Setting Priorities to Inform Assessment of Care Homes' Readiness to Participate in Healthcare Innovation: A Systematic Mapping Review and Consensus Process.

Organisational context is known to impact on the successful implementation of healthcare initiatives in care homes. We undertook a systematic mapping review to examine whether researchers have considered organisational context when planning, conducting, and reporting the implementation of healthcare innovations in care homes. Review data were mapped against the Alberta Context Tool, which was designed to assess organizational context in care homes. The review included 56 papers. No studies involved a systematic assessment of organisational context prior to implementation, but many provided post hoc explanations of how organisational context affected the success or otherwise of the innovation. Factors identified to explain a lack of success included poor senior staff engagement, non-alignment with care home culture, limited staff capacity to engage, and low levels of participation from health professionals such as general practitioners (GPs). Thirty-five stakeholders participated in workshops to discuss findings and develop questions for assessing care home readiness to participate in innovations. Ten questions were developed to initiate conversations between innovators and care home staff to support research and implementation. This framework can help researchers initiate discussions about health-related innovation. This will begin to address the gap between implementation theory and practice.

Improving living and dying for people with advanced dementia living in care homes: a realist review of Namaste Care and other multisensory interventions.

BACKGROUND: Seventy percent of people with advanced dementia live and die in care homes. Multisensory approaches, such as Namaste Care, have been developed to improve the quality of life and dying for people with advanced dementia but little is known about effectiveness or optimum delivery. The aim of this review was to develop an explanatory account of how the Namaste Care intervention might work, on what outcomes, and in what circumstances. METHODS: This is a realist review involving scoping of the literature and stakeholder interviews to develop theoretical explanations of how interventions might work, systematic searches of the evidence to test and develop the theories, and their validation with a purposive sample of stakeholders. Twenty stakeholders - user/patient representatives, dementia care providers, care home staff, researchers -took part in interviews and/or workshops. RESULTS: We included 85 papers. Eight focused on Namaste Care and the remainder on other types of sensory interventions such as music therapy or massage. We identified three context-mechanism-outcome configurations which together provide an explanatory account of what needs to be in place for Namaste Care to work for people living with advanced dementia. This includes: providing structured access to social and physical stimulation, equipping care home staff to cope effectively with complex behaviours and variable responses, and providing a framework for person-centred care. A key overarching theme concerned the importance of activities that enabled the development of moments of connection for people with advanced dementia. CONCLUSIONS: This realist review provides a coherent account of how Namaste Care, and other multisensory interventions might work. It provides practitioners and researchers with a framework to judge the feasibility and likely success of Namaste Care in long term settings. Key for staff and residents is that the intervention triggers feelings of familiarity, reassurance, engagement and connection. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016047512.

Have radiographic progression rates in early rheumatoid arthritis changed? A systematic review and meta-analysis of long-term cohorts.

OBJECTIVE: To evaluate, firstly, all published data on baseline and annual progression rates of radiographic damage from all longitudinal observational cohorts, and secondly, the association of standard clinical and laboratory parameters with long-term radiographic joint damage. METHODS: A comprehensive search of the literature from 1975 to 2014, using PubMed, SCOPUS and Cochrane databases, identified a total of 28 studies that investigated long-term radiographic progression, and 41 studies investigating predictors of long-term radiographic progression. This was submitted and approved by PROSPERO in February 2014 (Registration Number: CRD42014007589). RESULTS: Meta-analysis indicated an overall baseline rate of 2.02%, and a yearly increase of 1.08% of maximum damage. Stratified analysis found that baseline radiographic scores did not differ significantly between cohorts recruiting patients pre- and post-1990 (2.01% vs 2.03%; P > 0.01); however, the annual rate of progression was significantly reduced in the post-1990 cohorts (0.68% vs 1.50%; P < 0.05). High levels of acute phase markers, baseline radiographic damage, anti-CCP and RF positivity remain consistently predictive of long-term radiographic joint damage. CONCLUSION: Critical changes in treatment practices over the last three decades are likely to explain the reduction in the long-term progression of structural joint damage. Acute phase markers and presence of RF/anti-CCP are strongly associated with increased radiographic progression.

The size, burden and cost of disorders of the brain in the UK.

