Partnerships between deaf people and hearing dogs (PEDRO) : Effectiveness and Cost-Effectiveness of Receiving a Hearing Dog on Mental Well-Being and Health in People With Hearing Loss: Protocol for a Randomized Controlled Trial

Background People with hearing loss, particularly those who lose their hearing in adulthood, are at increased risk of social isolation, mental health difficulties, unemployment, loss of independence, risk of accidents, and impaired quality of life. In the United Kingdom (UK), a single third sector organisation provides hearing dogs, a specific type of assistance dog trained to provide sound support to people with hearing loss. These dogs may also deliver numerous psychosocial benefits to recipients. This has not previously been fully investigated. Objective To evaluate the impact of a hearing dog partnership on the lives of individuals with severe or profound hearing loss. Methods and Analysis A two-arm, randomised controlled trial conducted within the UK, with 162 hearing dog applicants, aged 18 years and over. Participants will be randomised 1:1 using a matched-pairs design to receive a hearing dog sooner than usual (intervention arm – Arm B) or to receive a hearing dog within the usual timeframe (comparator arm – Arm A). In the effectiveness analysis, the primary outcome is a comparison of mental wellbeing six-months after Arm B have received a hearing dog (Arm A: not yet received hearing dog), measured using the Short Warwick Edinburgh Mental Wellbeing Scale. Secondary outcome measures include the PHQ-9, GAD-7 and WSAS. An economic evaluation will assess cost-effectiveness including health-related quality-adjusted life years using the EQ-5D-5L and social-care-related-quality-adjusted life-years. Participants will be followed up for up to two years. A nested qualitative study will investigate the impacts of having a hearing dog and how these impacts come about. Results The study was funded by the National Institute for Health Research’s School for Social Care Research. Recruitment commenced in March 2017 and is now complete. 165 participants were randomised. Data collection will continue until January 2020. Results will be published in peer-reviewed journals and at conferences. A summary of the findings will be made available to participants. Ethical approval was received from the University of York’s Department of Social Policy and Social Work Research Ethics Committee (reference SPSW/S/17/1). Conclusions The findings from this study will provide, for the first time, strong and reliable evidence on the impact of having a hearing dog on people’s lives in terms of their quality of life, well-being and mental health. Trial registration The trial has been retrospectively registered International Standard Randomised Controlled Trial Number (ISRCTN) 36452009; https://doi.org/10.1186/ISRCTN36452009. Trial status: Ongoing

CATALISE: A multinational and multidisciplinary Delphi consensus study. Identifying language impairments in children

Delayed or impaired language development is a common developmental concern, yet thereis little agreement about the criteria used to identify and classify language impairments inchildren. Children's language difficulties are at the interface between education, medicineand the allied professions, who may all adopt different approaches to conceptualising them.Our goal in this study was to use an online Delphi technique to see whether it was possibleto achieve consensus among professionals on appropriate criteria for identifying childrenwho might benefit from specialist services. We recruited a panel of 59 experts representingten disciplines (including education, psychology, speech-language therapy/pathology, paediatricsand child psychiatry) from English-speaking countries (Australia, Canada, Ireland,New Zealand, United Kingdom and USA). The starting point for round 1 was a set of 46statements based on articles and commentaries in a special issue of a journal focusing onthis topic. Panel members rated each statement for both relevance and validity on a sevenpointscale, and added free text comments. These responses were synthesised by the firsttwo authors, who then removed, combined or modified items with a view to improving consensus.The resulting set of statements was returned to the panel for a second evaluation(round 2). Consensus (percentage reporting 'agree' or 'strongly agree') was at least 80 percentfor 24 of 27 round 2 statements, though many respondents qualified their responsewith written comments. These were again synthesised by the first two authors. The resultingconsensus statement is reported here, with additional summary of relevant evidence, and aconcluding commentary on residual disagreements and gaps in the evidence base.</p

Evaluating the Benefits of Aphasia Intervention Delivered in Virtual Reality: Results of a Quasi-Randomised Study

Introduction This study evaluated an intervention for people with aphasia delivered in a novel virtual reality platform called EVA Park. EVA Park contains a number of functional and fantastic locations and allows for interactive communication between multiple users. Twenty people with aphasia had 5 weeks’ intervention, during which they received daily language stimulation sessions in EVA Park from a support worker. The study employed a quasi randomised design, which compared a group that received immediate intervention with a waitlist control group. Outcome measures explored the effects of intervention on communication and language skills, communicative confidence and feelings of social isolation. Compliance with the intervention was also explored through attrition and usage data. Results There was excellent compliance with the intervention, with no participants lost to follow up and most (18/20) receiving at least 88% of the intended treatment dose. Intervention brought about significant gains on a measure of functional communication. Gains were achieved by both groups of participants, once intervention was received, and were well maintained. Changes on the measures of communicative confidence and feelings of social isolation were not achieved. Results are discussed with reference to previous aphasia therapy findings

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research

Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Combined point of care nucleic acid and antibody testing for SARS-CoV-2 following emergence of D614G Spike Variant

Rapid COVID-19 diagnosis in hospital is essential, though complicated by 30-50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant now dominates the pandemic and it is unclear how serological tests designed to detect anti-Spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95CI 57.8-92.9%) by rapid NAAT alone. Combined point of care antibody test and rapid NAAT is not impacted by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity

Phase 2 of CATALISE: a multinational and multidisciplinary Delphi consensus study of problems with language development: Terminology.

Background: Lack of agreement about criteria and terminology for children’s language problems affects access to services as well as hindering research and practice. We report the second phase of a study using an online Delphi method to address these issues. In the first phase, we focused on criteria for language disorder. Here we consider terminology.Methods: The Delphi method is an iterative process in which an initial set of statements is rated by a panel of experts, who then have the opportunity to view anonymised ratings from other panel members. On this basis they can either revise their views or make a case for their position. The statements are then revised based on panel feedback, and again rated by and commented on by the panel. In this study, feedback from a second round was used to prepare a final set of statements in narrative form. The panel included 57 individuals representing a range of professions and nationalities. Results: We achieved at least 78% agreement for 19 of 21 statements within two rounds of ratings. These were collapsed into 12 statements for the final consensus reported here. The term ‘Language Disorder’ is recommended to refer to a profile of difficulties that causes functional impairment in everyday life and is associated with poor prognosis. The term, ‘Developmental Language Disorder’ (DLD) was endorsed for use when the language disorder was not associated with a known biomedical aetiology. It was also agreed that (a) presence of risk factors (neurobiological or environmental) does not preclude a diagnosis of DLD, (b) DLD can co-occur with other neurodevelopmental disorders (e.g. ADHD) and (c) DLD does not require a mismatch between verbal and nonverbal ability. Conclusions: This Delphi exercise highlights reasons for disagreements about terminology for language disorders and proposes standard definitions and nomenclature. </p

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

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