National Research Ethics Service Research Articles

Children and Young People Who Die by Suicide: Childhood-Related Antecedents, Gender Differences and Service Contact

Background: Suicide rates in young people are rising. We sought to understand the stresses young people face before they take their lives, their contact with services that could be preventive and whether these factors differ in girls and boys. Methods: We identified a three-year UK national consecutive case series of deaths by suicide in people aged 10-19, based on national mortality data. We extracted information on factors preceding suicide from official investigations, primarily inquests. Outcomes: There were 595 suicides by young people during the study period, almost 200 per year; most were male (425, 71%). Suicide rates increased significantly from the mid-teens. We obtained data on factors preceding suicide for 544 (91%). A number of previous and recent stresses were reported including witnessing domestic violence, bullying, self-harm, bereavement (including by suicide), and academic pressures. These factors were generally more common in girls while drug misuse and workplace problems were more common in boys. 42 (8%) were looked after children. 28 (5%) young people had identified as LGBT. We found suicide-related internet use in 128 (24%), most often searching for information on suicide method. 329 (60%) had been in contact with specialist children's services at some time, and this was more common in girls. Interpretation: Several stressors precede suicide by young people, particularly girls, and are important in a multi-agency approach to prevention in education, social care, health services, and the third sector. Some of these factors may also have contributed to the recent rise. Funding Statement: The Healthcare Quality Improvement Partnership Declaration of Interests: LA chairs the National Suicide Prevention Strategy Advisory Group at the Department of Health and Social Care in England; NK is a member of the Group. NK chaired the guideline development group for the 2012 National Institute for Health and Clinical Excellence (NICE) guidelines on the longer term management of self-harm and currently chairs the guideline development group for the NICE depression in adults’ guidelines. All other authors declare no competing interests. Ethical Approval Statement: The study received approval from the National Research Ethics Service (NRES) Committee North West (Greater Manchester South, UK). Exemption under Section 251 of the NHS Act 2006, enabling access to confidential and identifiable information without informed consent in the interest of improving care, was obtained from the Health Research Authority Confidentiality Advisory Group (HRA-CAG) and the Public Benefit and Privacy Panel for Health and Social Care (PBPP).

Developing routinely recorded clinical data from electronic patient records as a national resource to improve neonatal health care: the Medicines for Neonates research programme

Developing routinely recorded clinical data from electronic patient records as a national resource to improve neonatal health care: the Medicines for Neonates research programme

Leg ischaemia management collaboration (LIMb): study protocol for a prospective cohort study at a single UK centre

IntroductionSevere limb ischaemia (SLI) is the end stage of peripheral arterial occlusive disease where the viability of the limb is threatened. Around 25% of patients with SLI will ultimately require...

A prospective trial of CONfocal endomicroscopy in CYSTic lesions of the pancreas: CONCYST-01.

Background and study aims Pancreatic cystic lesions (PCL) are common. While some harbor malignant potential, accurate preoperative diagnosis remains challenging. Needle-based confocal laser endomicroscopy (nCLE) via a 19G FNA needle enables real-time imaging of the cyst wall. This study evaluated the safety and utility of nCLE in patients with an indeterminate PCL undergoing EUS-FNA. Patients and methods The CONCYST study prospectively recruited patients with indeterminate PCL attending three hepatopancreaticobiliary (HPB) referral centers in the UK, with indeterminate PCL, who required EUS-FNA between July 2014 and October 2016. Following the procedure, all patients were followed up in telephone clinic for at least 12 months. Ethical approval for the study was granted by the National Research Ethics Service (14/LO/0040). Results Sixty-seven patient were recruited, 11 excluded and 56 included in the final analysis: 35 male, 21 female; median age 68 (range 28 – 80). Recognizable confocal images were obtained in 48 of 56 cases. Median nCLE scanning time was 5 minutes and did not exceed 10 minutes in any case. EUS-nCLE findings correlated with final diagnosis (based on imaging, cytology and multidisciplinary team review) in 43/56 (77 %) of cases, compared with 37/56 (66 %) for cytology alone ( P = 0.12). One patient experienced mild pruritus following the procedure and another developed an infected pseudocyst, which resolved with antibiotics. Conclusions EUS-nCLE under conscious sedation in the day case setting is safe and provides additional information to standard EUS-FNA for diagnosing indeterminate PCL.

