Patient and public involvement in the early stages of clinical trial development: a systematic cohort investigation

Incorporation of PPI within the development of the outline application or specification of plans for future involvement was low. Funder requests for applicants to provide information on PPI and justification for its absence should be welcomed but further research is needed to identify the impact of this on its contributions to research. Comments on PPI by reviewers should be directional rather than state that an increase is required. Challenges facing applicants in initiating PPI prior to funding need to be addressed

Increase in colonic PRopionate as a method of prEVENTing weight gain in adults aged 20–40 years (iPREVENT): a multi-centre, double-blind, randomised, parallel-group study to investigate the efficacy of inulin-propionate ester versus inulin (control) in the prevention of weight gain over 12 months

Introduction: Overweight and obesity affects over 70% of the UK population and is a major risk factor for the development of co-morbidities, including type 2 diabetes and cardiovascular disease. There now exists a considerable evidence base for the management of obesity. However, this is not the case for the prevention of obesity. Preventing weight gain in periods of life where there is an elevated risk of fat mass expansion could be beneficial to preventing associated diseases in later life. This protocol investigates the impact of novel food ingredient inulin propionate ester (IPE) in the prevention of weight gain. This trial aims to investigate the primary hypothesis that IPE has a superior effect on preventing body weight gain, compared with inulin, in young (<40 years old) adults over 12 months, whilst also investigating several complementary mechanisms that may explain the prevention of weight gain and improved long-term energy balance from consuming IPE. Methods: In this multi-centre, double-blind, randomised, parallel-group study, eligible participants will be randomly assigned to consume 10g IPE or 10g inulin (control) daily for 12 months. Study visits will be conducted at baseline, two-month, six-month and 12-month time points. The primary outcome is weight gain from baseline to 12 months. Secondary outcomes will examine changes in metabolic and cardiovascular health biomarkers, body composition and appetite. A mechanistic sub-group will explore causal mechanisms around energy balance, body composition, appetite regulation and the gut microbiota. Based on the power calculation, the sample size required is 270 participants or 135 per study group. Ethics and dissemination: The trial protocol and participant-facing documents have been reviewed and approved, by the London Hampstead Ethics Committee (REC Reference 19/LO/0095, 29th January 2019). Upon completion, the trial results will be published in peer-reviewed journals and presented at scientific conferences. Trial registration number: ISRCTN16299902, 1st March 2018

Red-flag sepsis and SOFA identifies different patient population at risk of sepsis-related deaths on the general ward

Controversy exists regarding the best diagnostic and screening tool for sepsis outside the intensive care unit (ICU). Sequential organ failure assessment (SOFA) score has been shown to be superior to systemic inflammatory response syndrome (SIRS) criteria, however, the performance of “Red Flag sepsis criteria” has not been tested formally. The aim of the study was to investigate the ability of Red Flag sepsis criteria to identify the patients at high risk of sepsis-related death in comparison to SOFA based sepsis criteria. We also investigated the comparison of Red Flag sepsis to quick SOFA (qSOFA), SIRS, and national early warning score (NEWS) scores and factors influencing patient mortality. Patients were recruited into a 24-hour point-prevalence study on the general wards and emergency departments across all Welsh acute hospitals. Inclusion criteria were: clinical suspicion of infection and NEWS 3 or above in-line with established escalation criteria in Wales. Data on Red Flag sepsis and SOFA criteria was collected together with qSOFA and SIRS scores and 90-day mortality. 459 patients were recruited over a 24-hour period. 246 were positive for Red Flag sepsis, mortality 33.7% (83/246); 241 for SOFA based sepsis criteria, mortality 39.4% (95/241); 54 for qSOFA, mortality 57.4% (31/54), and 268 for SIRS, mortality 33.6% (90/268). 55 patients were not picked up by any criteria. We found that older age was associated with death with OR (95% CI) of 1.03 (1.02–1.04); higher frailty score 1.24 (1.11–1.40); DNA-CPR order 1.74 (1.14–2.65); ceiling of care 1.55 (1.02–2.33); and SOFA score of 2 and above 1.69 (1.16–2.47). The different clinical tools captured different subsets of the at-risk population, with similar sensitivity. SOFA score 2 or above was independently associated with increased risk of death at 90 days. The sequalae of infection-related organ dysfunction cannot be reliably captured based on routine clinical and physiological parameters alone

Sepsis-related deaths in the at-risk population on the wards: attributable fraction of mortality in a large point-prevalence study

Objective Sepsis mortality is reported to be high worldwide, however recently the attributable fraction of mortality due to sepsis (AFsepsis) has been questioned. If improvements in treatment options are to be evaluated, it is important to know what proportion of deaths are potentially preventable or modifiable after a sepsis episode. The aim of the study was to establish the fraction of deaths directly related to the sepsis episode on the general wards and emergency departments. Results 839 patients were recruited over the two 24-h periods in 2016 and 2017. 521 patients fulfilled SEPSIS-3 criteria. 166 patients (32.4%) with sepsis and 56 patients (17.6%) without sepsis died within 90 days. Out of the 166 sepsis deaths 12 (7.2%) could have been directly related to sepsis, 28 (16.9%) possibly related and 96 (57.8%) were not related to sepsis. Overall AFsepsis was 24.1%. Upon analysis of the 40 deaths likely to be attributable to sepsis, we found that 31 patients (77.5%) had the Clinical Frailty Score ≥ 6, 28 (70%) had existing DNA-CPR order and 17 had limitations of care orders (42.5%)

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of &lt;1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. </jats:sec

Proceedings of the 13th annual conference of INEBRIA

CITATION: Watson, R., et al. 2016. Proceedings of the 13th annual conference of INEBRIA. Addiction Science & Clinical Practice, 11:13, doi:10.1186/s13722-016-0062-9.The original publication is available at https://ascpjournal.biomedcentral.comENGLISH SUMMARY : Meeting abstracts.https://ascpjournal.biomedcentral.com/articles/10.1186/s13722-016-0062-9Publisher's versio

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden