Effective health care for older people living and dying in care homes: A realist review

Background: Care home residents in England have variable access to health care services. There is currently no coherent policy or consensus about the best arrangements to meet these needs. The purpose of this review was to explore the evidence for how different service delivery models for care home residents support and/or improve wellbeing and health-related outcomes in older people living and dying in care homes. Methods: We conceptualised models of health care provision to care homes as complex interventions. We used a realist review approach to develop a preliminary understanding of what supported good health care provision to care homes. We completed a scoping of the literature and interviewed National Health Service and Local Authority commissioners, providers of services to care homes, representatives from the Regulator, care home managers, residents and their families. We used these data to develop theoretical propositions to be tested in the literature to explain why an intervention may be effective in some situations and not others. We searched electronic databases and related grey literature. Finally the findings were reviewed with an external advisory group. Results: Strategies that support and sustain relational working between care home staff and visiting health care professionals explained the observed differences in how health care interventions were accepted and embedded into care home practice. Actions that encouraged visiting health care professionals and care home staff jointly to identify, plan and implement care home appropriate protocols for care, when supported by ongoing facilitation from visiting clinicians, were important. Contextual factors such as financial incentives or sanctions, agreed protocols, clinical expertise and structured approaches to assessment and care planning could support relational working to occur, but of themselves appeared insufficient to achieve change. Conclusion: How relational working is structured between health and care home staff is key to whether health service interventions achieve health related outcomes for residents and their respective organisations. The belief that either paying clinicians to do more in care homes and/or investing in training of care home staff is sufficient for better outcomes was not supported.This research was funded by National Institute of Health Research Health Service Delivery and Research programme (HSDR 11/021/02)

Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers

Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

The absorption of vitamin E is influenced by the amount of fat in a meal and the food matrix

Vitamin E absorption requires the presence of fat; however, limited information exists on the influence of fat quantity on optimal absorption. In the present study we compared the absorption of stable-isotope-labelled vitamin E following meals of varying fat content and source. In a randomised four-way cross-over study, eight healthy individuals consumed a capsule containing 150 mg H-2-labelled RRR-alpha-tocopheryl acetate with a test meal of toast with butter (17.5 g fat), cereal with full-fat milk (17.5 g fat), cereal with semi-skimmed milk (2.7 g fat) and water (0g fat). Blood was taken at 0, 0.5, 1, 1.5, 2, 3, 6 and 9 h following ingestion, chylomicrons were isolated, and H-2-labelled alpha-tocopherol was analysed in the chylomicron and plasma samples. There was a significant time (P<0.001) and treatment effect (P<0.001) in H-2-labelled alpha-tocopherol concentration in both chylomicrons and plasma between the test meals. H-2-labelled alpha-tocopherol concentration was significantly greater with the higher-fat toast and butter meal compared with the low-fat cereal meal or water (P< 0.001), and a trend towards greater concentration compared with the high-fat cereal meal (P= 0.065). There was significantly greater H-2-labelled &alpha;-tocopherol concentration with the high-fat cereal meal compared with the low-fat cereal meal (P< 0.05). The H-2-labelled alpha-tocopherol concentration following either the low-fat cereal meal or water was low. These results demonstrate that both the amount of fat and the food matrix influence vitamin E absorption. These factors should be considered by consumers and for future vitamin E intervention studies

Innovative approach for increasing physical activity among breast cancer survivors: protocol for Project MOVE, a quasi-experimental study

Physical activity is a cost-effective and non-pharmaceutical strategy that can help mitigate the physical and psychological health challenges associated with breast cancer survivorship. However, up to 70% of women breast cancer survivors are not meeting minimum recommended physical activity guidelines. Project MOVE is an innovative approach to increase physical activity among breast cancer survivors through the use of Action Grants, a combination of microgrants (small amounts of money awarded to groups of individuals to support a physical activity initiative) and financial incentives. The purpose of this paper is to describe the rationale and protocol of Project MOVE

A preliminary trial examining a ‘real world’ approach for increasing physical activity among breast cancer survivors: findings from project MOVE

Background: Physical activity (PA) is a safe and effective strategy to help mitigate health challenges associated with breast cancer (BC) survivorship. However, the majority of BC survivors are not meeting the minimum recommended PA (≥150 min of moderate to vigorous intensity). Project MOVE was developed as a model for increasing PA that combined a) Microgrants: funds ($2000) awarded to applicant groups to develop and implement a PA initiative and b) Financial incentives: a reward ($500) for increasing group PA. The purpose of this paper was to provide an exploratory analysis of effectiveness of Project MOVE on PA behavior, PA motivation, and quality of life (QoL) in female BC survivors. The differential outcomes between women meeting and not meeting PA guidelines were also investigated. Methods: This pre-post test, preliminary trial included groups of adult (18+ years) self-identified female BC survivors, who were post-surgery and primary systemic chemo- and radiation therapy, and living in British Columbia, Canada. PA was assessed by accelerometry. PA motivation and QoL were assessed by self-report. Data were collected at baseline, 6-months, and 12-month time points. Repeated measures mixed ANOVAs were used to test changes in the main outcomes. Results: A total of 10 groups were awarded microgrants between May 2015 and January 2016. Groups comprised of 8 to 12 women with a total of 87 participants. A statistically significant increase was found between time points on weekly moderate to vigorous PA (p = .012). This was mediated by a significant interaction between those meeting PA guidelines and those not meeting guidelines at baseline by time points (p = .004), with those not meeting guidelines at baseline showing the greatest increase in MVPA. A statistically significant difference across time points was found for intrinsic motivation (p = .02), physical functioning (p < .001), physical health limitations (p = .001), emotional health limitations (p = .023), social functioning (p = .001) and general health (p = .004). Conclusion: These results provide promising support for a unique approach to increasing PA among BC survivors by empowering women and optimizing PA experiences through the use of microgrants and financial incentives. Trial registration: ClinicalTrials.gov NCT03548636 , Retrospectively registered June 7, 2018.Health and Social Development, Faculty of (Okanagan)Medicine, Faculty ofOther UBCNon UBCHealth and Exercise Sciences, School of (Okanagan)Nursing, School of (Okanagan)Physical Therapy, Department ofPopulation and Public Health (SPPH), School ofReviewedFacult

The effect of metformin vs placebo on sex hormones in CCTG MA.32.

BACKGROUND Metformin has been associated with lower breast cancer risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones (SHs). We evaluated the effect of metformin on SHs in MA.32, a phase III trial of nondiabetic BC subjects randomized to metformin or placebo. METHODS We studied the subgroup of post-menopausal hormone receptor negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after randomization. Sex hormone binding globulin (SHBG), bioavailable testosterone (BT) and estradiol levels were assayed using ECLIA (electrochemiluminescense immunoassay). Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. RESULTS 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2 negative BC and had received (neo)adjuvant chemotherapy. Mean age ± SD was 58.1±6.9 vs 57.5±7.9 years, mean BMI was 27.3±5.2 vs 28.9±6.4 kg/m2 for metformin vs placebo respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; p < 0.001) in univariable analysis and after controlling for baseline BMI and BMI change (p < 0.001). There was no change in SHBG or BT. CONCLUSION Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers