for older people, introduced in England across health and social care agencies from April 2004, aimed at improving assessment processes. We examined the impact of this policy in terms of the reliability of needs identification within statutory social services assessments. METHODS: An observational study compared the accuracy of needs identification in samples of older people before and after SAP introduction. Participants, at risk of entering care homes, were interviewed using standardized measures. Needs elicited from interviews were compared with those from statutory social services assessments to ascertain the reliability of needs identification at both times. Inter-rater reliabilities were calculated using the kappa (k) statistic. A Chi-squared statistic tested the equality of kappa values pre- and post-SAP. RESULTS: Most needs were identified more reliably after SAP introduction (range adjusted k = 0.05-0.58) than before (range adjusted k = -0.09 to 0.28), this being statistically significant for 9 out of 15 needs. Depression, and associated apathy, was an exception. CONCLUSION: Statutory social services assessments better captured need following the introduction of the SAP. However, the extent to which these findings can be attributed to SAP introduction is limited by the introduction of multiple policy initiatives throughout the study period.

UK self-care support initiatives for older patients with long-term conditions: a review.

OBJECTIVES: Supporting self-care for people with long-term conditions is an aim of UK health policy. As many with long-term conditions are older it is of interest to explore which self-care support interventions have positive impacts for this group. This review explores what types of intervention have been reported in the UK and their impact upon older people. METHODS: Studies were identified using existing reviews, electronic databases and through hand searching journals. After inclusion and exclusion criteria were applied data were extracted from 18 studies. These were summarized in a narrative synthesis supported by summary tables. RESULTS: All studies described interventions to support self-care, many targeted at people with arthritis. All used patient education, usually delivered to groups by a range of professionals. The majority of studies reported some significant positive outcomes, most frequently changes in physical functioning, illness knowledge and increased self-efficacy. The average age of participants was 60. DISCUSSION: This review shows that self-care interventions have had positive effects for older participants but it remains unknown how best to support self-care in participants over 75, a group of people with long-term conditions who may have different needs.

Granulomatous angiitis leading to a pulmonary veno-occlusive disease-like picture.

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension characterised by extensive fibrotic occlusion of pulmonary veins. PVOD has a similar insidious presentation to idiopathic pulmonary arterial hypertension but responds poorly to conventional therapies and has a worse prognosis. The current study reports the case of a Caucasian female with a long history of progressive dyspnoea ultimately diagnosed as focal granulomatous venulitis leading to a pulmonary veno-occlusive disease-like pathology. The present study highlights the challenges in diagnosing and treating this condition.

Identifying need in care homes for people with dementia: the relationship between two standard assessment tools.

Considerable effort has been invested in improving assessment processes for older people, some of the most vulnerable of whom live in care homes. The paper compares two well-known assessment tools used in care homes, the CANE and the Minimum Data Set/Resident Assessment Instrument. There was poor agreement between the tools in terms of domains of need covered. Nineteen pairs of items could be compared, with agreement greater than 60% found on 11 items. Of the 15 items where kappa could be computed, seven significant values were found. High levels of agreement existed in relation to behaviour, psychological wellbeing, mood state, psychotic symptoms, incontinence, mobility and inadvertent self-harm (risk). The study suggests that tools commonly used for assessment are not interchangeable and that the selection of assessment tool should be determined by the setting in which it is used, the needs of the population being assessed, the skills and knowledge of those undertaking the assessment and the purpose of the assessment itself.

The balance of care: reconfiguring services for older people with mental health problems.

The belief that most older people, including those with complex needs, can, and would prefer to be, cared for in their own homes underpins community care policy in many developed nations. There is thus a common desire to avoid the unnecessary or inappropriate placement of older people in care homes or in hospital by shifting the balance of provision. This paper demonstrates the utility of a 'balance of care' approach to address these issues in the context of commissioners' intention to reconfigure services for older people with mental health problems in a defined geographical area of the North West of England. The findings suggest that, if enhanced community services were available, a number of people currently admitted to residential or hospital beds could be more appropriately supported in their own homes at a cost that is no greater than local agencies currently incur.

The assessment of older people's needs in care homes.

In many countries there is a concern to improve assessment procedures for older people to avoid misplacement in nursing homes and ensure that rehabilitation takes place where possible. The study examined assessment documentation in 126 care homes in North West England. On a set of core domains for assessing need, the level of coverage varied considerably. The use of standardised scales was infrequent apart from those that measured risk of developing pressure sores. Some important key domains were infrequently mentioned on the assessment forms including mental health, pain, oral health and foot care. The most frequently covered items were the activities of daily living. There were clear differences in the assessment approaches employed in different types of home. The lack of inclusion of certain key health areas on some assessment forms suggests that the well-being and quality of life of some residents may be poorly addressed, and that further work is required for the standard of assessment in care homes to match that in community-based care.

Standards of care in home care services: a comparison of generic and specialist services for older people with dementia.

Current policy in England emphasises both the importance of caring for highly dependent older people for as long as possible in their own homes, and the development of specialist care services for people with dementia. However, the differences between specialist and generic home care services for people with dementia are poorly understood. This cross-sectional postal survey describes the standards of home care services for people with dementia in the North West of England, and investigates the differences in quality standards between specialist and generic home care services. Forty-six percent of identified services provided information on a range of quality indicators. Most services provided only a few of the indicators utilized by the study, and there was little evidence of services adopting national minimum standards. Few differences were found between the two service types, although generic services appeared to offer a greater degree of flexibility than specialist services. These results help to inform the understanding of home care service mix and provision, and the uptake of national minimum standards. They provide key material for shaping the future provision of home care for older people with dementia.

