Publications by authors named "Julie Williams"

267 Publications

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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http://dx.doi.org/10.1038/s41380-021-01152-8DOI Listing
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
June 2021

Tele-mental health services: a rapid umbrella review of pre-COVID-19 literature.

J Med Internet Res 2021 Apr 30. Epub 2021 Apr 30.

NIHR Mental Health Policy Research Unit, Division of Psychiatry, University College London, London, GB.

Background: Tele-mental health care has been rapidly adopted to maintain services during the COVID-19 pandemic, and there is now substantial interest in its future role. Service planning and policy making for recovery from the pandemic and beyond should draw not only on COVID-19 experiences, but also on the substantial research evidence accumulated prior to this.

Objective: To conduct an umbrella review of systematic reviews of research literature and evidence-based guidance on tele-mental health, including both qualitative and quantitative literature.

Methods: Three databases were searched between January 2010 and August 2020 for systematic reviews meeting pre-defined criteria. Reviews retrieved were independently screened and those meeting inclusion criteria were synthesised and assessed for risk of bias. Narrative synthesis was used to report findings.

Results: Nineteen systematic reviews met the inclusion criteria. Fifteen examined clinical effectiveness, eight reported on aspects of tele-mental health implementation, ten reported on acceptability to service users and clinicians, two on cost-effectiveness and one on guidance. Most reviews were assessed as low quality. Findings suggested that video-based communication could be as effective and acceptable as face-to-face formats, at least in the short-term. Evidence was lacking on the extent of digital exclusion and how it can be overcome, and on some significant contexts such as children and young people's services and inpatient settings.

Conclusions: This umbrella review suggests that tele-mental health has potential to be an effective and acceptable form of service delivery. However, we found limited evidence on impacts of large-scale implementation across catchment areas. Combining previous evidence and COVID-19 experiences may allow realistic planning for future tele-mental health implementation.

Clinicaltrial:
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http://dx.doi.org/10.2196/26492DOI Listing
April 2021

A feasibility hybrid II randomised controlled trial of volunteer 'Health Champions' supporting people with serious mental illness manage their physical health: study protocol.

Pilot Feasibility Stud 2021 May 31;7(1):116. Epub 2021 May 31.

Centre for Implementation Science, Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: People with serious mental illnesses (SMI) such as schizophrenia often also have physical health illnesses and interventions are needed to address the resultant multimorbidity and reduced life expectancy. Research has shown that volunteers can support people with SMI. This protocol describes a feasibility randomised controlled trial (RCT) of a novel intervention involving volunteer 'Health Champions' supporting people with SMI to manage and improve their physical health.

Methods: This is a feasibility hybrid II randomised effectiveness-implementation controlled trial. The intervention involves training volunteers to be 'Health Champions' to support individual people with SMI using mental health services. This face-to-face or remote support will take place weekly and last for up to 9 months following initial introduction. This study will recruit 120 participants to compare Health Champions to treatment as usual for people with SMI using secondary community mental health services in South London, UK. We will measure the clinical and cost effectiveness including quality of life. We will measure the implementation outcomes of acceptability, feasibility, appropriateness, fidelity, barriers and enablers, unintended consequences, adoption and sustainability.

Discussion: There is a need for interventions to support people with SMI with their physical health. If this feasibility trial is successful, a definitive trial will follow to fully evaluate the clinical, cost and implementation effectiveness of Health Champions supporting people with SMI.

Trial Registration: ClinicalTrials.gov, registration no: NCT04124744 .
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http://dx.doi.org/10.1186/s40814-021-00854-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165672PMC
May 2021

Defining functional variants associated with Alzheimer's disease in the induced immune response.

Brain Commun 2021 19;3(2):fcab083. Epub 2021 Apr 19.

Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.

Defining the mechanisms involved in the aetiology of Alzheimer's disease from genome-wide association studies alone is challenging since Alzheimer's disease is polygenic and most genetic variants are non-coding. Non-coding Alzheimer's disease risk variants can influence gene expression by affecting miRNA binding and those located within enhancers and within CTCF sites may influence gene expression through alterations in chromatin states. In addition, their function can be cell-type specific. They can function specifically in microglial enhancers thus affecting gene expression in the brain. Hence, transcriptome-wide association studies have been applied to test the genetic association between disease risk and cell-/tissue-specific gene expression. Many Alzheimer's disease-associated loci are involved in the pathways of the innate immune system. Both microglia, the primary immune cells of the brain, and monocytes which can infiltrate the brain and differentiate into activated macrophages, have roles in neuroinflammation and β-amyloid clearance through phagocytosis. In monocytes the function of regulatory variants can be context-specific after immune stimulation. To dissect the variants associated with Alzheimer's disease in the context of monocytes, we utilized data from naïve monocytes and following immune stimulation , in combination with genome-wide association studies of Alzheimer's disease in transcriptome-wide association studies. Of the nine genes with statistically independent transcriptome-wide association signals, seven are located in known Alzheimer's disease risk loci: and The transcriptome-wide association signal for and and the direction of effect replicated in an independent genome-wide association studies. Our analysis identified two novel candidate genes for Alzheimer's disease risk, and . replicated in a transcriptome-wide association study using independent expression weights. and are involved in mitochondrial function and lipid metabolism, respectively. Comparison of transcriptome-wide association study results from monocytes, whole blood and brain showed that the signal for is specific to blood and is specific to LPS stimulated monocytes.
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http://dx.doi.org/10.1093/braincomms/fcab083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087896PMC
April 2021

Multiomics integrative analysis identifies allele-specific blood biomarkers associated to Alzheimer's disease etiopathogenesis.

Aging (Albany NY) 2021 Apr 12;13(7):9277-9329. Epub 2021 Apr 12.

Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Alzheimer's disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by haplotype ( and ). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in and AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.
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http://dx.doi.org/10.18632/aging.202950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064208PMC
April 2021

The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's Disease.

Genes (Basel) 2021 Mar 20;12(3). Epub 2021 Mar 20.

UK Dementia Research Institute at Cardiff University, School of Medicine, Cardiff, CF24 4HQ, UK.

Late-onset Alzheimer's disease (LOAD), the most common cause of dementia, and a huge global health challenge, is a neurodegenerative disease of uncertain aetiology. To deliver effective diagnostics and therapeutics, understanding the molecular basis of the disease is essential. Contemporary large genome-wide association studies (GWAS) have identified over seventy novel genetic susceptibility loci for LOAD. Most are implicated in microglial or inflammatory pathways, bringing inflammation to the fore as a candidate pathological pathway. Among the most significant GWAS hits are three complement genes: , encoding the fluid-phase complement inhibitor clusterin; encoding complement receptor 1 (CR1); and recently, encoding the complement enzyme C1s. Complement activation is a critical driver of inflammation; changes in complement genes may impact risk by altering the inflammatory status in the brain. To assess complement gene association with LOAD risk, we manually created a comprehensive complement gene list and tested these in gene-set analysis with LOAD summary statistics. We confirmed associations of and genes with LOAD but showed no significant associations for the complement gene-set when excluding and . No significant association with other complement genes, including , was seen in the IGAP dataset; however, these may emerge from larger datasets.
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http://dx.doi.org/10.3390/genes12030443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003605PMC
March 2021

This Being is a Guest House: Embracing Humility, Liberation & Strengths in Therapy with Sexual and Gender Diverse Muslims.

J Homosex 2021 Jun 11;68(7):1196-1222. Epub 2021 Mar 11.

School of Professional Psychology, Wright State University, Dayton, USA.

The complexity of the lives of sexual and gender diverse Muslims within the United States calls for mental health providers to own our power and privilege. Embracing cultural humility in service of aligning ourselves with liberation psychology, we call for an intersectionally informed, strengths-based approach to empowering/affirming clients whose diverse religious experiences intersect with their experiences of marginalization as sexual and gender diverse (SGD) Muslims. Drawing on extant personal narratives around mental health and therapy of this population, the authors offer critical reflections, processes and opportunities for clinicians to take responsibility in honoring the diverse journeys and experiences of SGD Muslims in serving them in journeys of healing.
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http://dx.doi.org/10.1080/00918369.2021.1888587DOI Listing
June 2021

Development and rapid evaluation of services to support the physical health of people using psychiatric inpatient units during the COVID-19 pandemic: study protocol.

Implement Sci Commun 2021 Feb 3;2(1):12. Epub 2021 Feb 3.

Centre for Implementation Science, Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: People diagnosed with a serious mental illness have worse physical health and lower life expectancy than the general population. Integration of mental and physical health services is seen as one service development that could better support this. This protocol describes the evaluation of the provision of a Virtual Physical Health Clinic (VPHC) and Consultant Connect (CC) services to one UK-based mental health Trust.

Methods: Prospective, formative, pragmatic evaluation using both quantitative and qualitative techniques and driven by implementation science theoretical frameworks. The VPHC and CC are described along with the methodology being used to rapidly evaluate their implementation, effectiveness and potential economic impact in order to inform future roll out. We will assess the implementation process through quantitative data on uptake and reach and through self-reported data to be collected from interviews and the use of validated implementation outcome assessment measures. We will assess implementation strategies using the Expert Recommendations for Implementing Change (ERIC) strategies as a framework. We will assess the health economic impact of both services using established health economic methods including cost comparison scenarios and health service utilisation analyses.

Discussion: Supporting the physical health management of people in psychiatric inpatient units is important in improving the physical health of this population. Integration of mental and physical health can help this to happen effectively. This initiative provides one of the first service evaluation protocols of its kind to be reported in the UK at the time of the COVID-19 pandemic.
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http://dx.doi.org/10.1186/s43058-021-00113-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856607PMC
February 2021

Barriers and facilitators of clinician and researcher collaborations: a qualitative study.

BMC Health Serv Res 2020 Dec 5;20(1):1126. Epub 2020 Dec 5.

Addictions Department, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Background: The poor translation of research findings into routine clinical practice is common in all areas of healthcare. Having a better understanding of how researchers and clinicians experience engagement in and with research, their working relationships and expectations of each other, may be one way to help to facilitate collaborative partnerships and therefore increase successful translation of research into clinical practice.

Aims: To explore the views of clinical and research staff about their experiences of working together during research projects and identify the facilitators and barriers.

Methods: We conducted four focus groups with 18 participants - clinicians, researchers and those with a dual clinical-research role, recruited from one mental health Trust and one university. Data was analysed using thematic analysis.

Results: Eight themes were identified under the headings of two research questions 1) Barriers and facilitators of either engaging in or with research from the perspective of clinical staff, with themes of understanding the benefits of the research; perceived knowledge and personal qualities of researchers; lack of time and organisational support to be involved in and implement research; and lack of feedback about progress and outcome of research. 2) Barriers and facilitators for engaging with clinicians when conducting research, from the perspective of researchers, with themes of understanding what clinicians need to know and how they need to feel to engage with research; demonstrating an understanding of the clinician's world; navigating through the clinical world; and demands of the researcher role.

Conclusion: There was agreement between clinicians and researchers about the barriers and facilitators for engaging clinicians in research. Both groups identified that it was the researcher's responsibility to form and maintain good working relationships. Better support for researchers in their role calls for training in communication skills and bespoke training to understand the local context in which research is taking place.
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http://dx.doi.org/10.1186/s12913-020-05978-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718701PMC
December 2020

The Differential Influence of Immune, Endocytotic, and Lipid Metabolism Genes on Amyloid Deposition and Neurodegeneration in Subjects at Risk of Alzheimer's Disease.

J Alzheimers Dis 2021 ;79(1):127-139

Imperial College London, London, United Kingdom.

Background: Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer's disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects.

Objective: The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls.

Methods: AD biomarkers ([18F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes.

Results: Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism.

Conclusion: Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively.
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http://dx.doi.org/10.3233/JAD-200578DOI Listing
January 2021

A novel computational approach for predicting complex phenotypes in Drosophila (starvation-sensitive and sterile) by deriving their gene expression signatures from public data.

PLoS One 2020 26;15(10):e0240824. Epub 2020 Oct 26.

European Molecular Biology Laboratory, The European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridge, United Kingdom.

Many research teams perform numerous genetic, transcriptomic, proteomic and other types of omic experiments to understand molecular, cellular and physiological mechanisms of disease and health. Often (but not always), the results of these experiments are deposited in publicly available repository databases. These data records often include phenotypic characteristics following genetic and environmental perturbations, with the aim of discovering underlying molecular mechanisms leading to the phenotypic responses. A constrained set of phenotypic characteristics is usually recorded and these are mostly hypothesis driven of possible to record within financial or practical constraints. We present a novel proof-of-principal computational approach for combining publicly available gene-expression data from control/mutant animal experiments that exhibit a particular phenotype, and we use this approach to predict unobserved phenotypic characteristics in new experiments (data derived from EBI's ArrayExpress and ExpressionAtlas respectively). We utilised available microarray gene-expression data for two phenotypes (starvation-sensitive and sterile) in Drosophila. The data were combined using a linear-mixed effects model with the inclusion of consecutive principal components to account for variability between experiments in conjunction with Gene Ontology enrichment analysis. We present how available data can be ranked in accordance to a phenotypic likelihood of exhibiting these two phenotypes using random forest. The results from our study show that it is possible to integrate seemingly different gene-expression microarray data and predict a potential phenotypic manifestation with a relatively high degree of confidence (>80% AUC). This provides thus far unexplored opportunities for inferring unknown and unbiased phenotypic characteristics from already performed experiments, in order to identify studies for future analyses. Molecular mechanisms associated with gene and environment perturbations are intrinsically linked and give rise to a variety of phenotypic manifestations. Therefore, unravelling the phenotypic spectrum can help to gain insights into disease mechanisms associated with gene and environmental perturbations. Our approach uses public data that are set to increase in volume, thus providing value for money.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588067PMC
December 2020

The perceptions of preclinical and clinical dental students to altered smile aesthetics.

BDJ Open 2020 14;6:16. Epub 2020 Sep 14.

University of Bristol Dental Hospital, Lower Maudlin Street, Bristol, BS1 2LY UK.

Introduction: This prospective cohort study was designed to identify which components of a smile make it more or less aesthetically acceptable to dental students.

Aim: To investigate whether students at different stages of their undergraduate dental education held similar views on smile aesthetics. Additionally, to see whether students from the same ethnicity were more likely to have similar perceptions of smile aesthetics than students from different backgrounds.

Methodology: Dental students in either Year 1 (preclinical) or Year 5 (clinical) of their studies at the University of Bristol were asked to complete a questionnaire. Students were asked to rank 12 photographic images in order from most aesthetically pleasing (1) to least pleasing (12). The 12 images included one 'ideal' smile and 11 digitally altered images of the same "ideal" smile.

Results: A total of 123 questionnaires were completed. Clinical students were more likely to rank the 'ideal smile' as more aesthetically pleasing and identify it as the "best" smile from the set of images. Preclinical students considered retroclined incisors to be significantly less pleasing than clinical year students, whilst clinical year students found a midline diastema significantly less pleasing than preclinical students.

Conclusions: Dental students at different stages of their undergraduate dental education have different perceptions of smile aesthetics. There was no evidence that the perception of dental attractiveness was affected by students' ethnicities or location of upbringing.
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http://dx.doi.org/10.1038/s41405-020-00045-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490704PMC
September 2020

Socio-demographic, behavioural and health-related characteristics associated with active commuting in a regional Australian state: Evidence from the 2016 Tasmanian Population Health Survey.

Health Promot J Austr 2020 Sep 29. Epub 2020 Sep 29.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.

Issue Addressed: Physical activity is lower and rates of preventable common diseases are higher in regional/rural than urban Australia. Active commuting (walking/bicycling to get from one place to another) may benefit health through increased physical activity, but most evidence of its correlates come from urban studies. This study aimed to investigate associations between active commuting, socio-demographic characteristics, behaviours, total physical activity and health in a regional/rural Australian state.

Methods: This study used data from the 2016 Tasmanian Population Health Survey, a representative cross-sectional self-report survey of 6,300 adults in Tasmania, Australia. Logistic regression modelling investigated associations between socio-demographic, behavioural and health characteristics and past week active commuting frequency.

Results: In multivariable models, being younger, having tertiary qualifications, living in a socio-economically advantaged area, being physically active, having a healthy body mass index and good/excellent self-rated health were associated with engaging in more active commuting. Inner regional dwellers were no more likely than outer regional dwellers to actively commute after covariate adjustment.

Conclusion: Strategies to promote active commuting in regional/rural areas might consider targeting older adults, those less educated, those living in socio-economically disadvantaged areas, those less physically active, those with poorer health and those with higher body mass index. Research could further investigate why these groups appear to be less active for commuting purposes. SO WHAT?: Increasing physical activity and active commuting may help to reduce rates of preventable common diseases in regional/remote areas.
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http://dx.doi.org/10.1002/hpja.428DOI Listing
September 2020

School Breakfast Club Programs in Australian Primary Schools, Not Just Addressing Food Insecurity: A Qualitative Study.

Health Educ Behav 2020 08 31;47(4):619-630. Epub 2020 May 31.

University of Tasmania, Hobart, Tasmania, Australia.

Many Australian primary schools have established school breakfast clubs (SBCs) to address concerns about children arriving at school hungry and the subsequent impact on learning but their effectiveness is uncertain. This study aimed to identify the perceived benefits, impacts, operational practices, and challenges of running SBCs. Case studies with 10 Australian primary schools from different socioeconomic and geographic areas. Focus groups or interviews were held with 142 participants including students, parents/carers, school staff, and funding body representatives between July 2016 and October 2017. There were no eligibility criteria to attend SBCs with all students able to attend, regardless of household income. Thus, participating in the SBC was often reported as a matter of choice rather than a consequence of food insecurity. Participants, including children, discussed the many social benefits of SBCs (i.e., social eating, relationship building, school connection, and engagement) as well as perceived improved classroom behavior. Challenges for program delivery included resource limitations, particularly, the reliance on volunteers and sourcing food. SBCs offered a range of benefits beyond their primary goal of addressing food security. SBCs were highly valued by members of the school community for their social, welfare, well-being, and educational benefits, but program sustainability is constrained by resource limitations.
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http://dx.doi.org/10.1177/1090198120920193DOI Listing
August 2020

Age-dependent effect of APOE and polygenic component on Alzheimer's disease.

Neurobiol Aging 2020 09 30;93:69-77. Epub 2020 Apr 30.

UK Dementia Research Institute at Cardiff University, Cardiff, United Kingdom; UK Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. Electronic address:

Alzheimer's disease (AD) is a devastating neurodegenerative condition with significant genetic heritability. Several genes have been implicated in the onset of AD with the apolipoprotein E (APOE) gene being the strongest single genetic risk loci. Evidence suggests that the effect of APOE alters with age during disease progression. Here, we aim to investigate the impact of APOE and other variants outside the APOE region on AD risk in younger and older participants. Using data from both the Alzheimer's Disease Neuroimaging Initiative and the UK Biobank, we computed the polygenic risk score of each individual informed by the latest genetic study from the International Genomics of Alzheimer's Project. Our analysis showed that the effect of APOE on the disease risk is greater in younger participants and reduces as participants' age increases. Our findings indicate the increased impact of polygenic risk score as participants' age increases. Therefore, AD in older individuals can potentially be triggered by the cumulative effect of genes which are outside the APOE region.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308803PMC
September 2020

Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274.

Circ Genom Precis Med 2020 06 12;13(3):e002806. Epub 2020 May 12.

Division of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.

Background: Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize lipid metabolic changes in common Chr9p21 SNPs, which confer ≈30% elevated coronary heart disease risk associated with altered expression of ANRIL, a long ncRNA.

Methods: Untargeted and targeted lipidomics was applied to plasma from NPHSII (Northwick Park Heart Study II) homozygotes for AA or GG in rs10757274, followed by correlation and network analysis. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK-293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from induced pluripotent stem cells of individuals with/without Chr9p21 risk, nonrisk alleles, and corresponding knockout isogenic lines were next examined. Last, an in-silico analysis of miRNAs was conducted to identify how ANRIL might control lysoPL (lysophosphospholipid)/lysoPA (lysophosphatidic acid) genes.

Results: Elevated risk GG correlated with reduced lysoPLs, lysoPA, and ATX (autotaxin). Five other risk SNPs did not show this phenotype. LysoPL-lysoPA interconversion was uncoupled from ATX in GG plasma, suggesting metabolic dysregulation. Significantly altered expression of several lysoPL/lysoPA metabolizing enzymes was found in HEK cells lacking ANRIL. In the vascular smooth muscle cells data set, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed the expression of several lysoPL/lysoPA genes to nonrisk haplotype levels. Genes that were altered across both cell data sets were , and The in-silico analysis identified 4 ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, and miR-34a-5p.

Conclusions: A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their metabolism. Lipid metabolites and genomic pathways associated with coronary heart disease pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.
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http://dx.doi.org/10.1161/CIRCGEN.119.002806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299226PMC
June 2020

The Dementias Platform UK (DPUK) Data Portal.

Eur J Epidemiol 2020 Jun 23;35(6):601-611. Epub 2020 Apr 23.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.
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http://dx.doi.org/10.1007/s10654-020-00633-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320955PMC
June 2020

The multiplex model of the genetics of Alzheimer's disease.

Nat Neurosci 2020 03 28;23(3):311-322. Epub 2020 Feb 28.

Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

Genes play a strong role in Alzheimer's disease (AD), with late-onset AD showing heritability of 58-79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 50 loci are now implicated for AD, suggesting that AD is a disease of multiple components, as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD heritability has been captured, allowing researchers to calculate the accumulation of AD genetic risk through polygenic risk scores. A polygenic risk score predicts disease with up to 90% accuracy and is an exciting tool in our research armory that could allow selection of those with high polygenic risk scores for clinical trials and precision medicine. It could also allow cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.
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http://dx.doi.org/10.1038/s41593-020-0599-5DOI Listing
March 2020

Sleep and Cellular Stress.

Curr Opin Physiol 2020 Jun 31;15:104-110. Epub 2019 Dec 31.

Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Sleep is a universal phenomenon occurring in all species studied thus far. Sleep loss results in adverse physiological effects at both the organismal and cellular levels suggesting an adaptive role for sleep in the maintenance of overall health. This review examines the bidirectional relationship between sleep and cellular stress. Cellular stress in this review refers to a shift in cellular homeostasis in response to an external stressor. Studies that illustrate the fact that sleep loss induces cellular stress and those that provide evidence that cellular stress in turn promotes sleep will be discussed.
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http://dx.doi.org/10.1016/j.cophys.2019.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008961PMC
June 2020

What is the clinical efficacy and accuracy of a newly developed Bluetooth-enabled retainer when worn by orthodontic residents?

Authors:
Julie Williams

Evid Based Dent 2019 09;20(3):85

Bristol Dental School, University of Bristol, Bristol, UK.

Design A prospective pilot study. Study population Five orthodontic residents in a university setting were asked to wear Bluetooth-enabled Hawley retainers for 12 hours per day except for eating and brushing. The subjects used an iPod to record the exact times that the retainer was inserted and removed. Data analysis The Bluetooth-enabled device within the Hawley retainer takes a temperature reading every ten minutes. The median difference in retainer wear was reported across a five-day study period, measured in minutes either by the device or self-reported by each subject. As the device only takes a temperature reading every ten minutes, the potential for under-reporting retainer wear was considered using a calculation to adjust for the number of times the retainers were inserted and removed. The median difference between the adjusted and unadjusted wear times were reported. A Wilcoxon matched-pairs signed rank test was used to test clinical accuracy, defined as an overall median margin of error of 5% or less for the device. Results One device malfunctioned and was replaced. Two subjects failed to synchronise their device with their iPod within 24 hours and were reminded to do so by text. The median difference between the self- and device-reported wear times (percent error) was 35 minutes or 5.1 % (range 3.3%-7.5%) using unadjusted data and 13 minutes or 1.9% (range 0.5%-3.4%) using adjusted data.Conclusions The Bluetooth-enabled device showed a clinically acceptable level of accuracy compared to self-reported retainer wear, once the data was adjusted to account for the ten-minute time interval between measurements.
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http://dx.doi.org/10.1038/s41432-019-0042-5DOI Listing
September 2019

'Walk this way': results from a pilot randomised controlled trial of a health coaching intervention to reduce sedentary behaviour and increase physical activity in people with serious mental illness.

BMC Psychiatry 2019 09 18;19(1):287. Epub 2019 Sep 18.

Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Cardiovascular disease (CVD) is the leading cause of premature death among people with serious mental illness (SMI). Sedentary behaviour (SB) is an independent risk factor for CVD and mortality and people with SMI are highly sedentary. We developed a health coaching intervention called 'Walk this Way' to reduce SB and increase physical activity (PA) in people with SMI and conducted a pilot randomised controlled trial (RCT) to test its feasibility and acceptability.

Methods: We randomised people with SMI from three community mental health teams into either the WTW intervention or treatment as usual. The WTW intervention lasted 17 weeks and included an initial education session, fortnightly coaching, provision of pedometers and access to a weekly walking group. Objective SB and PA were measured with accelerometers. Cardiometabolic risk factors and wellbeing measures were collected.

Results: We recruited 40 people of whom 33 (82.5%) were followed up. 13/20 (65%) of participants allocated to the coaching intervention completed it. In the intervention group SB decreased by 56 min and total PA increased by 32 min per day on average which was sustained 6 months later. There was no change in PA or SB in the control group. When interviewed, participants in the intervention found the intervention helpful and acceptable. No adverse events were reported from the intervention.

Conclusions: The intervention was feasible and acceptable to participants. Preliminary results were encouraging with improvement seen in both SB and PA. A larger study is needed to assess the effectiveness of the intervention and address any implementation challenges.

Trial Registration: ISRCTN Registry identifier: ISRCTN37724980 , retrospectively registered 25 September 2015.
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http://dx.doi.org/10.1186/s12888-019-2274-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749630PMC
September 2019

Violence and Health Promotion Among First Nations, Métis, and Inuit Women: A Systematic Review of Qualitative Research.

Trauma Violence Abuse 2019 Sep 12:1524838019875696. Epub 2019 Sep 12.

School of Nursing, University of Ottawa, Ottawa, Ontario, Canada.

Indigenous women experience a disproportionate burden of intimate partner violence (IPV) compared to other women in post-colonial countries such as Canada. Intersections between IPV and other forms of structural violence including racism and gender-based discrimination create a dangerous milieu where 'help seeking' may be deterred and poor health outcomes occur. The aim of this review was to explore the perspectives of First Nations, Métis and Inuit (FNMI) women living in Canada about how violence influenced their health and wellbeing. This systematic review of qualitative research used thematic analysis to produce a configurative synthesis. A comprehensive search of electronic databases was conducted. Two reviewers screened studies for relevance and congruence with eligibility criteria. Sixteen studies were included in the review. Four themes with subthemes emerged: 1) ruptured connections between family and home, 2) that emptiness… my spirit being removed, 3) seeking help and being unheard, and 4) a core no one can touch. Together these themes form complex pathways that influenced health among women exposed to violence. Findings from this review highlight the need for collaboration with FNMI women and their communities to prevent IPV and ensure access to trauma and violence informed care (TVIC). The strength and resiliency of FNMI women is fundamental to healing from violence. Working with FNMI women and their communities to build effective interventions and promote culturally meaningful care will be important directions for researchers and policy makers.
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http://dx.doi.org/10.1177/1524838019875696DOI Listing
September 2019

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.

PLoS One 2019 8;14(7):e0218111. Epub 2019 Jul 8.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218111PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613773PMC
February 2020

A European multicentre drug utilisation study of the impact of regulatory measures on prescribing of codeine for pain in children.

Pharmacoepidemiol Drug Saf 2019 08 20;28(8):1086-1096. Epub 2019 Jun 20.

Pharmacovigilance and Epidemiology Department, European Medicines Agency, London, UK.

Purpose: In June 2013, following recommendations from the World Health Organization (WHO) and Food and Drug Administration (FDA), the European Medicines Agency agreed updates to the codeine product information regarding use for pain in children younger than 12 years and children undergoing tonsillectomy or adenoidectomy (TA) for obstructive sleep apnoea. This study was conducted to (a) assess effectiveness of these measures on codeine prescribing in the "real-world" setting and (b) test feasibility of a study using a common protocol by regulators with access to databases.

Methods: The study was performed using BIFAP (Spain), CPRD (UK), and IMS® Disease Analyzer (France and Germany) databases. Prescribers included general practitioners (GPs) (France and UK), GPs and paediatricians together (Spain), and GPs, paediatricians, and ear, nose, and throat (ENT) specialists separately (Germany). Between January 2010 and June 2015, prevalence of codeine prescribing was obtained every 6 months, and a time series analysis (joinpoint) was performed. Codeine prescribing within ±30 days of TA was also identified. Furthermore, doses, durations, and prior prescribing of other analgesics were investigated.

Results: Over the 5-year period, codeine prescribing decreased in children younger than 12 years (by 84% in France and Spain, 44% in GP practices in Germany, and 33% in the United Kingdom). The temporal pattern was compatible with the regulatory intervention in France and the United Kingdom, whereas a decrease throughout the study period was seen in Germany and Spain. Decreased prescribing associated with TA was suggested in ENT practices in Germany.

Conclusions: Codeine prescribing for children decreased in line with introduced regulatory measures. Multidatabase studies assessing impact of measures by EU regulators are feasible.
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http://dx.doi.org/10.1002/pds.4836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771637PMC
August 2019

Genetic risk for alzheimer disease is distinct from genetic risk for amyloid deposition.

Ann Neurol 2019 09 1;86(3):427-435. Epub 2019 Jul 1.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff.

Objective: Alzheimer disease (AD) is the most common form of dementia and is responsible for a huge and growing health care burden in the developed and developing world. The polygenic risk score (PRS) approach has shown 75 to 84% prediction accuracy of identifying individuals with AD risk.

Methods: In this study, we tested the prediction accuracy of AD, mild cognitive impairment (MCI), and amyloid deposition risks with PRS, including and excluding APOE genotypes in a large publicly available dataset with extensive phenotypic data, the Alzheimer's Disease Neuroimaging Initiative cohort. Among MCI individuals with amyloid-positive status, we examined PRS prediction accuracy in those who converted to AD. In addition, we divided polygenic risk score by biological pathways and tested them independently for distinguishing between AD, MCI, and amyloid deposition.

Results: We found that AD and MCI are predicted by both APOE genotype and PRS (area under the curve [AUC] = 0.82% and 68%, respectively). Amyloid deposition is predicted by APOE only (AUC = 79%). Further progression to AD of individuals with MCI and amyloid-positive status is predicted by PRS over and above APOE (AUC = 67%). In pathway-specific PRS analyses, the protein-lipid complex has the strongest association with AD and amyloid deposition even when genes in the APOE region were removed (p = 0.0055 and p = 0.0079, respectively).

Interpretation: The results showed different pattern of APOE contribution in PRS risk predictions of AD/MCI and amyloid deposition. Our study suggests that APOE mostly contributes to amyloid accumulation and the PRS affects risk of further conversion to AD. ANN NEUROL 2019;86:427-435.
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http://dx.doi.org/10.1002/ana.25530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771864PMC
September 2019

Instruments to measure the ability to self-reflect: A systematic review of evidence from workplace and educational settings including health care.

Eur J Dent Educ 2019 Nov 6;23(4):389-404. Epub 2019 Jun 6.

Bristol Veterinary School, Faculty of Health Sciences, University of Bristol, Bristol, UK.

Introduction: Self-reflection has become recognised as a core skill in dental education, although the ability to self-reflect is valued and measured within several professions. This review appraises the evidence for instruments available to measure the self-reflective ability of adults studying or working within any setting, not just health care.

Materials And Methods: A systematic review was conducted of 20 electronic databases (including Medline, ERIC, CINAHL and Business Source Complete) from 1975 to 2017, supplemented by citation searches. Data were extracted from each study and the studies graded against quality indicators by at least two independent reviewers, using a coding sheet. Reviewers completed a utility analysis of the assessment instruments described within included studies, appraising their reported reliability, validity, educational impact, acceptability and cost.

Results: A total of 131 studies met the inclusion criteria. Eighteen were judged to provide higher quality evidence for the review and three broad types of instrument were identified, namely: rubrics (or scoring guides), self-reported scales and observed behaviour.

Conclusions: Three types of instrument were identified to assess the ability to self-reflect. It was not possible to recommend a single most effective instrument due to under reporting of the criteria necessary for a full utility analysis of each. The use of more than one instrument may therefore be appropriate dependent on the acceptability to the faculty, assessor, student and cost. Future research should report on the utility of assessment instruments and provide guidance on what constitutes thresholds of acceptable or unacceptable ability to self-reflect, and how this should be managed.
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http://dx.doi.org/10.1111/eje.12445DOI Listing
November 2019

The changing role of Australian primary schools in providing breakfast to students: A qualitative study.

Health Promot J Austr 2020 Jan 30;31(1):58-67. Epub 2019 May 30.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Issue Addressed: In recent years, state governments throughout Australia have provided significant funding to support the expansion of school breakfast programs (SBPs), in response to concerns about children arriving at school hungry. This study investigated how schools have responded to the growing expectation that they provide breakfast for students.

Methods: This qualitative study draws on case studies of five Australian primary schools that operate SBPs. Interviews or focus groups were conducted with 78 children, parents, staff, volunteers and funders and data underwent thematic analysis.

Results: Three key themes were identified: Adjusting to the changing role of schools, SBPs reflecting the school's culture, Schools as an alternative or additional site for breakfast. Some staff and parents expressed unease about SBPs shifting responsibility for breakfast provision from parents to schools but were committed to supporting vulnerable students as part of the broader school culture. SBPs were found to provide an alternative or additional site for breakfast consumption for many children not experiencing food insecurity.

Conclusion: The expectation that schools provide breakfast has created some challenges and tensions that have not been fully resolved. The adoption of an inclusive approach, undertaken to ensure students were not stigmatised for attendance, had resulted in concerns about the resources used by the programs as well as over-consumption of breakfast by some students. SO WHAT?: Increasingly, Australian schools are providing breakfast for students. Concerns about shifting responsibility and over-consumption could be addressed if schools were given more advice on program management by government and non-government funding bodies.
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http://dx.doi.org/10.1002/hpja.259DOI Listing
January 2020

Triage to Observation: A Quality Improvement Initiative for Chest Pain Patients Presenting to the Emergency Department.

Crit Pathw Cardiol 2019 06;18(2):75-79

From the Duke University School of Nursing, Durham, North Carolina.

Objective: The objective of this study was to evaluate the impact of a rapid admission protocol for chest pain patients presenting to the emergency department (ED) on ED length-of-stay (LOS). In this study, ED LOS was defined as the time from triage check-in until the time the patient physically leaves the ED. The purpose of this quality improvement study was to decrease ED crowding.

Methods: This is a single-center prospective cohort study performed as a quality improvement initiative. This study implemented a rapid admission protocol for patients who were at moderate risk for a major adverse cardiac event based on the HEART score. When a patient presented to the ED through triage with a chief complaint of chest pain, this protocol allowed the provider-in-triage (PIT) to identify eligible patients for potential rapid admission to the hospital's clinical decision unit (CDU). The PIT would complete a rapid medical screening examination, initiate the patient's workup, and call the CDU providers to further evaluate the patient. By identifying these patients early, the lengthy ED chest pain workup contributing to longer ED LOS could then be completed in the CDU.

Results: The total number of patients seen in the ED over the study period was 34,251. The total number of patients admitted to the CDU during the study period was 1,442. The PIT identified 13 patients for rapid admission to the CDU during the study period. These patients had a statistically significant reduction in ED LOS (P < 0.001). ED LOS was also adjusted to identify delays in patient movement resulting in a statistically significant difference (P < 0.001).

Conclusion: Implementation of a rapid admission protocol for chest pain patients at moderate risk for a major adverse cardiac event resulted in a reduction in ED LOS. Adjusted ED LOS was also significant, highlighting a delay in patient movement from the ED to the CDU indicating continued barriers affecting ED holding times.
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http://dx.doi.org/10.1097/HPC.0000000000000175DOI Listing
June 2019