PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522.

Variants identified in genome-wide association studies have implicated immune pathways in the development of Alzheimer's disease (AD). Here, we investigated the mechanistic basis for protection from AD associated with PLCγ2 R522, a rare coding variant of the PLCG2 gene. We studied the variant's role in macrophages and microglia of newly generated PLCG2-R522-expressing human induced pluripotent cell lines (hiPSC) and knockin mice, which exhibit normal endogenous PLCG2 expression. In all models, cells expressing the R522 mutation show a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This manifests as enhanced release of cellular calcium ion stores in response to physiologically relevant stimuli like Fc-receptor ligation or exposure to Aß oligomers. Expression of the PLCγ2-R522 variant resulted in increased stimulus-dependent PIP2 depletion and reduced basal PIP2 levels in vivo. Furthermore, it was associated with impaired phagocytosis and enhanced endocytosis. PLCγ2 acts downstream of other AD-related factors, such as TREM2 and CSF1R, and alterations in its activity directly impact cell function. The inherent druggability of enzymes such as PLCγ2 raises the prospect of PLCγ2 manipulation as a future therapeutic approach in AD.

Metabolomics profiling reveals distinct, sex-specific signatures in serum and brain metabolomes in mouse models of Alzheimer's disease.

INTRODUCTION: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation. METHODS: We investigated differences in serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at 6 months of age. RESULTS: We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum. DISCUSSION: Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of apolipoprotein E (apoE) ε4 carriers and replicating the serum metabolic imprint of the APOE ε4 genotype. Our work thus represents a significant step toward translating metabolic dysregulation from model organisms to human AD. HIGHLIGHTS: This was a metabolomic assessment of two mouse models relevant to Alzheimer's disease. Mouse models exhibit broad sex-specific metabolic differences, similar to human study cohorts. The early-onset 5XFAD mouse model primarily alters brain metabolites while the late-onset LOAD1 model primarily changes serum metabolites. Apolipoprotein E (apoE) ε4 mice recapitulate glycerophospolipid signatures of human APOE ε4 carriers in both brain and serum.

In vivo validation of late-onset Alzheimer's disease genetic risk factors.

INTRODUCTION: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. METHODS: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. RESULTS: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. DISCUSSION: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. HIGHLIGHTS: A novel approach to validate genetic risk factors for late-onset AD (LOAD) is presented. LOAD risk variants were knocked in to conserved mouse loci. Variant effects were assayed by transcriptional analysis. Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease. This approach should generate more translationally relevant animal models.

Dietary interventions with dietitian involvement in adults with chronic kidney disease: A systematic review.

BACKGROUND: A comprehensive evidence base is needed to support recommendations for the dietetic management of adults with chronic kidney disease (CKD). The present study aimed to determine the effect of dietary interventions with dietitian involvement on nutritional status, well-being, kidney risk factors and clinical outcomes in adults with CKD. METHODS: Cochrane Central Register of Controlled Trials, CINAHL, MEDLINE, PsycINFO and EMBASE.com were searched from January 2000 to November 2019. Intentional weight loss and single nutrient studies were excluded. Risk of bias was assessed using the Cochrane risk-of-bias tool. Effectiveness was summarised using the mean difference between groups for each outcome per study. RESULTS: Twelve controlled trials (1906 participants) were included. High fruit and vegetable intake, as well as a multidisciplinary hospital and community care programme, slowed the decline in glomerular filtration rate in adults with stage 3-4 CKD. Interventions addressing nutrition-related barriers increased protein and energy intake in haemodialysis patients. A Mediterranean diet and a diet with high n-3 polyunsaturated fatty acids improved the lipid profile in kidney transplant recipients. CONCLUSIONS: A limited number of studies suggest benefits as a result of dietary interventions that are delivered by dietitians and focus on diet quality. We did not identify any studies that focussed on our primary outcome of nutritional status or studies that examined the timing or frequency of the nutritional assessment. This review emphasises the need for a wider body of high-quality evidence to support recommendations on what and how dietetic interventions are delivered by dietitians for adults with CKD.

'The Listening Series': increasing equity, diversity and inclusion in patient and public involvement and engagement for policy research by listening to and learning from under-represented groups.

BACKGROUND: Policy research aims to provide evidence to inform government policy decisions about health and social care. Engaging and involving the public and patients in this work is widely recognised as essential. Research funders prioritise equality, diversity and inclusion (EDI) in patient and public involvement and engagement (PPIE), but people who are most likely to experience poor outcomes are also those least likely to be involved in research. This paper describes our experience of setting out to understand how to overcome barriers to EDI in PPIE in the research carried out by the National Institute for Health and Care Research (NIHR) Policy Research Unit in Maternal and Neonatal Health and Care (PRU-MNHC), in a PPIE consultation project we called The Listening Series. METHODS: We convened five video-recorded online discussion groups involving 20 individuals advocating for groups who are under-represented in our research. Those taking part included people working with Black and Asian women and families, young parents, those from socially deprived backgrounds, and women and families with physical and learning disabilities. Discussions focussed on practical solutions to addressing challenges to people being excluded, and how to improve EDI in our research. LEARNING AND REFLECTION: Five key themes were identified: 'build trust'; 'involve us from the beginning'; 'show us impact'; 'use clear, appropriate and inclusive communication'; and 'imagine life in our shoes'. We used the learning to create a guidance document for researchers and an accompanying 15-minute film. We also took practical steps to embed the learning strategically by expanding our Task Group for PPIE in the PRU-MNHC to include four Listening Series invitees with a remit to champion EDI in our research and ensure that it is embedded in our PPIE activities. We continue to reflect on and work to address the associated challenges. CONCLUSIONS: The Listening Series helped us rethink our processes for inclusion to go beyond traditional methods of involvement and engagement. The themes identified pose challenges that require time, resource and empathic engagement from researchers to be meaningfully resolved. This has implications for policy makers and research funders who need to consider this in their processes.

WHAT WE KNOW: It is important that health care researchers involve patients and the public from a wide range of social and ethnic backgrounds in research, but we know that this often does not happen. We are a group of researchers and patient/public representatives, working in research to improve care for pregnant women and babies. We wanted to find out how to involve people from more diverse backgrounds in our research. WHAT WE DID: We organised five online discussion groups with 20 people working with Black and Asian families, young parents, those from socially deprived backgrounds and parents with physical or learning disabilities. We asked them what we should do to involve a wider range of people in our research. We called this The Listening Series. We summarised the most important things people said in a written guide for researchers and a short film. We then asked people who had been invited to take part in The Listening Series to join us to develop new ways of working together. WHAT WE LEARNED: The five themes we identified were: 'build trust'; 'involve us from the beginning'; 'show us impact'; 'use clear, appropriate and inclusive communication'; and 'imagine life in our shoes'. In summary, researchers need to take the time to build trusting relationships with patients and the public; actively listening and learning from them. This can be challenging for researchers and patient representatives. Research funders need to allow time and money for this to happen in a meaningful way.

Metabolomics profiling reveals distinct, sex-specific signatures in the serum and brain metabolomes in the mouse models of Alzheimer's disease.

INTRODUCTION: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species provides a promising entry point for translation. METHODS: We investigated differences of serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at six months of age. RESULTS: We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum. DISCUSSION: Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of APOE4 carriers and replicating the serum metabolic imprint of the APOE4 genotype. Our work thus represents a significant step towards translating metabolic dysregulation from model organisms to human AD.

In vivo validation of late-onset Alzheimer's disease genetic risk factors.

Introduction: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. Methods: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. Results: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. Discussion: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.

Dissemination of an evidence-based program to reduce fear of falling, South Carolina, 2006-2009.

INTRODUCTION: Falls among older adults are a serious public health issue, and fear of falling can limit mobility, which in turn increases fall risk. A Matter of Balance/Volunteer Lay Leader Model is an evidence-based program designed to address fear of falling. The objective of this study was to describe implementation, dissemination, and outcomes of this program in 3 regions of South Carolina with a predominantly African American and largely underserved population. METHODS: We developed partnerships throughout the state, organized master and lay leader trainings, and documented numbers of lay leaders, programs offered, demographic characteristics of participants, program fidelity, and attendance. Outcome measures were self-reported confidence to prevent and manage falls and a quantitative measure of functional mobility. Both measures were assessed at baseline and after program completion. RESULTS: Older adults (N = 235) attended 18 classes at 16 sites. Barriers to implementation were program teams' limited familiarity with the concept of evidence-based programs and the importance of adhering to program content. Facilitators were state-level leadership and a history of state, regional, and local groups collaborating successfully on other projects. Outcomes indicated greater confidence in managing falls and carrying out activities of daily living. Mobility improved significantly, suggesting a reduced risk for falls. CONCLUSION: Evidence-based programs such as A Matter of Balance/Volunteer Lay Leader Model can be successfully disseminated in underserved areas. Outcomes indicate that participation in fall prevention programs can benefit groups of predominantly African American older adults.

Corrigendum: Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H.

[This corrects the article DOI: 10.3389/fnagi.2021.735524.].

Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODEL-AD preclinical testing core study.

Introduction: Hyperexcitability and epileptiform activity are commonplace in Alzheimer's disease (AD) patients and associated with impaired cognitive function. The anti-seizure drug levetiracetam (LEV) is currently being evaluated in clinical trials for ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of our studies was to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship with LEV in an amyloidogenic mouse model of AD to enable predictive preclinical to clinical translation, using the rigorous preclinical testing pipeline of the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease Preclinical Testing Core. Methods: A multi-tier approach was applied that included quality assurance and quality control of the active pharmaceutical ingredient, PK/PD modeling, positron emission tomography/magnetic resonance imaging (PET/MRI), functional outcomes, and transcriptomics. 5XFAD mice were treated chronically with LEV for 3 months at doses in line with those allometrically scaled to the clinical dose range. Results: Pharmacokinetics of LEV demonstrated sex differences in Cmax, AUC0-∞, and CL/F, and a dose dependence in AUC0-∞. After chronic dosing at 10, 30, 56 mg/kg, PET/MRI tracer 18F-AV45, and 18F-fluorodeoxyglucose (18F-FDG) showed specific regional differences with treatment. LEV did not significantly improve cognitive outcomes. Transcriptomics performed by nanoString demonstrated drug- and dose-related changes in gene expression relevant to human brain regions and pathways congruent with changes in 18F-FDG uptake. Discussion: This study represents the first report of PK/PD assessment of LEV in 5XFAD mice. Overall, these results highlighted non-linear kinetics based on dose and sex. Plasma concentrations of the 10 mg/kg dose in 5XFAD overlapped with human plasma concentrations used for studies of mild cognitive impairment, while the 30 and 56 mg/kg doses were reflective of doses used to treat seizure activity. Post-treatment gene expression analysis demonstrated LEV dose-related changes in immune function and neuronal-signaling pathways relevant to human AD, and aligned with regional 18F-FDG uptake. Overall, this study highlights the importance of PK/PD relationships in preclinical studies to inform clinical study design. Highlights: Significant sex differences in pharmacokinetics of levetiracetam were observed in 5XFAD mice.Plasma concentrations of 10 mg/kg levetiracetam dose in 5XFAD overlapped with human plasma concentration used in the clinic.Drug- and dose-related differences in gene expression relevant to human brain regions and pathways were also similar to brain region-specific changes in 18F-fluorodeoxyglucose uptake.

Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice.

Introduction: Alzheimer's disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer's Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline. Methods: 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aß) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data. Results: Prophylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma Aß40 and Aß42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake. Discussion: Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aß levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD.

Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H.

Late-onset Alzheimer's disease (AD; LOAD) is the most common human neurodegenerative disease, however, the availability and efficacy of disease-modifying interventions is severely lacking. Despite exceptional efforts to understand disease progression via legacy amyloidogenic transgene mouse models, focus on disease translation with innovative mouse strains that better model the complexity of human AD is required to accelerate the development of future treatment modalities. LOAD within the human population is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes parallel to those often muted by the early and aggressive aggregate formation in popular mouse strains. In addition to extracellular deposits of amyloid plaques and inclusions of the microtubule-associated protein tau, AD is also defined by synaptic/neuronal loss, vascular deficits, and neuroinflammation. These underlying processes need to be better defined, how the disease progresses with age, and compared to human-relevant outcomes. To create more translatable mouse models, MODEL-AD (Model Organism Development and Evaluation for Late-onset AD) groups are identifying and integrating disease-relevant, humanized gene sequences from public databases beginning with APOEε4 and Trem2*R47H, two of the most powerful risk factors present in human LOAD populations. Mice expressing endogenous, humanized APOEε4 and Trem2*R47H gene sequences were extensively aged and assayed using a multi-disciplined phenotyping approach associated with and relative to human AD pathology. Robust analytical pipelines measured behavioral, transcriptomic, metabolic, and neuropathological phenotypes in cross-sectional cohorts for progression of disease hallmarks at all life stages. In vivo PET/MRI neuroimaging revealed regional alterations in glycolytic metabolism and vascular perfusion. Transcriptional profiling by RNA-Seq of brain hemispheres identified sex and age as the main sources of variation between genotypes including age-specific enrichment of AD-related processes. Similarly, age was the strongest determinant of behavioral change. In the absence of mouse amyloid plaque formation, many of the hallmarks of AD were not observed in this strain. However, as a sensitized baseline model with many additional alleles and environmental modifications already appended, the dataset from this initial MODEL-AD strain serves an important role in establishing the individual effects and interaction between two strong genetic risk factors for LOAD in a mouse host.

