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Background: Agitation is a common, challenging symptom affecting large numbers of people with dementia and impacting on quality of life (QoL). There is an urgent need for evidence-based, cost-effective psychosocial interventions to improve these outcomes, particularly in the absence of safe, effective pharmacological therapies. This study aimed to evaluate the efficacy of a person-centred care and psychosocial intervention incorporating an antipsychotic review, WHELD, on QoL, agitation, and antipsychotic use in people with dementia living in nursing homes, and to determine its cost.Methods and Findings: This was a randomised controlled cluster trial conducted between 1 January 2013 and 30 September 2015 that compared the WHELD intervention with treatment as usual (TAU) in people with dementia living in 69 UK nursing homes, using an intention to treat analysis. All nursing homes allocated to the intervention received staff training in person-centred care and social interaction and education regarding antipsychotic medications (antipsychotic review), followed by ongoing delivery through a care staff champion model. The primary outcome measure was QoL (DEMQOL-Proxy). Secondary outcomes were agitation (Cohen-Mansfield Agitation Inventory [CMAI]), neuropsychiatric symptoms (Neuropsychiatric Inventory-Nursing Home Version [NPI-NH]), antipsychotic use, global deterioration (Clinical Dementia Rating), mood (Cornell Scale for Depression in Dementia), unmet needs (Camberwell Assessment of Need for the Elderly), mortality, quality of interactions (Quality of Interactions Scale [QUIS]), pain (Abbey Pain Scale), and cost. Costs were calculated using cost function figures compared with usual costs. In all, 847 people were randomised to WHELD or TAU, of whom 553 completed the 9-month randomised controlled trial. The intervention conferred a statistically significant improvement in QoL (DEMQOL-Proxy Z score 2.82, p = 0.0042; mean difference 2.54, SEM 0.88; 95% CI 0.81, 4.28; Cohen's D effect size 0.24). There were also statistically significant benefits in agitation (CMAI Z score 2.68, p = 0.0076; mean difference 4.27, SEM 1.59; 95% CI -7.39, -1.15; Cohen's D 0.23) and overall neuropsychiatric symptoms (NPI-NH Z score 3.52, p < 0.001; mean difference 4.55, SEM 1.28; 95% CI -7.07,-2.02; Cohen's D 0.30). Benefits were greatest in people with moderately severe dementia. There was a statistically significant benefit in positive care interactions as measured by QUIS (19.7% increase, SEM 8.94; 95% CI 2.12, 37.16, p = 0.03; Cohen's D 0.55). There were no statistically significant differences between WHELD and TAU for the other outcomes. A sensitivity analysis using a pre-specified imputation model confirmed statistically significant benefits in DEMQOL-Proxy, CMAI, and NPI-NH outcomes with the WHELD intervention. Antipsychotic drug use was at a low stable level in both treatment groups, and the intervention did not reduce use. The WHELD intervention reduced cost compared to TAU, and the benefits achieved were therefore associated with a cost saving. The main limitation was that antipsychotic review was based on augmenting processes within care homes to trigger medical review and did not in this study involve proactive primary care education. An additional limitation was the inherent challenge of assessing QoL in this patient group.Conclusions: These findings suggest that the WHELD intervention confers benefits in terms of QoL, agitation, and neuropsychiatric symptoms, albeit with relatively small effect sizes, as well as cost saving in a model that can readily be implemented in nursing homes. Future work should consider how to facilitate sustainability of the intervention in this setting.Trial Registration: ISRCTN Registry ISRCTN62237498. [ABSTRACT FROM AUTHOR]

Background Pain is common in people with dementia, yet identification is challenging. A number of pain assessment tools exist, utilizing observation of pain-related behaviours, vocalizations and facial expressions. Whilst they have been developed robustly, these often lack sufficient evidence of psychometric properties, like reliability, face and construct validity, responsiveness and usability, and are not internationally implemented. The EU-COST initiative "Pain in impaired cognition, especially dementia" aims to combine the expertise of clinicians and researchers to address this important issue by building on previous research in the area, identifying existing pain assessment tools for dementia, and developing consensus for items for a new universal meta-tool for use in research and clinical settings. This paper reports on the initial phase of this collaboration task. Methods All existing observational pain behaviour tools were identified and elements categorised using a three-step reduction process. Selection and refinement of items for the draft Pain Assessment in Impaired Cognition (PAIC) meta-tool was achieved through scrutiny of the evidence, consensus of expert opinion, frequency of use and alignment with the American Geriatric Society guidelines. The main aim of this process was to identify key items with potential empirical, rather than theoretical value to take forward for testing. Results 12 eligible assessment tools were identified, and pain items categorised according to behaviour, facial expression and vocalisation according to the AGS guidelines (Domains 1 - 3). This has been refined to create the PAIC meta-tool for validation and further refinement. A decision was made to create a supporting comprehensive toolkit to support the core assessment tool to provide additional resources for the assessment of overlapping symptoms in dementia, including AGS domains four to six, identification of specific types of pain and assessment of duration and location of pain. Conclusions This multidisciplinary, cross-cultural initiative has created a draft meta-tool for capturing pain behaviour to be used across languages and culture, based on the most promising items used in existing tools. The draft PAIC meta-tool will now be taken forward for evaluation according to COSMIN guidelines and the EU-COST protocol in order to exclude invalid items, refine included items and optimise the meta-tool. [ABSTRACT FROM AUTHOR]

There are around 35 million people worldwide with dementia, more than half of whom have Alzheimer's disease (AD). Presently there are only four licensed pharmacological treatments available for treating the neuropsychological symptoms of AD. These include cholinesterase inhibitors, licensed for the treatment of people with mild to moderate AD, and an N-methyl-D-aspartate antagonist (memantine) licensed for the treatment of people with moderate to severe AD. These treatment options have modest symptomatic benefits for at least 6 months and possibly for 2 years or longer. Increasing evidence from randomized controlled trials has shown the potential value of cognitive training and cognitive rehabilitation in people with AD. There is a good evidence base to support the use of cognitive stimulation as a nonpharmacological treatment approach for people with AD, of which the most promising is cognitive stimulation therapy (CST). CST has shown benefits for cognition and well-being in people with dementia across a number of randomized controlled trials. There are important key issues related to the use of CST for people with AD, such as long-term benefits, implementation of individualized CST, adjunctive benefits with pharmacological treatments, and optimizing overall implementation of CST. Some of these key issues are already being addressed by ongoing clinical trials. Nevertheless, the strength of the current evidence from randomized controlled trials gives strong support to clinical implementation of CST in practice. Ongoing clinical trials will help to reine and optimize the use of CST in clinical practice. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery. [ABSTRACT FROM AUTHOR]

Many elderly people experience pain and regularly take analgesic medication. Pain is also frequent in people with dementia, particularly those with severe disease. As no robust clinical guidelines are available for the treatment of pain in the context of dementia, the risk of inadequate treatment in individuals with this condition is high. Furthermore, our understanding of the aetiology of pain and the potential role of dementia-associated neuropathology in pain is limited. These issues are important in the clinical management of individuals with dementia, as untreated pain is a major contributor to reduced quality of life and disability, and can lead to increased behavioural and psychological symptoms. Assessment scales to identify pain in people with dementia have been highlighted in recent studies, but there is little evidence for consistency between these tools. Numerous studies have evaluated various approaches for the treatment of pain, including stepped-care protocols and/or administration of paracetamol and opioid medications. In this Review, we summarize the best-available evidence regarding the aetiology, assessment and treatment of pain in people with dementia. Further validation of assessment tools and large-scale trials of treatment approaches in people with dementia are needed to improve clinical guidance for the treatment of pain in these individuals. [ABSTRACT FROM AUTHOR]

Many elderly people experience pain and regularly take analgesic medication. Pain is also frequent in people with dementia, particularly those with severe disease. As no robust clinical guidelines are available for the treatment of pain in the context of dementia, the risk of inadequate treatment in individuals with this condition is high. Furthermore, our understanding of the aetiology of pain and the potential role of dementia-associated neuropathology in pain is limited. These issues are important in the clinical management of individuals with dementia, as untreated pain is a major contributor to reduced quality of life and disability, and can lead to increased behavioural and psychological symptoms. Assessment scales to identify pain in people with dementia have been highlighted in recent studies, but there is little evidence for consistency between these tools. Numerous studies have evaluated various approaches for the treatment of pain, including stepped-care protocols and/or administration of paracetamol and opioid medications. In this Review, we summarize the best-available evidence regarding the aetiology, assessment and treatment of pain in people with dementia. Further validation of assessment tools and large-scale trials of treatment approaches in people with dementia are needed to improve clinical guidance for the treatment of pain in these individuals. [ABSTRACT FROM AUTHOR]

How effective is EU cooperation in higher education? This article treats the issue as one of effectiveness in policy-making. What are the policy ideas which the EU wishes to feed into a policy domain where it has to operate largely through political cooperation and a modest degree of incentive funding? What outcomes are possible? The question is of interest since Europe has two processes which aim for a better regional integration of higher education in order to boost the quality of European higher education and to make a global impact. These are the world- famous Bologna Process and the EU process to drive Europe's universities to make better use of their interlinked roles of education, research and innovation, part of a larger strategy (EU 2020, Lisbon) for European Union growth to support employment, productivity and social cohesion. Building on the theoretical insights of an institutionalist literature concerned with the dynamics of European policy-making in the knowledge domain (Maassen & Olsen, 2007; Gornitzka, 2006, 2010) and complementary theories of historical institutionalism (Pierson, 2003, Thelen, 2003) and agenda setting (Kingdon, 1995), this article examines policy-making on higher education cooperation in the European arena since the Treaty of Maastricht in 1992. It seeks answers to two questions. Why did the Bologna Process dominate the agenda from 1999 to 2004? How did the European Commission acquire the power to shape the issue of European higher education cooperation? Rejecting simple spillover explanations, it theorises in terms of policy entrepreneurship why the EU has latterly been effective in shaping European cooperation in higher education. [ABSTRACT FROM AUTHOR]

Oxidative stress is a principal cause of DNA damage, and mechanisms to repair this damage are among the most highly conserved of biological processes. Oxidative stress is also used by phagocytes to attack bacterial pathogens in defence of the host. We have identified and characterised two apurinic/apyrimidinic (AP) endonuclease paralogues in the human pathogen Neisseria meningitidis. The presence of multiple versions of DNA repair enzymes in a single organism is usually thought to reflect redundancy in activities that are essential for cellular viability. We demonstrate here that these two AP endonuclease paralogues have distinct activities in DNA repair: one is a typical Neisserial AP endonuclease (NApe), whereas the other is a specialised 3′-phosphodiesterase Neisserial exonuclease (NExo). The lack of AP endonuclease activity of NExo is shown to be attributable to the presence of a histidine side chain, blocking the abasic ribose-binding site. Both enzymes are necessary for survival of N. meningitidis under oxidative stress and during bloodstream infection. The novel functional pairing of NExo and NApe is widespread among bacteria and appears to have evolved independently on several occasions. [ABSTRACT FROM AUTHOR]

Focuses on the European Community (EC) policy-making in education and the conceptualization of policy processes in the creation and development of EC policy activity in higher education. Changes and development in EC Higher Education Policy from 1955-1987; Impact of the agreement between France and Italy on the principle of EC educational cooperation and on the European University issue; Development in the policy design for EC education from 1973-1976; Characteristics of the process launched by the EC at the meeting in Lisbon, Portugal in 2000.