AIM: The aim of this paper is to increase awareness of the prevalence and cost of psychiatric and neurological disorders (brain disorders) in the UK. METHOD: UK data for 18 brain disorders were extracted from a systematic review of European epidemiological data and prevalence rates and the costs of each disorder were summarized (2010 values). RESULTS: There were approximately 45 million cases of brain disorders in the UK, with a cost of €134 billion per annum. The most prevalent were headache, anxiety disorders, sleep disorders, mood disorders and somatoform disorders. However, the five most costly disorders (€ million) were: dementia: €22,164; psychotic disorders: €16,717; mood disorders: €19,238; addiction: €11,719; anxiety disorders: €11,687. Apart from psychosis, these five disorders ranked amongst those with the lowest direct medical expenditure per subject (<€3000). The approximate breakdown of costs was: 50% indirect costs, 25% direct non-medical and 25% direct healthcare costs. DISCUSSION: The prevalence and cost of UK brain disorders is likely to increase given the ageing population. Translational neurosciences research has the potential to develop more effective treatments but is underfunded. Addressing the clinical and economic challenges posed by brain disorders requires a coordinated effort at an EU and national level to transform the current scientific, healthcare and educational agenda.

Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1.

Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase-arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterized by dispersed chromosomes and disorganized bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation combined with high expression of mitotic cyclins and EZH2 predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature cyclin-dependent kinase (CDK)1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor combinations represent a promising targeted therapy.

Functional viability profiles of breast cancer.

UNLABELLED: The design of targeted therapeutic strategies for cancer has largely been driven by the identification of tumor-specific genetic changes. However, the large number of genetic alterations present in tumor cells means that it is difficult to discriminate between genes that are critical for maintaining the disease state and those that are merely coincidental. Even when critical genes can be identified, directly targeting these is often challenging, meaning that alternative strategies such as exploiting synthetic lethality may be beneficial. To address these issues, we have carried out a functional genetic screen in >30 commonly used models of breast cancer to identify genes critical to the growth of specific breast cancer subtypes. In particular, we describe potential new therapeutic targets for PTEN-mutated cancers and for estrogen receptor-positive breast cancers. We also show that large-scale functional profiling allows the classification of breast cancers into subgroups distinct from established subtypes. SIGNIFICANCE: Despite the wealth of molecular profiling data that describe breast tumors and breast tumor cell models, our understanding of the fundamental genetic dependencies in this disease is relatively poor. Using high-throughput RNA interference screening of a series of pharmacologically tractable genes, we have generated comprehensive functional viability profiles for a wide panel of commonly used breast tumor cell models. Analysis of these profiles identifies a series of novel genetic dependencies, including that of PTEN-null breast tumor cells upon mitotic checkpoint kinases, and provides a framework upon which additional dependencies and candidate therapeutic targets may be identified.

FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo.

PURPOSE: The oncogenic drivers of triple-negative (TN) and basal-like breast cancers are largely unknown. Substantial evidence now links aberrant signaling by the fibroblast growth factor receptors (FGFR) to the development of multiple cancer types. Here, we examined the role of FGFR signaling in TN breast cancer. EXPERIMENTAL DESIGN: We examined the sensitivity of a panel of 31 breast cancer cell lines to the selective FGFR inhibitor PD173074 and investigated the potential mechanisms underlying sensitivity. RESULTS: TN breast cancer cell lines were more sensitive to PD173074 than comparator cell lines (P = 0.011), with 47% (7/15) of TN cell lines showing significantly reduced growth. The majority of TN cell lines showed only modest sensitivity to FGFR inhibition in two-dimensional growth but were highly sensitive in anchorage-independent conditions. PD173074 inhibited downstream mitogen-activated protein kinase and PI3K-AKT signaling and induced cell-cycle arrest and apoptosis. Basal-like breast cancer cell lines were found to express FGF2 ligand (11/21 positive) and, similarly, 62% of basal-like breast cancers expressed FGF2, as assessed by immunohistochemistry compared with 5% of nonbasal breast cancers (P < 0.0001). RNA interference targeting of FGF2 in basal-like cell lines significantly reduced growth in vitro and reduced down stream signaling, suggesting an autocrine FGF2 signaling loop. Treatment with PD173074 significantly reduced the growth of CAL51 basal-like breast cancer cell line xenografts in vivo. CONCLUSIONS: Basal-like breast cancer cell lines, and breast cancers, express autocrine FGF2 and show sensitivity to FGFR inhibitors, identifying a potential novel therapeutic approach for these cancers.