The use of assessment scales in Old Age Psychiatry Services in England and Northern Ireland.

Implementation of the Single Assessment Process in the UK is designed to ensure that more standardized assessment procedures are in place across all areas and agencies, that practice improves and older people's needs are comprehensively assessed. This study provides a unique picture of the range and prevalence of standardized scales used within Old Age Psychiatry Services in England and Northern Ireland, reported by 73% of old age psychiatrists. Most services (64%) used three or more standardized assessment scales (range 1-12). Sixty-two separate instruments were identified. The six most used measures were the Mini Mental State Examination (95%), the Geriatric Depression Scale (52%) and the Clock Drawing (50%), the Clifton Assessment Procedures for the elderly (26%), the Barthel Index (18%) and the Health of the Nation Outcome Scales (HoNOS) 65 + (18%). A number of factors were associated with greater use of certain standardized assessment scales. Shared documentation, along with other indicators of integration between health and social care were associated with greater use of standardized scales. The provision of a memory clinic was associated with greater use of neuropsychiatric scales and lower levels of use of cognitive scales. These results provide key material for shaping the provision of psychiatric services for older people

Does integration really make a difference? A comparison of old age psychiatry services in England and Northern Ireland.

OBJECTIVE: This paper seeks to address whether integrated structures are associated with more integrated forms of service. Northern Ireland has one of the most structurally integrated and comprehensive models of health and personal social services in Europe. Social and health services are jointly administered and this arrangement should, in theory, promote collaborative working and interdisciplinary arrangements. DESIGN: The study employed a cross-sectional survey of consultants in old age psychiatry in England and Northern Ireland. Potential respondents were sourced from the UK Royal College of Psychiatrists membership list and locally collected information. MEASURES: A self-administered postal questionnaire. Along with general service arrangements, the domains measured reflect core policy issues for older people's services. Under particular scrutiny in this study were the degree of integration of health and social service provision, as well as inter-professional team working. RESULTS: The integrated health and social care services in Northern Ireland do appear to provide more integrated patterns of working, primarily in managerial arrangements and in the location of staff. There was no evidence of the impact of integration on practice in areas such as: assessment, referral and medical screening. The factors found to be associated with greater integration of health and social care in the prediction model fell into three categories: provision of specialist services; provision of outreach activities; and shared policies by which the whole team worked. CONCLUSIONS: Health and personal social services in Northern Ireland have a distinct advantage over their counterparts in comparable areas of England. The results indicate that integrated structures in old age psychiatry services are associated more with integrated management systems and less with integrated practice-related activities. Further research is required on the effectiveness and cost effectiveness of integrating services in general. It is important that future intervention studies systematically measure the component parts, nature and extent of integration and their individual and joint contribution to the effectiveness and efficacy of services.

Anti-Mta associated with three cases of hemolytic disease of the newborn.

The Mta antigen is a low-frequency red blood cell (RBC) surface antigen and is an established antigen of the MNSs blood group system. There has been one report of anti-Mta-induced hemolytic disease of the newborn (HDN) in the literature to date. We describe a family in which three children were affected by neonatal anemia. The clinical and hematologic findings were consistent with HDN, despite repeatedly negative direct antiglobulin tests (DAT) on cord RBCs. Serologic investigations showed that the mother's serum contained anti-Mta. The father and all three children phenotyped as Mta+, while the mother was Mta-. Adsorption and elution experiments gave results which suggested that anti-Mta may be implicated in recurrent HDN in this family.

Intensive care-management at home: an alternative to institutional care?

BACKGROUND: Care management and assessment of need are the cornerstones of the community care reforms in the UK. Although much of the research base has been on highly vulnerable older people, in practice, care management has been implemented for a wider group. OBJECTIVE: To examine how intensive care-management at home has developed. DESIGN: Postal survey of all local authority social services departments in England. METHOD: We used an overview questionnaire (85% response) and an old-age services questionnaire (77% response). We classified local authorities according to the presence or absence of seven indicators of intensive care management at home. RESULTS: 97% of social services departments had a goal of providing a community-based alternative to residential and nursing-home care. However, only 5% had specialist intensive care-management services for older people. Other key indicators of intensive care-management, such as devolved budgets, health service care managers, small caseloads and clear eligibility criteria, were uncommon. CONCLUSIONS: There was little evidence of intensive care-management at home in older peoples' services. This is of concern, given the move towards community-based provision for frail older people. Closer links between secondary health-care services (such as geriatric medicine) and intensive care-management at home may promote more effective care at home for those who are most vulnerable.

Care management and the care programme approach: towards integration in old age mental health services.

OBJECTIVE: To examine the relationship between care management arrangements and the Care Programme Approach (CPA) in the context of old age mental health services and, particularly, dementia services. METHOD: The information reported is from a national study of care management arrangements, funded by the Department of Health. A response rate of 77% was obtained from local authority social services departments. RESULTS: In old age mental health services over half of the respondents reported joint screening arrangements for health and social care, almost four-fifths reported both joint criteria for the allocation of key workers and a clear definition of monitoring responsibilities. Of the latter over two-fifths were reported as being the same in care management and the CPA. Forty-six per cent of respondents provided a specialist service for people with dementia. Three-fifths of respondents reported that they did not apply CPA to people with dementia who were in receipt of care management or did so in less than 20% of cases. Where the CPA was applied it was more likely that a priority would be accorded to care management. A quarter of respondents reported the shared use of assessment documentation for people with dementia. DISCUSSION: The findings are set in the context of service developments to date and the implementation of the two systems of community based coordinated care for older people with mental health problems. Inter-authority variations are noted and the potential for greater service integration within the current legislative framework assessed.