Validation of the 6-Item Cognitive Impairment Test and the 4AT test for combined delirium and dementia screening in older Emergency Department attendees

Background screening for cognitive impairment in Emergency Department (ED) requires short, reliable tools. Objective to validate the 4AT and 6-Item Cognitive Impairment Test (6-CIT) for ED dementia and delirium screening. Design diagnostic accuracy study. Setting/subjects attendees aged ≥70 years in a tertiary care hospital’s ED. Methods: trained researchers assessed participants using the Standardised Mini Mental State Examination, Delirium Rating Scale-Revised 98 and Informant Questionnaire on Cognitive Decline in the Elderly, informing ultimate expert diagnosis using Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria for dementia and delirium (reference standards). Another researcher blindly screened each participant, within 3 h, using index tests 4AT and 6-CIT.Resultof 419 participants (median age 77 years), 15.2% had delirium and 21.5% had dementia. For delirium detection, 4AT had positive predictive value (PPV) 0.68 (95% confidence intervals: 0.58–0.79) and negative predictive value (NPV) 0.99 (0.97–1.00). At a pre-specified 9/10 cut-off (9 is normal), 6-CIT had PPV 0.35 (0.27–0.44) and NPV 0.98 (0.95–0.99). Importantly, 52% of participants had no family present. A novel algorithm for scoring 4AT item 4 where collateral history is unavailable (score 4 if items 2–3 score ≥1; score 0 if items 1–3 score is 0) proved reliable; PPV 0.65 (0.54–0.76) and NPV 0.99 (0.97–1.00). For dementia detection, 4AT had PPV 0.39 (0.32–0.46) and NPV 0.94 (0.89–0.96); 6-CIT had PPV 0.46 (0.37–0.55) and NPV 0.94 (0.90–0.97). Conclusion: 6-CIT and 4AT accurately exclude delirium and dementia in older ED attendees. 6-CIT does not require collateral history but has lower PPV for delirium

Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing

Acknowledgements This study would not be possible without the families, patients, clinicians, nurses, research scientists, laboratory staff, informaticians and the wider Scottish Genomes Partnership team to whom we give grateful thanks. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health). The Scottish Genomes Partnership was funded by the Chief Scientist Office of the Scottish Government Health Directorates (SGP/1) and The Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure.Peer reviewedPublisher PD

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

In-situ estimation of ice crystal properties at the South Pole using LED calibration data from the IceCube Neutrino Observatory

The IceCube Neutrino Observatory instruments about 1 km3 of deep, glacial ice at the geographic South Pole using 5160 photomultipliers to detect Cherenkov light emitted by charged relativistic particles. A unexpected light propagation effect observed by the experiment is an anisotropic attenuation, which is aligned with the local flow direction of the ice. Birefringent light propagation has been examined as a possible explanation for this effect. The predictions of a first-principles birefringence model developed for this purpose, in particular curved light trajectories resulting from asymmetric diffusion, provide a qualitatively good match to the main features of the data. This in turn allows us to deduce ice crystal properties. Since the wavelength of the detected light is short compared to the crystal size, these crystal properties do not only include the crystal orientation fabric, but also the average crystal size and shape, as a function of depth. By adding small empirical corrections to this first-principles model, a quantitatively accurate description of the optical properties of the IceCube glacial ice is obtained. In this paper, we present the experimental signature of ice optical anisotropy observed in IceCube LED calibration data, the theory and parametrization of the birefringence effect, the fitting procedures of these parameterizations to experimental data as well as the inferred crystal properties.</p

In situ estimation of ice crystal properties at the South Pole using LED calibration data from the IceCube Neutrino Observatory