Stereology and ultrastructure of chronic phase axonal and cell soma pathology in stretch-injured central nerve fibers.

Magnetic resonance imaging (MRI) suggests that with survival after human traumatic brain injury (TBI), there is ongoing loss of white and grey matter from the injured brain during the chronic phase. However; direct quantitative experimental evidence in support of this observation is lacking. Using the guinea pig stretch-injury optic nerve model, quantitative evidence by stereology of damage to the optic nerve and retina was sought. Stretch injury was applied to the right optic nerve of 15 adult male guinea pigs. Three animals each at 1, 2, 3, 8, or 12 weeks' survival were killed and prepared for transmission electron microscopy (TEM). The estimated number of intact and injured axons within bins of transverse diameters 0-0.5, 0.51-1.0, 1.01-1.5, 1.51-2.0, 2.01-2.5, and 2.51-3.0 µm in the middle segment of each injured optic nerve and from 5 control animals were compared across all survival time points. The estimated numbers of intact and pyknotic retinal ganglion cells from the same animals were also compared. Loss of myelinated fibers continued throughout the experimental period. The most rapid loss was of the largest fibers; loss of intermediate-sized fibers continued, but the numbers of the smallest fibers increased from 3 weeks onward. There was hypertrophy and proliferation of glial cells within the surrounding neuropil. A relatively low-grade loss of retinal ganglion cells occurred throughout the experiment, with about 60% remaining at 12 weeks' survival. We provide quantitative evidence that after traumatic axonal injury (TAI) there is a continuing loss of nerve fibers and their cell bodies from a CNS tract over a 3-month post-traumatic interval.

FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer.

Amplification of fibroblast growth factor receptor 1 (FGFR1) occurs in approximately 10% of breast cancers and is associated with poor prognosis. However, it is uncertain whether overexpression of FGFR1 is causally linked to the poor prognosis of amplified cancers. Here, we show that FGFR1 overexpression is robustly associated with FGFR1 amplification in two independent series of breast cancers. Breast cancer cell lines with FGFR1 overexpression and amplification show enhanced ligand-dependent signaling, with increased activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase-AKT signaling pathways in response to FGF2, but also show basal ligand-independent signaling, and are dependent on FGFR signaling for anchorage-independent growth. FGFR1-amplified cell lines show resistance to 4-hydroxytamoxifen, which is reversed by small interfering RNA silencing of FGFR1, suggesting that FGFR1 overexpression also promotes endocrine therapy resistance. FGFR1 signaling suppresses progesterone receptor (PR) expression in vitro, and likewise, amplified cancers are frequently PR negative, identifying a potential biomarker for FGFR1 activity. Furthermore, we show that amplified cancers have a high proliferative rate assessed by Ki67 staining and that FGFR1 amplification is found in 16% to 27% of luminal B-type breast cancers. Our data suggest that amplification and overexpression of FGFR1 may be a major contributor to poor prognosis in luminal-type breast cancers, driving anchorage-independent proliferation and endocrine therapy resistance.

Nefazodone in the treatment of patients with post-traumatic stress disorder.

Post-traumatic stress disorder occurs in patients who have undergone a traumatic experience and manifests itself through a cluster of symptoms, including re-experiencing, avoidance and hyperarousal. Post-traumatic stress disorder is commonly found among veterans of war and victims of sexual trauma, natural disasters and accidents. Nefazodone is a medication that has an FDA-approved indication for treating depression. Nefazodone has also been reported to be efficacious in treating post-traumatic stress disorder. Despite recent reports of hepatotoxicity, when used appropriately, nefazodone is generally as well-tolerated as the medications currently FDA-indicated for post-traumatic stress disorder, the selective serotonin reuptake inhibitors. Through its mechanism inhibiting neuronal uptake of serotonin and norepinephrine and as a potent postsynaptic serotonergic antagonist, nefazodone has proven to be effective in treating post-traumatic stress disorder in several open-label trials. The results of such trials warrant its study in larger, double-blind, placebo-controlled clinical trials.