Objectives: To investigate the course of activities of daily living (IADL) functioning and possible predictors of performance changes in healthy older adults conducting either a General Cognitive Training (GCT) or a Reasoning Cognitive Training (ReaCT) or no training (control group, CG) over a period of 6 weeks, 3 months, and 6 months. Setting and participants: An online, home‐based GCT and ReaCT including n = 2913 healthy participants (GCT: n = 1096; ReaCT: n = 1022; CG: n = 794) aged 60 years and older. Methods: Multilevel analysis were calculated to explore the nature of our outcome variables of IADL part A (independence) and part B (difficulty of tasks), and to detect possible predictors for participants' performance on IADL after CT. Results: The random slopes models fitted better for the outcomes IADL Part B in the GCT group (χ2(2) = 18.78, p <.01), and both IADL Part A and Part B in the ReaCT group (χ2(2) = 28.57, p <.01; χ2(2) = 63.38, p <.01, respectively), indicating different changes over time for individual participants. Female sex was a significant predictor of IADL change in the ReaCT group, showing that females benefited most in both IADL scores (IADL A: 0.01, p <.01; IADL B: 0.004, p <.01). No other significant predictors for IADL changes were identified. Conclusion and implication: The particular effectiveness in women is of clinical relevance, as IADL is typically more impaired in women than in men in advanced age. Following a personalized medicine approach, identifying predictors of non‐pharmacological intervention success is of utmost importance. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies demonstrate that Alzheimer's disease (AD) has a highly polygenic architecture, where thousands of independent genetic variants explain risk with high classification accuracy. This AD polygenic risk score (AD-PRS) has been previously linked to preclinical cognitive and neuroimaging features observed in asymptomatic individuals. However, shared variance between AD-PRS and neurocognitive features are small, suggesting limited preclinical utility. Methods: Here, we recruited sixteen clinically asymptomatic individuals (mean age 67; range 58–76) with either extremely low / high AD-PRS (defined as at least 2 standard deviations from the wider sample mean (N = 4504; NEFFECTIVE = 90)) with comparable age sex and education level. We assessed group differences in autobiographical memory and T1-weighted structural neuroimaging features. Results: We observed marked reductions in autobiographical recollection (Cohen's d = − 1.66; PFDR = 0.014) and midline structure (cingulate) thickness (Cohen's d = − 1.55, PFDR = 0.05), with no difference in hippocampal volume (P > 0.3). We further confirm the negative association between AD-PRS and cingulate thickness in a larger study with a comparable age (N = 31,966, β = − 0.002, P = 0.011), supporting the validity of our approach. Conclusions: These observations conform with multiple streams of prior evidence suggesting alterations in cingulate structures may occur in individuals with higher AD genetic risk. We were able to use a genetically informed research design strategy that significantly improved the efficiency and power of the study. Thus, we further demonstrate that the recall-by-genotype of AD-PRS from wider samples is a promising approach for the detection, assessment, and intervention in specific individuals with increased AD genetic risk. [ABSTRACT FROM AUTHOR]

Background: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. Methods: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. Results: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. Conclusions: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions. [ABSTRACT FROM AUTHOR]

Objectives: To investigate predictors of performance changes and their time course in healthy older adults. Design: A post hoc analysis of a RCT investigating the effect of reasoning cognitive training (ReaCT) compared to an active control group (CG) during a time course. Setting and participants: An online, home‐based RCT including n = 4,310 healthy participants (ReaCT: n = 2,557; CG: n = 1,753) aged 50 years and older. Methods: Multiple regression analyses were conducted to investigate predictors (age, sex, education, severity of depression, number of training sessions the participants attended, and neuropsychological baseline values) of the outcome measures grammatical reasoning, working memory, digit vigilance, verbal short‐term memory, and verbal learning at 6 weeks, 3, and 6 months. Results: Being female and lower education predicted improvements in grammatical reasoning scores at 6 weeks and 3 months of training. Conclusion and implication: Identifying predictors for nonpharmacological interventions may help to set up a personalized medicine approach in order to prevent cognitive decline in healthy older adults. [ABSTRACT FROM AUTHOR]

The article discusses guidelines issued by the European Federation of Neurological Societies-European Neurological Society (EFNS-ENS) on the diagnosis and treatment of disorders associated with dementia. The guidelines are based on extensive investigation of updated evidence base and are important in informing clinical practice. Among the recommendations cited in the guidelines is the use of specific cognitive tests validated for different types of dementia.