The IceCube Neutrino Observatory instruments about 1 km3 of deep, glacial ice at the geographic South Pole. It uses 5160 photomultipliers to detect Cherenkov light emitted by charged relativistic particles. An unexpected light propagation effect observed by the experiment is an anisotropic attenuation, which is aligned with the local flow direction of the ice. We examine birefringent light propagation through the polycrystalline ice microstructure as a possible explanation for this effect. The predictions of a first-principles model developed for this purpose, in particular curved light trajectories resulting from asymmetric diffusion, provide a qualitatively good match to the main features of the data. This in turn allows us to deduce ice crystal properties. Since the wavelength of the detected light is short compared to the crystal size, these crystal properties include not only the crystal orientation fabric, but also the average crystal size and shape, as a function of depth. By adding small empirical corrections to this first-principles model, a quantitatively accurate description of the optical properties of the IceCube glacial ice is obtained. In this paper, we present the experimental signature of ice optical anisotropy observed in IceCube light-emitting diode (LED) calibration data, the theory and parameterization of the birefringence effect, the fitting procedures of these parameterizations to experimental data, and the inferred crystal properties.Peer Reviewe

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Education: a space to survive and thrive?

The article presents our response to some ideas presented by David Kirk in his 2012 Scholar Lecture to the Physical Education and Sport Pedagogy Special Interest Group of the British Educational Research Association Annual Conference in September 2012. We seek to present an alternate view to one aspect of Kirk's argument which supports a view that physical education pedagogues are marginalised in academia and that such a status is attributed at least in part to their professional positioning within the field of education and within schools or faculties of education. We argue that a career as a scholar in the university sector means understanding the goals and priorities of the particular university where you work and how your interests and capacities align. We argue that being a teacher educator or a sport pedagogy scholar in a College of Education or in a Department of Human Movement Studies is not the central defining characteristic in progressing your career. What matters is that the priorities of your department and the attitude of your colleagues to your teaching and research align with your capacities and interests. We reject what we read as the message that being involved in teacher education is not a good career move in the contemporary university. While we acknowledge challenges to teacher education in England and elsewhere, this is not a reason to abandon research on teaching/teacher education or careers in schools/departments of education

Implementation of a Frailty Care Bundle (FCB) to reduce hospital associated decline in older orthopaedic trauma patients: pretest-posttest intervention study

BackgroundHospital associated decline (HAD) in older patients is an under-recognised and under-treated hospital harm. Fundamental care prioritising mobilisation, nutrition and cognitive well-being is protective against HAD, but it is inconsistently priortised in busy clinical settings. ObjectiveThe study aimed to implement and evaluate a frailty care bundle (FCB) for orthopaedic trauma patients in acute and rehabilitation settings to increase mobilisation, nutrition and cognitive well-being to reduce HAD. The intervention was delivered during the COVID-19 pandemic. DesignThe implementation science study used a step wedge pre-post design with multi-methods evaluation. Setting: Four wards across two hospitals: two acute trauma orthopaedic wards (n=62 beds) and two orthopaedic rehabilitation wards (n=33 beds). Participants: We enrolled 120 participants (pre n=60 and post n=60 implementation of the FCB across sites and wards), and at post-discharge follow-up there were 74 participants (pre n=43, post n=36).MethodsThe intervention implementation was underpinned by behaviour change theory COM-B and Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS). All wards received the intervention. A clinical facilitator worked with ward teams to prioritise and implement changes. The main changes were: setting a daily patient mobility goal, promoting assisted meal times, additional snacks, provision of distraction resources, and communication. Implementation strategies included establishing a multdisciplinary team local implementation group, staff education, audit and feedback, coaching, and role modelling. The main outcomes were participants' return to pre-trauma baseline functional capability at 6-8 weeks post-hospital discharge measured using the modified Bartels Index (mBI) and median hospital step count measured using accelerometers. Descriptive statistics included medians, interquartile ranges (IQR), proportions and percentages. Pre versus post group differences were estimated using log-linear models for step count and ordinal regression models for mBI and other outcomes. Odds ratios (OR) and 95% confidence intervals (CI) are reported. ResultsParticipants median age was 78 years, 83% were female and the post intervention group tended to be more frail. During hospitalisation, accelerometer data indicated a non-significant 11% (OR 1.11 95% 0.72-1.7) increase in post-intervention step count compared to pre. Post-intervention participants were more likely than pre-intervention participants to report higher post-discharge mBI scores relative to pre-admission scores OR 2.29( 95% CI 0.98-5.36), but it was not statistically significant (p=0.056). ConclusionIt was feasible to implement aspects of the FCB that ward teams had influence over, but system barriers persisted in addition to COVID-19 challenges. The changes remain tentative and require ongoing facilitation and monitoring for sustainability. Improved consistency in fundamental care, especially mobilisation may accelerate functional recovery<br/