Protocol for a feasibility randomised trial of low-intensity interventions for antenatal depression: ADAGIO trial comparing interpersonal counselling with cognitive behavioural therapy

IntroductionOne in eight women suffer from depression during pregnancy. Currently, low-intensity brief treatment based on cognitive behavioural therapy (CBT) is the only talking treatment widely available in the National Health...

The Association between Quantified Training Load and Bone Adaptation

PURPOSE: Habitual mechanical loading during pubertal stages has consistently been associated with current and future anabolic effects on bone characteristics. However, the specific aspects of mechanical loading that bring about anabolic effects are yet to be established. The present study investigated the relationship between soccer specific loading patterns and subsequent bone adaptation in youth soccer players. METHODS: 17 elite adolescent soccer players (mean ± SD =age: 16.3±0.5 years; height: 1.79±0.07m; body mass:74.9±6.7 kg) gave informed consent to take part in a study approved by the National Research Ethics Service. Peripheral quantitative computed tomography scans of the tibia of the dominant leg were taken at the beginning of pre-season training and 12-weeks later. Tibial mass (g), trabecular area (mm2), cortical area (mm2) and density (mg·cm2), periosteal circumference (mm) and strength strain index (SSI) (mm3) at the 4, 14, 38 and 66% sites were measured. During the 12 week training period, workload was quantified using a global positioning system (GPS). The following metrics were analysed: session duration (min), total distance covered (m), and high-speed running distance (17.0 km.h-1). Changes in bone characteristics were assessed using paired sample t-tests, and associations between GPS metrics and bone adaptation were assessed using Person’s correlation coefficient. RESULTS: Tibial mass increased by 2.9, 1.2 and 0.7% at the 4, 14 and 38% tibial sites (P < .05). SSI (38%; 2337.1±340.9 compared to 2383.1±317.3, P = .05) and cortical area (38%; 380.9±23.2 mm2 compared to 383.1±30.8 mm2, P = .02) increased following 12-weeks of soccer specific training. Average session duration was positively correlated with increased trabecular area (4%; P=.02, r=0.61) and periosteal circumference (38%; P=.03, r=0.55). Average high-speed running was positively correlated with changes in SSI (14%; P=.05, r=0.51) and cortical density (38%; P=.05, r=0.52). CONCLUSIONS: Soccer specific training increases tibial bone characteristics at the 4, 14 and 38% sites. Moreover, session duration and high-speed running were associated with increased tibial strength, size and density following 12-weeks of soccer specific training. These factors should be considered when recommending exercise for bone health.

Individualised screening for diabetic retinopathy: the ISDR study—rationale, design and methodology for a randomised controlled trial comparing annual and individualised risk-based variable-interval screening

IntroductionCurrently, all people with diabetes (PWD) aged 12 years and over in the UK are invited for screening for diabetic retinopathy (DR) annually. Resources are not increasing despite a 5%...

Efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with Community-Acquired Pneumonia: a protocol for a randomIsed controlled Trial (CAP-IT)

IntroductionCommunity-acquired pneumonia (CAP) is a common indication for antibiotic treatment in young children. Data are limited regarding the ideal dose and duration of amoxicillin, leading to practice variation which may...

Randomised Ambulatory Management of Primary Pneumothorax (RAMPP): protocol of an open-label, randomised controlled trial

IntroductionPneumothorax is a common clinical problem. Primary spontaneous pneumothorax (PSP) occurs in otherwise fit young patients, but optimal management is not clearly defined and often results in a long hospital...

Association of the GDF5 and COL27A1 Genes with Knee Pain in UK Biobank (N = 171, 516) Based on a Genome-Wide Association Study

Objective: Knee pain is one of the most common musculoskeletal complaints that brings people to medical attention. We sought to identify the genetic variants associated with pain in 171,516 subjects from the UK Biobank cohort and replicate them using cohorts from 23andMe, the Osteoarthritis Initiative (OAI), and the Johnston County Osteoarthritis Study (JoCo). Methods: We performed a genome-wide association study of pain in the UK Biobank, where pain was ascertained through self-report and defined as knee pain in the last month interfering with usual activities. A total of 22,204 cases and 149,312 controls were included in the discovery analysis. We tested our top and independent SNPs (P < 5 x 10-8) for replication in 23andMe, OAI, and JoCo, then performed a joint meta-analysis between discovery and replication cohorts using GWAMA. We calculated the narrow-sense heritability of pain using Genome-wide Complex Trait Analysis (GCTA). Results: We identified 2 loci that reached genome-wide significance, rs143384 located in the GDF5 (P = 1.32 x 10-12), a gene previously implicated in osteoarthritis, and rs2808772, located near COL27A1 (P = 1.49 x 10-8). These findings were subsequently replicated in independent cohorts and increased in significance in the joint meta-analysis (rs143384: P = 4.64 x 10-18; rs2808772: P = 2.56 x 10-11). The narrow sense heritability of pain was 0.08. Conclusion: In this first reported genome-wide association meta-analysis of pain, we identified and replicated two loci in or near GDF5 and COL27A1 that are associated with pain. Funding Statement: This work was supported by the STRADL project (Wellcome Trust, grant number: 104036/Z/14/Z). The Osteoarthritis Initiative (OAI) was public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01- AR-2-2261; N01-AR-2-2262) funded by the NIH. The the Johnston County Osteoarthritis Study (JoCo) was supported in part by S043, S1734, & S3486 from the CDC/Association of Schools of Public Health; 5-P60-AR30701 & 5-P60- AR49465-03 from NIAMS/NIH; genotyping was supported by Algynomics, Inc. Additional support was obtained from NIH grant P30-DK072488. Declaration of Interests: J.S., A.A., and members of the 23andMe Research Team are employees of 23andMe, Inc., and hold stock or stock options in 23andMe. Other coauthors have no conflicts of interest. Ethics Approval Statement: Ethical approval was granted by the National Health Service National Research Ethics Service (reference 11/NW/0382). All participants included in the analyses provided informed consent and answered surveys online according to 23andMe’s human subjects protocol, which was reviewed and approved by Ethical & Independent Review Services, a private institutional review board.

Volatile organic compounds emitted from faeces as a biomarker for colorectal cancer.

SummaryBackgroundColorectal cancer remains a leading cause of mortality and morbidity. The UK Bowel Cancer Screening Programme (BCSP) has demonstrated that detection of colorectal cancer at an earlier stage and identification of advanced pre‐malignant adenomas reduces mortality and morbidity.AimTo assess the utility of volatile organic compounds as a biomarker for colorectal neoplasia.MethodsFaeces were collected from symptomatic patients and people participating in the UK BCSP, prior to colonoscopy. Headspace extraction followed by gas chromatography mass spectrometry was performed on faeces to identify volatile organic compounds. Logistic regression modelling and 10‐fold cross‐validation were used to test potential biomarkers.ResultsOne hundred and thirty‐seven participants were included (mean age 64 years [range 22‐85], 54% were male): 60 had no neoplasia, 56 had adenomatous polyp(s) and 21 had adenocarcinoma. Propan‐2‐ol was significantly more abundant in the cancer samples (P < 0.0001, q = 0.004) with an area under ROC (AUROC) curve of 0.76. When combined with 3‐methylbutanoic acid the AUROC curve was 0.82, sensitivity 87.9% (95% CI 0.87‐0.99) and specificity 84.6% (95% CI 0.65‐1.0). Logistic regression analysis using the presence/absence of specific volatile organic compounds, identified a three volatile organic compound panel (propan‐2‐ol, hexan‐2‐one and ethyl 3‐methyl‐ butanoate) to have an AUROC of 0.73, with a person six times more likely to have cancer if all three volatile organic compounds were present (P < 0.0001).ConclusionsVolatile organic compound analysis may have a superior diagnostic ability for the identification of colorectal adenocarcinoma, when compared to other faecal biomarkers, including those currently employed in UK. Clinical trial details: National Research Ethics Service Committee South West ‐ Central Bristol (REC reference 14/SW/1162) with R&D approval from University of Liverpool and Broadgreen University Hospital Trust (UoL 001098).

App to support Recovery in Early Intervention Services (ARIES) study: protocol of a feasibility randomised controlled trial of a self-management Smartphone application for psychosis

IntroductionMental health interventions delivered through digital technology have potential applications in promoting recovery and improving outcomes among people in the early stages of psychosis. Self-management approaches are recommended for the...

Assessment of breath volatile organic compounds in acute cardiorespiratory breathlessness: a protocol describing a prospective real-world observational study

IntroductionPatients presenting with acute undifferentiated breathlessness are commonly encountered in admissions units across the UK. Existing blood biomarkers have clinical utility in distinguishing patients with single organ pathologies but have...