Traumatic brain injury (TBI) causes cognitive impairment but it remains contested regarding which cognitive domains are most affected. Further, moderate-severe TBI is known to be deleterious, but studies of mild TBI (mTBI) show a greater mix of negative and positive findings. This study examines the longer-term cognitive effects of TBI severity and number of mTBIs in later life. We examined a subset (n = 15,764) of the PROTECT study, a cohort assessing risk factors for cognitive decline (ages between 50 and 90 years). Participants completed cognitive assessments annually for 4 years. Cognitive tests were grouped using a principal components analysis (PCA) into working memory, episodic memory, attention, processing speed, and executive function. Lifetime TBI severity and number were retrospectively recalled by participants using the Brain Injury Screening Questionnaire (BISQ). Linear mixed models (LMMs) examined the effect of severity of head injury (non-TBI head strike, mTBI, and moderate-severe TBI) and number of mTBI at baseline and over time. mTBI was considered as a continuous and categorical variable (groups: 0 mTBI, 1 mTBI, 2 mTBIs, 3 mTBIs, and 4+ mTBIs). Of the participants 5725 (36.3%) reported at least one mTBI and 510 (3.2%) at least one moderate-severe TBI, whereas 3711 (23.5%) had suffered at worst a non-TBI head strike and 5818 (32.9%) reported no head injuries. The participants had suffered their last reported head injury an average (standard deviation, SD) of 29.6 (20.0) years prior to the study. Regarding outcomes, there was no worsening in longitudinal cognitive trajectories over the study duration but at baseline there were significant cognitive deficits associated with TBI. At baseline, compared with those without head injury, individuals reporting at least one moderate-severe TBI had significantly poorer attention (B = −0.163, p< 0.001), executive scores (B = −0.151, p = 0.004), and processing speed (B = −0.075, p = 0.033). Those who had suffered at least a single mTBI also demonstrated significantly poorer attention scores at baseline compared with the no head injury group (B = −0.052, p = 0.001). Compared with those with no mTBI, those in the 3 mTBI group manifested poorer baseline executive function (B = −0.149, p = 0.025) and attention scores (B = −0.085, p = 0.015). At baseline, those who had suffered four or more mTBIs demonstrated poorer attention (B = −0.135, p < 0.001), processing speed (B = −0.072, p = 0.009), and working memory (B = −0.052, p = 0.036), compared with those reporting no mTBI. TBI is associated with fixed, dose, and severity-dependent cognitive deficits. The most sensitive cognitive domains are attention and executive function, with approximately double the effect compared with processing speed and working memory. Post-TBI cognitive rehabilitation should be targeted appropriately to domain-specific effects. Significant long-term cognitive deficits were associated with three or more lifetime mTBIs, a critical consideration when counseling individuals post-TBI about continuing high-risk activities. [ABSTRACT FROM AUTHOR]

Context Many older nursing home (NH) residents with cancer experience pain and distressing symptoms. Although some develop cancer during their time in the institution, an increasing number are admitted during their final stages of their lives. Numerous studies have evaluated various treatment approaches, but how pain and symptoms are assessed and managed in people with cancer with and without dementia is unclear. Objectives The objective of this review was to summarize the evidence on cancer-related symptoms among NH residents with and without dementia. Methods We systematically searched the PubMed (1946–2012), Embase (1974–2012), CINAHL (1981–2012), AgeLine, and Cochrane Library (1998–2012) databases using the search terms neoplasms, cancer, tumor, and nursing home. The inclusion criteria were studies including NH residents with a diagnosis of cancer and outcome measures including pain and cancer-related symptoms. Results We identified 11 studies (cross-sectional, longitudinal, clinical trial, and qualitative studies). Ten studies investigated the prevalence and treatment of cancer-related symptoms such as vomiting, nausea, urinary tract infections, and depression. Studies clearly report a high prevalence of pain and reduced prescribing and treatment, regardless of the cognitive status. Only one small study included people with cancer and a diagnosis of dementia. Studies of new cancer diagnoses in NHs could not be identified. Conclusion This review clearly reports a high prevalence of pain and reduced drug prescribing and treatment among NH residents with cancer. This issue appears to be most critical among people with severe dementia, emphasizing the need for better guidance and evidence on pain assessment for these individuals. [ABSTRACT FROM AUTHOR]