Implementation of the Frailty Care Bundle (FCB) to promote mobilisation, nutrition and cognitive engagement in older people in acute care settings: protocol for an implementation science study

Background: Older people are among the most vulnerable patients in acute care hospitals. The hospitalisation process can result in newly acquired functional or cognitive deficits termed hospital associated decline (HAD). Prioritising fundamental care including mobilisation, nutrition, and cognitive engagement can reduce HAD risk. Aim: The Frailty Care Bundle (FCB) intervention aims to implement and evaluate evidence-based principles on early mobilisation, enhanced nutrition and increased cognitive engagement to prevent functional decline and HAD in older patients. Methods: A hybrid implementation science study will use a pragmatic prospective cohort design with a pre-post mixed methods evaluation to test the effect of the FCB on patient, staff, and health service outcomes. The evaluation will include a description of the implementation process, intervention adaptations, and economic costs analysis. The protocol follows the Standards for Reporting Implementation Studies (StaRI). The intervention design and implementation strategy will utilise the behaviour change theory COM-B (capability, motivation, opportunity) and the Promoting Action on Research Implementation in Health Services (i-PARIHS). A clinical facilitator will use a co-production approach with staff. All patients will receive care as normal, the intervention is delivered at ward level and focuses on nurses and health care assistants (HCA) normative clinical practices. The intervention will be delivered in three hospitals on six wards including rehabilitation, acute trauma, medical and older adult wards. Evaluation: The evaluation will recruit a volunteer sample of 180 patients aged 65 years or older (pre 90; post 90 patients). The primary outcomes are measures of functional status (modified Barthel Index (MBI)) and mobilisation measured as average daily step count using accelerometers. Process data will include ward activity mapping, staff surveys and interviews and an economic cost-impact analysis. Conclusions: This is a complex intervention that involves ward and system level changes and has the potential to improve outcomes for older patients

Clinical case study meets population cohort: Identification of a BRCA1 pathogenic founder variant in Orcadians

Acknowledgements The study team wish to thank staff from the NHS Grampian genetics team and the ORCADES Study for their contribution to these datasets, in particular, Barbara Gibbons for genetic counselling of family members, the NHS Grampian genomics laboratory team for finding and testing for the variant in the clinically ascertained cases, and Laura Taylor of NHS Grampian and the Public Health Scotland genealogy team for assembling the clinical pedigree. ORCADES DNA extractions were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. ORCADES Sanger sequencing was performed by Camilla Drake and the technical services team at the MRC HGU. Emily Weiss and Reka Nagy assembled the ORCADES pedigree using records at the General Register Office and study information, building on earlier pedigree work by Ruth McQuillan and Jim Wilson (45). Regeneron Genetics Center performed the exome sequencing. We thank Thibaud Boutin for phasing the GSA chip data and Kiera Johnston for help with analysis of other cancer susceptibility genes. The data in the EHR was provided by patients and collected by the NHS as part of their care and support. The authors acknowledge the support of the eDRIS Team (Public Health Scotland) for their involvement in obtaining approvals, provisioning and linking this data. We would also like to acknowledge the invaluable contributions of the research nurses in Orkney and the administrative team in Edinburgh. Finally and most importantly, we thank the people of Orkney for their involvement in and ongoing support for our research. Funding: This work was funded by the MRC University Unit award to the MRC Human Genetics Unit, University of Edinburgh, MC_UU_00007/10. LK was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276 and CZB/4/710), a Royal Society URF to JFW and Arthritis Research UK.Peer reviewedPublisher PD