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study.

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer's disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram, in vivo imaging, biochemical characterization, and behavioral assessments. The data from this study is publicly available through the AD Knowledge Portal.

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer's disease.

BACKGROUND: Late-onset Alzheimer's disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer's have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes. RESULTS: This resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString nCounter® Mouse AD panel was designed to correlate key human disease processes and pathways with mRNA from mouse brains. Analysis of the 5xFAD mouse, a widely used amyloid pathology model, and three mouse models based on LOAD genetics carrying APOE4 and TREM2*R47H alleles demonstrated overlaps with distinct human AD modules that, in turn, were functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq showed strong correlation between gene expression changes independent of experimental platform. CONCLUSIONS: Taken together, we show that the nCounter Mouse AD panel offers a rapid, cost-effective and highly reproducible approach to assess disease relevance of potential LOAD mouse models.

Non-contact infrared thermometers compared with current approaches in primary care for children aged 5 years and under: a method comparison study.

BACKGROUND: Current options for temperature measurement in children presenting to primary care include either electronic axillary or infrared tympanic thermometers. Non-contact infrared thermometers could reduce both the distress of the child and the risk of cross-infection. OBJECTIVES: The objective of this study was to compare the use of non-contact thermometers with the use of electronic axillary and infrared tympanic thermometers in children presenting to primary care. DESIGN: Method comparison study with a nested qualitative study. SETTING: Primary care in Oxfordshire. PARTICIPANTS: Children aged ≤ 5 years attending with an acute illness. INTERVENTIONS: Two types of non-contact infrared thermometers [i.e. Thermofocus (Tecnimed, Varese, Italy) and Firhealth (Firhealth, Shenzhen, China)] were compared with an electronic axillary thermometer and an infrared tympanic thermometer. MAIN OUTCOME MEASURES: The primary outcome was agreement between the Thermofocus non-contact infrared thermometer and the axillary thermometer. Secondary outcomes included agreement between all other sets of thermometers, diagnostic accuracy for detecting fever, parental and child ratings of acceptability and discomfort, and themes arising from our qualitative interviews with parents. RESULTS: A total of 401 children (203 boys) were recruited, with a median age of 1.6 years (interquartile range 0.79-3.38 years). The readings of the Thermofocus non-contact infrared thermometer differed from those of the axillary thermometer by -0.14 °C (95% confidence interval -0.21 to -0.06 °C) on average with the lower limit of agreement being -1.57 °C (95% confidence interval -1.69 to -1.44 °C) and the upper limit being 1.29 °C (95% confidence interval 1.16 to 1.42 °C). The readings of the Firhealth non-contact infrared thermometer differed from those of the axillary thermometer by -0.16 °C (95% confidence interval -0.23 to -0.09 °C) on average, with the lower limit of agreement being -1.54 °C (95% confidence interval -1.66 to -1.41 °C) and the upper limit being 1.22 °C (95% confidence interval 1.10 to 1.34 °C). The difference between the first and second readings of the Thermofocus was -0.04 °C (95% confidence interval -0.07 to -0.01 °C); the lower limit was -0.56 °C (95% confidence interval -0.60 to -0.51 °C) and the upper limit was 0.47 °C (95% confidence interval 0.43 to 0.52 °C). The difference between the first and second readings of the Firhealth thermometer was 0.01 °C (95% confidence interval -0.02 to 0.04 °C); the lower limit was -0.60 °C (95% confidence interval -0.65 to -0.54 °C) and the upper limit was 0.61 °C (95% confidence interval 0.56 to 0.67 °C). Sensitivity and specificity for the Thermofocus non-contact infrared thermometer were 66.7% (95% confidence interval 38.4% to 88.2%) and 98.0% (95% confidence interval 96.0% to 99.2%), respectively. For the Firhealth non-contact infrared thermometer, sensitivity was 12.5% (95% confidence interval 1.6% to 38.3%) and specificity was 99.4% (95% confidence interval 98.0% to 99.9%). The majority of parents found all methods to be acceptable, although discomfort ratings were highest for the axillary thermometer. The non-contact thermometers required fewer readings than the comparator thermometers. LIMITATIONS: A method comparison study does not compare new methods against a reference standard, which in this case would be central thermometry requiring the placement of a central line, which is not feasible or acceptable in primary care. Electronic axillary and infrared tympanic thermometers have been found to have moderate agreement themselves with central temperature measurements. CONCLUSIONS: The 95% limits of agreement are > 1 °C for both non-contact infrared thermometers compared with electronic axillary and infrared tympanic thermometers, which could affect clinical decision-making. Sensitivity for fever was low to moderate for both non-contact thermometers. FUTURE WORK: Better methods for peripheral temperature measurement that agree well with central thermometry are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15413321. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 53. See the NIHR Journals Library website for further project information.

General practitioners commonly measure children's temperature using a thermometer placed in the armpit or ear canal. New 'non-contact' thermometers use infrared light to measure temperature without touching the child. They are easy to use and there is no risk of passing on infections. However, we do not know how well they measure temperature compared with thermometers that use the armpit or the ear. This study aimed to compare two non-contact thermometers with current thermometers. We measured children's temperature with all thermometer types, and asked children and their parents about their views. The study was performed in general practices in Oxfordshire with children aged ≤ 5 years who had come to see their general practitioner because they had recently become unwell. Both the cheaper and more expensive non-contact thermometers gave slightly lower temperature readings on average than current thermometers. The vast majority of readings ranged from 1.6 °C lower to 1.3 °C higher than current thermometers. The detection of fever of at least 38 °C was low to moderate for both non-contact thermometers. Most parents did not think that their child was distressed by having their temperature taken using any of the thermometers, but the armpit thermometer was rated as the least comfortable. When interviewed, parents were more negative about the armpit thermometers, although still willing to use them if they were recommended by doctors. Although we found that the readings from the different thermometers did not match, we do not know whether the non-contact or the current thermometers were giving readings that were closer to the real temperature of the child. To understand this, we would need to do a study that included a more invasive procedure for temperature assessment.

Health-related quality of life in people with predementia Alzheimer's disease, mild cognitive impairment or dementia measured with preference-based instruments: a systematic literature review.

BACKGROUND: Obtaining reliable estimates of the health-related quality of life (HR-QoL) of people with predementia Alzheimer's disease [AD] (preclinical or prodromal AD), mild cognitive impairment (MCI) and dementia is essential for economic evaluations of related health interventions. AIMS: To provide an overview of which quality of life instruments are being used to assess HR-QoL in people with predementia AD, MCI or dementia; and, to summarise their reported HR-QoL levels at each stage of the disease and by type of respondent. METHODS: We systematically searched for and reviewed eligible studies published between January 1990 and the end of April 2017 which reported HR-QoL for people with predementia AD, MCI or dementia. We only included instruments which are preference-based, allowing index scores/utility values to be attached to each health state they describe based on preferences obtained from population surveys. Summary results were presented by respondent type (self or proxy), type of instrument, geographical location and, where possible, stage of disease. Health state utility values derived using the EuroQoL 5-Dimensions (EQ-5D) were meta-analysed by pooling reported results across all studies by disease severity (MCI, mild, mild to moderate, moderate, severe dementia, not specified) and by respondent (person with dementia, carer, general public, not specified), using a fixed-effects approach. RESULTS: We identified 61 studies which reported HR-QoL for people with MCI or dementia using preference-based instruments, of which 48 used the EQ-5D. Thirty-six studies reported HR-QoL for mild and/or moderate disease severities, and 12 studies reported utility values for MCI. We found systematic differences between self-rated and proxy-rated HR-QoL, with proxy-rated utility valued being significantly lower in more severe disease states. CONCLUSIONS: A substantial literature now exists quantifying the impact of dementia on HR-QoL using preference-based measures, giving researchers and modellers a firmer basis on which to select appropriate utility values when estimating the effectiveness and cost-effectiveness of interventions in this area. Further research is required on HR-QoL of people with preclinical and prodromal AD and MCI, possible differences by type of dementia, the effects of comorbidities, study setting and the informal caregiver's own HR-QoL, including any effect of that on their proxy-ratings.

Functional status assessment for community long-term care: preliminary observations.

The Community Long-Term Care (CLTC) program in South Carolina offers services to nursing home eligible persons that allow them to remain at home and receive help with activities of daily living. Variation in the ways potential clients are evaluated often produces inconsistent eligibility determinations. We developed a simple, objective assessment tool to complement CLTC evaluations. A conceptual framework, based on Nagi's model of disablement, was tested on community-dwelling healthy older adults and CLTC clients. Three simple physiologic tasks assessing mobility, functional leg strength, and manual dexterity discriminated between community-dwelling older adults and CLTC clients, classifying them with 80% to 90% accuracy.

Pembrolizumab-induced autoimmune haemolytic anaemia and cholangitis.

Increasing numbers of patients are now offered immunotherapy as part of their cancer treatment. These treatments, while often very effective, have a wide range of adverse effects that are distinct from those of traditional chemotherapy regimens. Thyroid disease, dermatological disease, colitis and pneumonitis are some of the most commonly reported immune side effects. We present a case of life-threatening de novo autoimmune haemolytic anaemia (AIHA) complicated by immune cholangitis induced by pembrolizumab. An 81-year-old woman with metastatic melanoma completed a two-year course of pembrolizumab in August 2018 and six weeks later presented to hospital with jaundice. Admission haemoglobin (Hb) was 91 g/L, rapidly decreasing to 31 g/L, at which point she required admission to the intensive care unit. AIHA is a rare but potentially life-threatening complication of checkpoint inhibitors and should be considered in patients presenting with anaemia during or after immunotherapy treatment.

Mechanisms that underlie coordination in children with developmental coordination disorder.

The authors examined potential mechanisms underlying motor coordination in children with developmental coordination disorder (DCD). Because children with DCD experience difficulty processing visual, auditory, and vibrotactile information, the authors explored patterns of choice reaction time (RT) in young (6-7 years) and older (9-10 years) children with and without DCD by using a compatibility-incompatibility paradigm and different sensory modalities. Young children responded more slowly than older children to visual, auditory, and vibrotactile stimuli. Children with DCD took longer than typical children to process visual and vibrotactile stimuli under more complex stimulus-response mappings. Young children with DCD responded more slowly than typical children to visual and vibrotactile information under incompatible conditions. Children with DCD responded faster than unaffected children to auditory stimuli. The results suggest that there is a developmental nature in the processing of visual and auditory input and imply that the vibrotactile sensory modality may be key to the motor coordination difficulties of children with DCD.

A randomised study of the effects of massage therapy compared to guided relaxation on well-being and stress perception among older adults.

OBJECTIVE: The objective was to assess the effects of massage compared to guided relaxation on stress perception and well-being among older adults. DESIGN: A randomised pilot study enrolled adults ages 60 and older to receive 50 min, twice weekly massage therapy or guided relaxation sessions. Questionnaires were administered at pre-test (1 week before the first session) and post-test (after the last session). SETTING: Participants came to the University of South Carolina campus for sessions. Adults aged 60 and older were recruited from community venues and were briefly screened by telephone for contraindications. INTERVENTION: Participants (n=54) received 50 min massage or guided relaxation sessions twice weekly for 4 weeks. The massage included Swedish, neuromuscular, and myofascial techniques. For the relaxation group, an appropriately trained assistant read a script to guide the participant in using visualization and muscle relaxation. MAIN OUTCOME MEASURES: The General Well-being Schedule is an 18-item scale with subscales measuring anxiety, depression, positive well-being, self-control, vitality, and general health. The Perceived Stress Scale is a 14-item scale assessing the degree to which situations in one's life are appraised as stressful during the past month. RESULTS: Significant improvements were found for the anxiety, depression, vitality, general health, and positive well-being subscales of the General Well-being Schedule and for Perceived Stress among the massage participants compared to guided relaxation. CONCLUSIONS: Findings indicate that massage therapy enhances positive well-being and reduces stress perception among community-dwelling older adults.