Background: Awareness of positive and negative age-related changes (AARC gains and losses) captures the perceived changes that older individuals experience in several domains of their lives including physical, cognitive and social functioning; interpersonal relationships; and lifestyle. Exploring antecedents of AARC is important to identify those individuals that could benefit the most from interventions promoting positive experiences of ageing and/or adaptation to age-related changes. This study investigates the experience of pain as a predictor of lower AARC gains and higher AARC losses. Methods: Analyses are based on cross-sectional data from the PROTECT cohort (2019); 1013 UK residents (mean (SD; range) age: 65.3 (7.1; 51.4–92) years, 84.4% women) completed measures of AARC and pain and provided demographic information. Linear regression models were fitted to examine pain as a predictor of AARC gains and AARC losses. Results: Higher levels of pain predicted more AARC losses both before (regression coefficient, B = 0.36; 95% confidence interval (CI): 0.29 to 0.42, p -value < 0.001; R 2 = 0.11) and after adjusting for demographic covariates (B = 0.34; 95% CI: 0.27 to 0.40; p -value < 0.001; Partial R 2 = 0.11). Pain was not significantly associated with AARC gains (unadjusted B = 0.05; 95% CI: −0.03 to 0.12, p -value = 0.21; Partial R 2 = 0.01). Conclusion: Individuals experiencing pain may perceive more AARC losses. Interventions aiming to decrease levels of pain could include a component targeting self-perceptions of ageing and/or promoting acceptance of the negative changes that can happen with ageing. Statement of significance: The predictive role of greater levels of pain for more negative perceptions of age-related changes extends the literature on the negative psychological outcomes of pain and on predictors of perceived awareness of age-related changes (AARC). As individuals experiencing pain may be more at risk of perceiving their own ageing in a more negative way, they may benefit from interventions that combine strategies to reduce levels of pain and the interference that pain exerts on their daily activities with an educational component enhancing positive self-perceptions of ageing and promoting acceptance of negative age-related changes. [ABSTRACT FROM AUTHOR]

Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning. [ABSTRACT FROM AUTHOR]

Background: Pain is often poorly managed in people who have a dementia. Little is known about how this patient population is managed in hospital, with research to date focused mainly on care homes. This study aimed to investigate how pain is recognised, assessed and managed in patients with dementia in a range of acute hospital wards, to inform the development of a decision support tool to improve pain management for this group.Methods: A qualitative, multi-site exploratory case study. Data were collected in four hospitals in England and Scotland. Methods included non-participant observations, audits of patient records, semi-structured interviews with staff and carers, and analysis of hospital ward documents. Thematic analysis was performed through the lens of decision making theory.Results: Staff generally relied on patients' self-report of pain. For patients with dementia, however, communication difficulties experienced because of their condition, the organisational context, and time frames of staff interactions, hindered patients' ability to provide staff with information about their pain experience. This potentially undermined the trials of medications used to provide pain relief to each patient and assessments of their responses to these treatments. Furthermore, given the multidisciplinary environment, a patient's communication about their pain involved several members of staff, each having to make sense of the patient's pain as in an 'overall picture'. Information about patients' pain, elicited in different ways, at different times and by different health care staff, was fragmented in paper-based documentation. Re-assembling the pieces to form a 'patient specific picture of the pain' required collective staff memory, 'mental computation' and time.Conclusions: There is a need for an efficient method of eliciting and centralizing all pain-related information for patients with dementia, which is distributed in time and between personnel. Such a method should give an overall picture of a patient's pain which is rapidly accessible to all involved in their care. This would provide a much-needed basis for making decisions to support the effective management of the pain of older people with dementia in hospital. [ABSTRACT FROM AUTHOR]

Background: Vascular dementia is the second most common cause of dementia affecting over seven million people worldwide, yet there are no licensed treatments. There is an urgent need for a clinical trial in this patient group. Subcortical ischaemic vascular dementia is the most common variant of vascular dementia. This randomised trial will investigate whether use of calcium channel blockade with amlodipine, a commonly used agent, can provide the first evidence-based pharmacological treatment for subcortical ischaemic vascular dementia.Methods/design: This is a randomised controlled trial of calcium channel blockade with Amlodipine For the treatment oF subcortical ischaEmic vasCular demenTia (AFFECT) to test the hypothesis that treatment with amlodipine can improve outcomes for these patients in a phase IIb, multi-centre, double-blind, placebo-controlled randomised trial. The primary outcome is the change from baseline to 12 months in the Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog). Secondary outcomes include cognitive function, executive function, clinical global impression of change, change in blood pressure, quantitative evaluation of lesion accrual based on magnetic resonance imaging (MRI), health-related quality of life, activities of daily living, non-cognitive dementia symptoms, care-giver burden and care-giver health-related quality of life, cost-effectiveness and institutionalisation. A total of 588 patients will be randomised in a 1:1 ratio to either amlodipine or placebo, recruited from sites across the UK and enrolled in the trial for 104 weeks.Discussion: There are no treatments licensed for vascular dementia. The most common subtype is subcortical ischaemic vascular dementia (SIVD). This study is designed to investigate whether amlodipine can produce benefits compared to placebo in established SIVD. It is estimated that the numbers of people with VaD and SIVD will increase globally in the future and the results of this study should inform important treatment decisions.Trial Registration: Current Controlled Trials ISRCTN31208535 . Registered on 7 March 2014. [ABSTRACT FROM AUTHOR]

Background: Up to 90 % of people living with dementia in care homes experience one or more behaviours that staff may describe as challenging to support (BSC). Of these agitation is the most common and difficult to manage. The presence of agitation is associated with fewer visits from relatives, poorer quality of life and social isolation. It is recommended that agitation is treated through psychosocial interventions. Dementia Care Mapping™ (DCM™) is an established, widely used observational tool and practice development cycle, for ensuring a systematic approach to providing person-centred care. There is a body of practice-based literature and experience to suggests that DCM™ is potentially effective but limited robust evidence for its effectiveness, and no examination of its cost-effectiveness, as a UK health care intervention. Therefore, a definitive randomised controlled trial (RCT) of DCM™ in the UK is urgently needed.Methods/design: A pragmatic, multi-centre, cluster-randomised controlled trial of Dementia Care Mapping (DCM™) plus Usual Care (UC) versus UC alone, where UC is the normal care delivered within the care home following a minimum level of dementia awareness training. The trial will take place in residential, nursing and dementia-specialist care homes across West Yorkshire, Oxfordshire and London, with residents with dementia. A random sample of 50 care homes will be selected within which a minimum of 750 residents will be registered. Care homes will be randomised in an allocation ratio of 3:2 to receive either intervention or control. Outcome measures will be obtained at 6 and 16 months following randomisation. The primary outcome is agitation as measured by the Cohen-Mansfield Agitation Inventory, at 16 months post randomisation. Key secondary outcomes are other BSC and quality of life. There will be an integral cost-effectiveness analysis and a process evaluation.Discussion: The protocol was refined following a pilot of trial procedures. Changes include replacement of a questionnaire, whose wording caused some residents distress, to an adapted version specifically designed for use in care homes, a change to the randomisation stratification factors, adaption in how the staff measures are collected to encourage greater compliance, and additional reminders to intervention homes of when mapping cycles are due, via text message.Trial Registration: Current Controlled Trials ISRCTN82288852 . Registered on 16 January 2014. Full protocol version and date: v7.1: 18 December 2015. [ABSTRACT FROM AUTHOR]

Background: Preliminary evidence suggests that goal-oriented cognitive rehabilitation (CR) may be a clinically effective intervention for people with early-stage Alzheimer's disease, vascular or mixed dementia and their carers. This study aims to establish whether CR is a clinically effective and cost-effective intervention for people with early-stage dementia and their carers. Methods/design: In this multi-centre, single-blind randomised controlled trial, 480 people with early-stage dementia, each with a carer, will be randomised to receive either treatment as usual or cognitive rehabilitation (10 therapy sessions over 3 months, followed by 4 maintenance sessions over 6 months). We will compare the effectiveness of cognitive rehabilitation with that of treatment as usual with regard to improving self-reported and carer-rated goal performance in areas identified as causing concern by people with early-stage dementia; improving quality of life, self-efficacy, mood and cognition of people with early-stage dementia; and reducing stress levels and ameliorating quality of life for carers of participants with early-stage dementia. The incremental cost-effectiveness of goal-oriented cognitive rehabilitation compared to treatment as usual will also be examined. Discussion: If the study confirms the benefits and cost-effectiveness of cognitive rehabilitation, it will be important to examine how the goal-oriented cognitive rehabilitation approach can most effectively be integrated into routine health-care provision. Our aim is to provide training and develop materials to support the implementation of this approach following trial completion. [ABSTRACT FROM AUTHOR]

Background: The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery. Methods and Trial Design: The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery. Results: In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (x2 = 17.9 p<0.0001), moderate (x2 = 7.8 p = 0.005) and severe (x2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher's Exact Test p = 0.018, x2 = 5.1 p = 0.02 and x2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (x2 = 4.4 p = 0⋅037 and x2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z = -2.1 p = 0.03, MWU Z =-2.7 p = 0.004, MWU Z =-3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z =-2.9 p = 0.003, MWU Z =-3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z =-2.4 p = .0.018, MWU Z =-2.4 p = 0.019). Conclusion: POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment. Trial Registration: Controlled-Trials.com ISRCTN39503939 [ABSTRACT FROM AUTHOR]

Summary Polymorphonuclear neutrophil leucocytes (PMNs) are a critical part of innate immune defence against bacterial pathogens, and only a limited subset of microbes can escape killing by these phagocytic cells. Here we show that Neisseria meningitidis, a leading cause of septicaemia and meningitis, can avoid killing by PMNs and this is dependent on the ability of the bacterium to acquire l-glutamate through its GltT uptake system. We demonstrate that the uptake of available l-glutamate promotes N. meningitidis evasion of PMN reactive oxygen species produced by the oxidative burst. In the meningococcus, l-glutamate is converted to glutathione, a key molecule for maintaining intracellular redox potential, which protects the bacterium from reactive oxygen species such as hydrogen peroxide. We show that this mechanism contributes to the ability of N. meningitidis to cause bacteraemia, a critical step in the disease process during infections caused by this important human pathogen. [ABSTRACT FROM AUTHOR]

Background: Preliminary evidence suggests that goal-oriented cognitive rehabilitation (CR) may be a clinically effective intervention for people with early-stage Alzheimer's disease, vascular or mixed dementia and their carers. This study aims to establish whether CR is a clinically effective and cost-effective intervention for people with early-stage dementia and their carers.Methods/design: In this multi-centre, single-blind randomised controlled trial, 480 people with early-stage dementia, each with a carer, will be randomised to receive either treatment as usual or cognitive rehabilitation (10 therapy sessions over 3 months, followed by 4 maintenance sessions over 6 months). We will compare the effectiveness of cognitive rehabilitation with that of treatment as usual with regard to improving self-reported and carer-rated goal performance in areas identified as causing concern by people with early-stage dementia; improving quality of life, self-efficacy, mood and cognition of people with early-stage dementia; and reducing stress levels and ameliorating quality of life for carers of participants with early-stage dementia. The incremental cost-effectiveness of goal-oriented cognitive rehabilitation compared to treatment as usual will also be examined.Discussion: If the study confirms the benefits and cost-effectiveness of cognitive rehabilitation, it will be important to examine how the goal-oriented cognitive rehabilitation approach can most effectively be integrated into routine health-care provision. Our aim is to provide training and develop materials to support the implementation of this approach following trial completion. [ABSTRACT FROM AUTHOR]