The effect of intranasal oxytocin on the perception of affective touch and multisensory integration in anorexia nervosa: protocol for a double-blind placebo-controlled crossover study

IntroductionAnorexia nervosa (AN) is an eating disorder characterised by restriction of energy intake, fears of gaining weight and related body image disturbances. The oxytocinergic system has been proposed as a...

Enhanced Liver Fibrosis Test Predicts Liver-Related Outcomes in Postmenopausal Women with Risk Factors - A Case Control Study Nested within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Background: Chronic liver disease (CLD) is usually asymptomatic but earlier detection is critical to permit life-saving interventions for those at risk due to high alcohol consumption and increased body mass index (BMI). We evaluated performance of the Enhanced Liver Fibrosis (ELF) test in predicting CLD in postmenopausal women with risk factors in a nested case control study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS). Methods: ELF was measured in blinded samples from 58 participants with selfreported high alcohol use and/or BMI ≥25kg/m2 who developed liver-related events (LRE) (cases), and in 115 controls matched for age, alcohol and BMI who did not develop LRE during median follow-up of 8*5 years. Findings: Using Cox regression at an ELF threshold of 9*8 hazard ratio (HR) for LRE was 2*21 (unadjusted model) and 2*18 (adjusted for deprivation and selfreported hypertension, heart disease, hypercholesterolaemia or diabetes). At a threshold of 10*51, HR was 4*88 (unadjusted) and 4*62 (adjusted). ELF was evaluated as a time dependent variable by generating timedependent Cox models; HRs at an ELF threshold of 9*8 were 1*85 (unadjusted) and 1*80 (adjusted), and at a threshold of 10*51 HRs were 1*94 (unadjusted) and 2*05 (adjusted). Interpretation: This study demonstrates that the ELF test predicts complications of CLD in postmenopausal women with risk factors, creating the opportunity to intervene to reduce liver-related mortality and morbidity. Although larger studies are required, these results demonstrate the possible role for ELF as a prognostic tool in health checks in primary care. Funding Statement: No external funding for this nested study. The trial, UKCTOCS, was funded by Medical Research Council (G9901012 and G0801228), Cancer Research UK (C1479/A2884), and the UK Department of Health, with additional support from The Eve Appeal. UM and WMR are supported by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre. SA was funded by Abcodia Pvt Ltd. Declaration of Interests: UM has stocks awarded to her by UCL in Abcodia Pvt. Ltd. WMR is an inventor of the ELF test and has received fees from Siemens Healthineers for lecturing, travel, and consulting and research support. All the other authors declare no conflict of interest. Ethics Approval Statement: The current study was approved by the National Research Ethics Service (NRES) Committee London - Bentham (Ref: 05/Q0505/57) on 10th August 2011.

Safety and efficacy of 2% chlorhexidine gluconate aqueous versus 2% chlorhexidine gluconate in 70% isopropyl alcohol for skin disinfection prior to percutaneous central venous catheter insertion in preterm neonates: the ARCTIC randomised-controlled feasibility trial protocol

IntroductionCatheter-related sepsis is one of the most dangerous complications of neonatal intensive care and is associated with significant morbidity and mortality. Use of catheter-care ‘bundles’ has reduced the incidence of...

Dietary Approaches to the Management Of type 2 Diabetes (DIAMOND): protocol for a randomised feasibility trial

IntroductionSome clinicians have observed that low-carbohydrate, low-energy diets can improve blood glucose control, with reports of remission from type 2 diabetes in some patients. In clinical trials, support for low-carbohydrate,...

Transdiagnostic Expression of Interoceptive Abnormalities in Psychiatric Conditions

Background: Interoception, the sense of internal bodily physiology, influences our thoughts and feelings. Interoceptive dysfunction is implicated in some psychiatric disorders. We undertook a systematic characterisation to determine if abnormalities in cardiac interoception underlie symptoms and diagnoses in patients accessing mental health services. Methods: This cross-sectional study recruited 306 patients (clinical diagnoses spanning affective disorders, personality disorder, and psychoses) and 67 controls. We recorded measures of cardiac physiology (heart rate and heart rate variability; HRV); objective interoceptive influences on perception, and subjective (self-report) sensitivity to interoceptive signals. Outcomes: Patients differed from controls in; 1) HRV (RMSSD ms, patients vs controls mean ± SD: 51.6; ± 42.6 vs 70.19 ± 58.4, [F(1,341)=8.8, P=0.003]); 2) cardiac afferent effects on processing emotional stimuli ([fear - neutral] x [systole - diastole] %intensity change: 5.2 ± 16.1 vs 10.5 ± 16.1, [F(1,324)=4.8, P<0.03]); 3) heartbeat discrimination accuracy (0.52 ± 0.1 vs 0.57 ± 0.2, [F(1,331)=4.8, P=0.03]), and heartbeat detection confidence (VAS mean ± SD: 4.2 ± 2.6 vs 5.4 ± 1.8, [F(1,332)=8.82, P=0.003]). Anxiety and depression scores correlated particularly with subjective interoception (Body Perception Questionnaire-awareness; depression: R=0.34, P<0.001; trait anxiety: R=0.39, P<0.001). Differences between clinical diagnoses were observed for HRV (F(6,234)=3.3, P=0.004), cardiac afferent effects on processing emotional stimuli (F(6,234)=3.1, P=0.006) and subjective interoception (F(6,236)=2.4, P=0.03). Patients with schizophrenia showed distinct differences that merit further investigation. Interpretation: Interoceptive differences in patients relate to psychiatric symptoms and diagnoses, highlighting value in developing interoceptive targets for therapeutic intervention. Trial Registration: ISRCTN13588109. Funding Statement: The study was supported by an Advanced Grant from the European Research Council to HDC: Cardiac control of Fear in the Brain CCFIB 324150. Declaration of Interests: The study was supported by an Advanced Grant from the European Research Council to HDC. HH-B was a medical student at the time of involvement with the study. Other authors were employees of Brighton and Sussex Medical School, University of Sussex at the time of the study. Ethics Approval Statement: The study was approved by the National Research Ethics Service (13/LO/1866MHRNA).

Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial: study protocol for a multicentre international trial of cardiac output-guided fluid therapy with low-dose inotrope infusion compared with usual care in patients undergoing major elective gastrointestinal surgery

IntroductionPostoperative morbidity and mortality in older patients with comorbidities undergoing gastrointestinal surgery are a major burden on healthcare systems. Infections after surgery are common in such patients, prolonging hospitalisation and...

Habitual Glucosamine Use is Associated with a Reduced Risk of Cardiovascular Disease, a Prospective Study in the UK Biobank

Background: Glucosamine is a common supplement for treating osteoarthritis, while its effectiveness on osteoarthritis and joint pain continues to be debated. Recently emerging evidence from animal studies and cross-sectional studies in humans suggest that glucosamine may have potential benefits on reduction of cardiovascular disease (CVD) and mortality; however, evidence from prospective studies is lacking. Methods: In the UK biobank cohort study, a total of 466,039 participants without CVD at baseline completed the questionnaire on supplement use, including glucosamine, were analyzed in this study. These participants were enrolled from 2006 to 2010 and followed up to 2016. Cox proportional hazards models were used to compare hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CVD events in participants who did and did not use glucosamine. Findings: During a median of 7·0 years of follow-up, we documented 10,204 incident cases of CVD events, 3,060 cases of CVD death, 5,745 cases of CHD and 3,263 cases of stroke. After adjustment for age, sex, body mass index, race, lifestyle factors, dietary intakes, medication use and other supplements use, glucosamine use was associated with significantly reduced risks of total CVD events (HR: 0·85: 95% confidence interval [CI], 0·80-0·90), CVD death (HR: 0·78: 95% [CI], 0·70-0·87), CHD (HR: 0·82: 95% [CI], 0·76-0·88) and stroke (HR: 0·91: 95% [CI], 0·83-1·00). In addition, the associations of glucosamine use with risks of total CVD events and CHD were more pronounced in smokers than non-smokers (P-interaction=0·018 and 0·004, respectively). Interpretation: Beyond its original use for treating osteoarthritis, habitual use of glucosamine supplement was associated with significantly reduced risks of CVD events, especially among smokers. Further investigations in both prospective cohorts and clinical trials are warranted to verify our findings. Funding: The study was supported by grants from the National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024), the National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383, DK078616). Declaration of Interest: We declare no competing interests. Ethical Approval: All participants provided written informed consent and the study was approved by the NHS National Research Ethics Service. The present analysis was approved by the Tulane University (New Orleans, Louisiana) Institutional Review Board. Data from 502, 616 participants were available for our study.